Sample records for nash korrespondent tatjana

  1. A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis.

    PubMed

    Younossi, Zobair M; Page, Sandra; Rafiq, Nila; Birerdinc, Aybike; Stepanova, Maria; Hossain, Noreen; Afendy, Arian; Younoszai, Zahra; Goodman, Zachary; Baranova, Ancha

    2011-04-01

    Patients with biopsy-proven NASH and especially those with fibrosis are at risk for progressive liver disease, emphasizing the clinical importance of developing non-invasive biomarkers for NASH and NASH-related fibrosis. This study examines the performance of a new biomarker panel for NASH and NASH-related fibrosis with a combination of clinical and laboratory variables. Enrolled patients had biopsy-proven NAFLD. Clinical data, laboratory data, and serum samples were collected at the time of biopsy. Fasting serum was assayed for adiponectin, resistin, glucose, M30, M65, Tissue inhibitor of metalloproteinases-1 (Timp-1), ProCollagen 3 N-terminal peptide (PIIINP), and hyaluronic acid (HA). Regression models predictive of NASH, NASH-related fibrosis, and NASH-related advanced fibrosis were designed and cross-validated. Of the 79 enrolled NAFLD patients, 40 had biopsy-proven NASH and 39 had non-NASH NAFLD. Clinical and laboratory data were from this cohort were used to develop a NAFLD Diagnostic Panel that includes three models (models for NASH, NASH-related fibrosis, and NASH-related advanced fibrosis). The model for predicting NASH includes diabetes, gender, BMI, triglycerides, M30 (apoptosis), and M65-M30 (necrosis) [AUC: 0.81, 95% CI, 0.70-0.89, 300 p value <9E 301 (-06)]. The NASH-related fibrosis prediction model includes the same predictors [AUC: 0.80, 95% CI 0.68-0.88, 307 p value <0.00014]. Finally, the NASH-related advanced fibrosis model includes type 2 diabetes, serum triglycerides, Timp-1, and AST [AUC: 0.81, 95% CI, 0.70-0.89; p value, 0.000062]. This NAFLD Diagnostic Panel based on a clinical and laboratory data has good performance characteristics and is easy to use. This biomarker panel could become useful in the management of patients with NAFLD.

  2. Molecular Pathogenesis of NASH

    PubMed Central

    Caligiuri, Alessandra; Gentilini, Alessandra; Marra, Fabio

    2016-01-01

    Nonalcoholic steatohepatitis (NASH) is the main cause of chronic liver disease in the Western world and a major health problem, owing to its close association with obesity, diabetes, and the metabolic syndrome. NASH progression results from numerous events originating within the liver, as well as from signals derived from the adipose tissue and the gastrointestinal tract. In a fraction of NASH patients, disease may progress, eventually leading to advanced fibrosis, cirrhosis and hepatocellular carcinoma. Understanding the mechanisms leading to NASH and its evolution to cirrhosis is critical to identifying effective approaches for the treatment of this condition. In this review, we focus on some of the most recent data reported on the pathogenesis of NASH and its fibrogenic progression, highlighting potential targets for treatment or identification of biomarkers of disease progression. PMID:27657051

  3. The Nash equilibrium: A perspective

    PubMed Central

    Holt, Charles A.; Roth, Alvin E.

    2004-01-01

    In 1950, John Nash contributed a remarkable one-page PNAS article that defined and characterized a notion of equilibrium for n- person games. This notion, now called the “Nash equilibrium,” has been widely applied and adapted in economics and other behavioral sciences. Indeed, game theory, with the Nash equilibrium as its centerpiece, is becoming the most prominent unifying theory of social science. In this perspective, we summarize the historical context and subsequent impact of Nash's contribution. PMID:15024100

  4. Nash: genius with schizophrenia or vice versa?

    PubMed

    Funaki, Tevita

    2009-11-01

    Schizophrenia has many negative impacts on the wellbeing of individuals (sufferers). I will critically analyse Nash's experience with his illness of schizophrenia and his concept of wellness based on themes, his journey with schizophrenia and the support of this wife and friends. Ron Howard directed the movie, A Beautiful Mind based on Nash's biography about his mathematical genius and his struggle with schizophrenia. Nash only had one sister, Martha Nash who was born on November 16th, 1930. In terms of his mental health and wellness, Nash began to show signs of schizophrenia in 1958, on the threshold of his career. After 1970, by his choice, he never took antipsychotic medication again. In 1978, Nash was awarded the John von Neumann Theory Prize for his discovery of non-cooperative equilibria, now called Nash equilibria. As a result of Nash's illness, he adopted unhealthy practices that did not help him cope with schizophrenia. Recovery from mental illness has emphasised the importance of hope for the people experiencing mental illness. Nash's self-determinations enabled him to overcome the stigmatisation suffering due to schizophrenia. Nash experienced the five stages of coping with mental illness. The support of Nash's wife Alicia and the few close friends he had were paramount to his recovery and living with schizophrenia. Alicia had used cognitive coping strategies with her caring for Nash by having positive thinking in attempting to accept Nash's illness rather than denying that it existed and to understand the life experiences of a person with schizophrenia. Howard (2001) stated that it's about a 25% chance, that survivors of schizophrenia can regain clarity as Nash did within a certain time period.

  5. Wrestling J. B. Nash.

    ERIC Educational Resources Information Center

    Ellis, Gary D.

    This paper focuses on how between 1965 and the present, the field of recreation has and has not accomplished the goals of author and educator J. B. Nash's in regard to recreation, physical education, and health, focusing on public recreation sponsored by city governments, county governments, and special tax districts. The paper looks at Nash's…

  6. Is cryptogenic cirrhosis different from NASH cirrhosis?

    PubMed

    Thuluvath, Paul J; Kantsevoy, Sergey; Thuluvath, Avesh J; Savva, Yulia

    2018-03-01

    We hypothesized that patients currently diagnosed with cryptogenic cirrhosis (CC) have truly 'cryptogenic' liver disease, which is unlikely to have evolved from NASH. The aim of this study is to characterize patients with CC, and compare their characteristics to patients with cirrhosis of other etiologies. To investigate this, we compared the clinical characteristics of adults with CC (n = 7,999) to those with cirrhosis caused by non-alcoholic steatohepatitis (NASH) (n = 11,302), alcohol (n = 21,714) and autoimmune hepatitis (n = 3,447), using the UNOS database from 2002-16. We performed an age, gender and year of listing matched comparison of CC and NASH (n = 7,201 in each group), and also stratified patients by the presence of obesity or diabetes mellitus (DM). From 2002 to 2016, patients listed with a diagnosis of NASH increased from about 1% to 16% while CC decreased from 8% to 4%. A logistic regression model using the entire United Network for Organ Sharing data (n = 138,021) suggested that the strongest predictors of NASH were type 2 DM, obesity, age ≥60 years, female gender and white race. Type 2 DM was more common in patients with NASH (53%) than those with CC (29%), alcoholic cirrhosis (16%) and autoimmune hepatitis (16%), and obesity was more common in NASH (65.3%) compared to the other three groups (33-42%). There were more white individuals (82.3%) in the NASH group and a lower prevalence of black, Hispanic and Asian individuals, compared to the other three groups. Hepatocellular carcinoma was more commonly seen in NASH (19% vs. 9-13% in the other groups) and this is not influenced by obesity and type 2 DM. The differences between CC and NASH remained unchanged even when two groups were matched for age, gender and year of listing, or when stratified by the presence or absence of obesity or type 2DM. Based on risk perspectives, CC should not be equated with the term 'NASH cirrhosis'. We hypothesized that cryptogenic cirrhosis

  7. Dendritic Cells Limit Fibro-Inflammatory Injury in NASH

    PubMed Central

    Henning, Justin R.; Graffeo, Christopher S.; Rehman, Adeel; Fallon, Nina C.; Zambirinis, Constantinos P.; Ochi, Atsuo; Barilla, Rocky; Jamal, Mohsin; Deutsch, Michael; Greco, Stephanie; Ego-Osuala, Melvin; Saeed, Usama Bin; Rao, Raghavendra S.; Badar, Sana; Quesada, Juan P.; Acehan, Devrim; Miller, George

    2013-01-01

    Non-alcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DC) are antigen presenting cells with an emerging role in hepatic inflammation. We postulated that DC are important in the progression of NASH. We found that intrahepatic DC expand and mature in NASH liver and assume an activated immune-phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibro-inflammation. Our mechanistic studies support a regulatory role for DC in NASH by limiting sterile inflammation via their role in clearance of apoptotic cells and necrotic debris. We found that DC limit CD8+ T cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. Conclusion Our findings support a role for DC in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH. PMID:23322710

  8. Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model.

    PubMed

    van Koppen, Arianne; Verschuren, Lars; van den Hoek, Anita M; Verheij, Joanne; Morrison, Martine C; Li, Kelvin; Nagabukuro, Hiroshi; Costessi, Adalberto; Caspers, Martien P M; van den Broek, Tim J; Sagartz, John; Kluft, Cornelis; Beysen, Carine; Emson, Claire; van Gool, Alain J; Goldschmeding, Roel; Stoop, Reinout; Bobeldijk-Pastorova, Ivana; Turner, Scott M; Hanauer, Guido; Hanemaaijer, Roeland

    2018-01-01

    The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. A time-course study in low-density lipoprotein-receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames.

  9. Computing Nash equilibria through computational intelligence methods

    NASA Astrophysics Data System (ADS)

    Pavlidis, N. G.; Parsopoulos, K. E.; Vrahatis, M. N.

    2005-03-01

    Nash equilibrium constitutes a central solution concept in game theory. The task of detecting the Nash equilibria of a finite strategic game remains a challenging problem up-to-date. This paper investigates the effectiveness of three computational intelligence techniques, namely, covariance matrix adaptation evolution strategies, particle swarm optimization, as well as, differential evolution, to compute Nash equilibria of finite strategic games, as global minima of a real-valued, nonnegative function. An issue of particular interest is to detect more than one Nash equilibria of a game. The performance of the considered computational intelligence methods on this problem is investigated using multistart and deflection.

  10. Local Nash equilibrium in social networks.

    PubMed

    Zhang, Yichao; Aziz-Alaoui, M A; Bertelle, Cyrille; Guan, Jihong

    2014-08-29

    Nash equilibrium is widely present in various social disputes. As of now, in structured static populations, such as social networks, regular, and random graphs, the discussions on Nash equilibrium are quite limited. In a relatively stable static gaming network, a rational individual has to comprehensively consider all his/her opponents' strategies before they adopt a unified strategy. In this scenario, a new strategy equilibrium emerges in the system. We define this equilibrium as a local Nash equilibrium. In this paper, we present an explicit definition of the local Nash equilibrium for the two-strategy games in structured populations. Based on the definition, we investigate the condition that a system reaches the evolutionary stable state when the individuals play the Prisoner's dilemma and snow-drift game. The local Nash equilibrium provides a way to judge whether a gaming structured population reaches the evolutionary stable state on one hand. On the other hand, it can be used to predict whether cooperators can survive in a system long before the system reaches its evolutionary stable state for the Prisoner's dilemma game. Our work therefore provides a theoretical framework for understanding the evolutionary stable state in the gaming populations with static structures.

  11. Local Nash Equilibrium in Social Networks

    NASA Astrophysics Data System (ADS)

    Zhang, Yichao; Aziz-Alaoui, M. A.; Bertelle, Cyrille; Guan, Jihong

    2014-08-01

    Nash equilibrium is widely present in various social disputes. As of now, in structured static populations, such as social networks, regular, and random graphs, the discussions on Nash equilibrium are quite limited. In a relatively stable static gaming network, a rational individual has to comprehensively consider all his/her opponents' strategies before they adopt a unified strategy. In this scenario, a new strategy equilibrium emerges in the system. We define this equilibrium as a local Nash equilibrium. In this paper, we present an explicit definition of the local Nash equilibrium for the two-strategy games in structured populations. Based on the definition, we investigate the condition that a system reaches the evolutionary stable state when the individuals play the Prisoner's dilemma and snow-drift game. The local Nash equilibrium provides a way to judge whether a gaming structured population reaches the evolutionary stable state on one hand. On the other hand, it can be used to predict whether cooperators can survive in a system long before the system reaches its evolutionary stable state for the Prisoner's dilemma game. Our work therefore provides a theoretical framework for understanding the evolutionary stable state in the gaming populations with static structures.

  12. Local Nash Equilibrium in Social Networks

    PubMed Central

    Zhang, Yichao; Aziz-Alaoui, M. A.; Bertelle, Cyrille; Guan, Jihong

    2014-01-01

    Nash equilibrium is widely present in various social disputes. As of now, in structured static populations, such as social networks, regular, and random graphs, the discussions on Nash equilibrium are quite limited. In a relatively stable static gaming network, a rational individual has to comprehensively consider all his/her opponents' strategies before they adopt a unified strategy. In this scenario, a new strategy equilibrium emerges in the system. We define this equilibrium as a local Nash equilibrium. In this paper, we present an explicit definition of the local Nash equilibrium for the two-strategy games in structured populations. Based on the definition, we investigate the condition that a system reaches the evolutionary stable state when the individuals play the Prisoner's dilemma and snow-drift game. The local Nash equilibrium provides a way to judge whether a gaming structured population reaches the evolutionary stable state on one hand. On the other hand, it can be used to predict whether cooperators can survive in a system long before the system reaches its evolutionary stable state for the Prisoner's dilemma game. Our work therefore provides a theoretical framework for understanding the evolutionary stable state in the gaming populations with static structures. PMID:25169150

  13. How Do Doctors Diagnose NAFLD and NASH?

    MedlinePlus

    ... NAFLD and NASH, such as overweight or obesity insulin resistance high levels of triglycerides or abnormal levels of ... NASH, such as an enlarged liver signs of insulin resistance such as darkened skin patches over your knuckles, ...

  14. The Hopeful Traveler Jay Bryan Nash.

    ERIC Educational Resources Information Center

    Jessup, Harvey M., Comp.

    This book is one of a series of publications preserving the best writing and speeches of outstanding leaders of the American Alliance for Health, Physical Education, Recreation and Dance. Jay Bryan Nash was one of the founders of the Alliance. The speeches and essays by Nash in this collection are, for the most part, appearing in published form…

  15. NARSTO SOS99NASH WIND PROFILER DATA

    Atmospheric Science Data Center

    2018-04-16

    NARSTO SOS99NASH WIND PROFILER DATA Project Title:  NARSTO ... Platform:  Ground Station Instrument:  Wind Profiler Location:  Nashville, Tennessee Spatial ... Data Guide Documents:  SOS99Nash Wind Profiler Guide Related Data:  Southern Oxidants ...

  16. Jay B. Nash.

    ERIC Educational Resources Information Center

    Jable, J. Thomas

    1985-01-01

    Jay B. Nash's accomplishments and professional service have long been recognized by physical educators. This article examines the major forces and events that made him one of the most important leaders in American physical education. (MT)

  17. Pre-Collegiate Teachers and Gary Nash

    ERIC Educational Resources Information Center

    Sesso, Gloria

    2009-01-01

    In this article, the author recalls the time she met Gary Nash at UCLA on July 13, 1992, when they began the work of creating the National Standards in History. Professor Nash was the leader in the development of the United States History Standards. In creating the Standards, they were to focus on Historical Thinking. They needed to organize the…

  18. Nash Social Welfare in Multiagent Resource Allocation

    NASA Astrophysics Data System (ADS)

    Ramezani, Sara; Endriss, Ulle

    We study different aspects of the multiagent resource allocation problem when the objective is to find an allocation that maximizes Nash social welfare, the product of the utilities of the individual agents. The Nash solution is an important welfare criterion that combines efficiency and fairness considerations. We show that the problem of finding an optimal outcome is NP-hard for a number of different languages for representing agent preferences; we establish new results regarding convergence to Nash-optimal outcomes in a distributed negotiation framework; and we design and test algorithms similar to those applied in combinatorial auctions for computing such an outcome directly.

  19. Pathophysiology of NASH: perspectives for a targeted treatment

    PubMed Central

    Marra, Fabio; Lotersztajn, Sophie

    2013-01-01

    Non alcoholic steatohepatitis (NASH) is the more severe form of nonalcoholic fatty liver disease. In NASH, fatty liver, hepatic inflammation, hepatocyte injury and fibrogenesis are associated, and thi condition may eventually lead to cirrhosis. Current treatment of NASH relies on the reduction of body weight and increase in physical activity, but there is no pharmacologic treatment approved as yet. Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue, the gut and the gastrointestinal tract. Thus, dysfunction of the adipose tissue through enhanced flow of free fatty acids and release of adipocytokines, and alterations in the gut microbiome generate proinflammatory signals that underly NASH progression. Additional ‘extrahepatic hits’ include dietary factors and gastrointestinal hormones. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress are key contributors to hepatocellular injury. In addition, lipotoxic mediators and danger signals activate Kupffer cells which initiate and perpetuate the inflammatory response by releasing inflammatory mediators that contribute to inflammatory cell recruitment and development of fibrosis. Inflammatory and fibrogenic mediators include chemokines, the cannabinoid system, the inflammasome and activation of pattern-recognition receptors. Here we review the major mechanisms leading to appearance and progression of NASH, focusing on both extrahepatic signals and local inflammatory mechanisms, in an effort to identify the most promising molecular targets for the treatment of this condition. PMID:23394092

  20. Nash equilibrium and evolutionary dynamics in semifinalists' dilemma.

    PubMed

    Baek, Seung Ki; Son, Seung-Woo; Jeong, Hyeong-Chai

    2015-04-01

    We consider a tournament among four equally strong semifinalists. The players have to decide how much stamina to use in the semifinals, provided that the rest is available in the final and the third-place playoff. We investigate optimal strategies for allocating stamina to the successive matches when players' prizes (payoffs) are given according to the tournament results. From the basic assumption that the probability to win a match follows a nondecreasing function of stamina difference, we present symmetric Nash equilibria for general payoff structures. We find three different phases of the Nash equilibria in the payoff space. First, when the champion wins a much bigger payoff than the others, any pure strategy can constitute a Nash equilibrium as long as all four players adopt it in common. Second, when the first two places are much more valuable than the other two, the only Nash equilibrium is such that everyone uses a pure strategy investing all stamina in the semifinal. Third, when the payoff for last place is much smaller than the others, a Nash equilibrium is formed when every player adopts a mixed strategy of using all or none of its stamina in the semifinals. In a limiting case that only last place pays the penalty, this mixed-strategy profile can be proved to be a unique symmetric Nash equilibrium, at least when the winning probability follows a Heaviside step function. Moreover, by using this Heaviside step function, we study the tournament by using evolutionary replicator dynamics to obtain analytic solutions, which reproduces the corresponding Nash equilibria on the population level and gives information on dynamic aspects.

  1. Nash equilibrium and evolutionary dynamics in semifinalists' dilemma

    NASA Astrophysics Data System (ADS)

    Baek, Seung Ki; Son, Seung-Woo; Jeong, Hyeong-Chai

    2015-04-01

    We consider a tournament among four equally strong semifinalists. The players have to decide how much stamina to use in the semifinals, provided that the rest is available in the final and the third-place playoff. We investigate optimal strategies for allocating stamina to the successive matches when players' prizes (payoffs) are given according to the tournament results. From the basic assumption that the probability to win a match follows a nondecreasing function of stamina difference, we present symmetric Nash equilibria for general payoff structures. We find three different phases of the Nash equilibria in the payoff space. First, when the champion wins a much bigger payoff than the others, any pure strategy can constitute a Nash equilibrium as long as all four players adopt it in common. Second, when the first two places are much more valuable than the other two, the only Nash equilibrium is such that everyone uses a pure strategy investing all stamina in the semifinal. Third, when the payoff for last place is much smaller than the others, a Nash equilibrium is formed when every player adopts a mixed strategy of using all or none of its stamina in the semifinals. In a limiting case that only last place pays the penalty, this mixed-strategy profile can be proved to be a unique symmetric Nash equilibrium, at least when the winning probability follows a Heaviside step function. Moreover, by using this Heaviside step function, we study the tournament by using evolutionary replicator dynamics to obtain analytic solutions, which reproduces the corresponding Nash equilibria on the population level and gives information on dynamic aspects.

  2. Near-Nash targeting strategies for heterogeneous teams of autonomous combat vehicles

    NASA Astrophysics Data System (ADS)

    Galati, David G.; Simaan, Marwan A.

    2008-04-01

    Military strategists are currently seeking methodologies to control large numbers of autonomous assets. Automated planners based upon the Nash equilibrium concept in non-zero sum games are one option. Because such planners inherently consider possible adversarial actions, assets are able to adapt to, and to some extent predict, potential enemy actions. However, these planners must function properly both in cases in which a pure Nash strategy does not exist and in scenarios possessing multiple Nash equilibria. Another issue that needs to be overcome is the scalability of the Nash equilibrium. That is, as the dimensionality of the problem increases, the Nash strategies become unfeasible to compute using traditional methodologies. In this paper we introduce the concept of near-Nash strategies as a mechanism to overcome these difficulties. We then illustrate this concept by deriving the near-Nash strategies and using these strategies as the basis for an intelligent battle plan for heterogeneous teams of autonomous combat air vehicles in the Multi-Team Dynamic Weapon Target Assignment model.

  3. Quantum Nash Equilibria and Quantum Computing

    NASA Astrophysics Data System (ADS)

    Fellman, Philip Vos; Post, Jonathan Vos

    In 2004, At the Fifth International Conference on Complex Systems, we drew attention to some remarkable findings by researchers at the Santa Fe Institute (Sato, Farmer and Akiyama, 2001) about hitherto unsuspected complexity in the Nash Equilibrium. As we progressed from these findings about heteroclinic Hamiltonians and chaotic transients hidden within the learning patterns of the simple rock-paper-scissors game to some related findings on the theory of quantum computing, one of the arguments we put forward was just as in the late 1990's a number of new Nash equilibria were discovered in simple bi-matrix games (Shubik and Quint, 1996; Von Stengel, 1997, 2000; and McLennan and Park, 1999) we would begin to see new Nash equilibria discovered as the result of quantum computation. While actual quantum computers remain rather primitive (Toibman, 2004), and the theory of quantum computation seems to be advancing perhaps a bit more slowly than originally expected, there have, nonetheless, been a number of advances in computation and some more radical advances in an allied field, quantum game theory (Huberman and Hogg, 2004) which are quite significant. In the course of this paper we will review a few of these discoveries and illustrate some of the characteristics of these new "Quantum Nash Equilibria". The full text of this research can be found at http://necsi.org/events/iccs6/viewpaper.php?id-234

  4. Quantum gambling based on Nash-equilibrium

    NASA Astrophysics Data System (ADS)

    Zhang, Pei; Zhou, Xiao-Qi; Wang, Yun-Long; Liu, Bi-Heng; Shadbolt, Pete; Zhang, Yong-Sheng; Gao, Hong; Li, Fu-Li; O'Brien, Jeremy L.

    2017-06-01

    The problem of establishing a fair bet between spatially separated gambler and casino can only be solved in the classical regime by relying on a trusted third party. By combining Nash-equilibrium theory with quantum game theory, we show that a secure, remote, two-party game can be played using a quantum gambling machine which has no classical counterpart. Specifically, by modifying the Nash-equilibrium point we can construct games with arbitrary amount of bias, including a game that is demonstrably fair to both parties. We also report a proof-of-principle experimental demonstration using linear optics.

  5. Non-alcoholic steatohepatitis (NASH) in patients with polycystic ovarian syndrome (PCOS).

    PubMed

    Hossain, Noreen; Stepanova, Maria; Afendy, Arian; Nader, Fatema; Younossi, Youssef; Rafiq, Nila; Goodman, Zachary; Younossi, Zobair M

    2011-04-01

    Both non-alcoholic steatohepatitis (NASH) and polycystic ovary syndrome (PCOS) are associated with metabolic syndrome (MS) and insulin resistance (IR). Except for a few case reports, there are no systematic assessments of NASH in PCOS patients. To determine the prevalence of NASH and independent factors associated with NASH in a cohort of patients with documented PCOS. Patients with established diagnosis of PCOS and matched controls (matched for gender, age, and body mass index (BMI)) were included in the study. Causes of other liver diseases were systematically excluded by clinical and laboratory tests. Excessive alcohol use was defined as alcohol consumption of greater than 10 g/day. All liver biopsies were read by a single pathologist blinded to the clinical data. Histologic NASH was defined as steatosis with lobular inflammation and ballooning degeneration of hepatocytes with or without Mallory-Denk bodies or pericellular fibrosis. Univariate and multivariate analyses with logistic regression were performed to compare PCOS to matched controls. Sixty-six patients were included in the study (34 PCOS and 32 matched controls). Of PCOS patients, 73% had a liver biopsy while 78% of the matched controls had a liver biopsy. In comparing PCOS patients to the matched controls, clinical (BMI, waist circumference, type 2 diabetes, MS, or its components, any alcohol consumption in the prior year, ethnic background, age, gender, etc.) and laboratory data (aminotransferases, ferritin, glucose, etc.) were not significantly different (p > 0.05). However, PCOS patients tended to have more histologic NASH on their liver biopsies (44.0% vs. 20.8%, p = 0.08). Independent predictors of histologic NASH in PCOS patients were elevated aspartate aminotransferase (AST), high triglycerides and small amounts of alcohol consumption (p = 0.019, 10-fold cross-validated AUC = 0.80, 95% CI = 0.56-0.94). Although about half of PCOS patients did not report any alcohol consumption, 50% did report

  6. Development of a novel diagnostic algorithm to predict NASH in HCV-positive patients.

    PubMed

    Gallotta, Andrea; Paneghetti, Laura; Mrázová, Viera; Bednárová, Adriana; Kružlicová, Dáša; Frecer, Vladimir; Miertus, Stanislav; Biasiolo, Alessandra; Martini, Andrea; Pontisso, Patrizia; Fassina, Giorgio

    2018-05-01

    Non-alcoholic steato-hepatitis (NASH) is a severe disease characterised by liver inflammation and progressive hepatic fibrosis, which may progress to cirrhosis and hepatocellular carcinoma. Clinical evidence suggests that in hepatitis C virus patients steatosis and NASH are associated with faster fibrosis progression and hepatocellular carcinoma. A safe and reliable non-invasive diagnostic method to detect NASH at its early stages is still needed to prevent progression of the disease. We prospectively enrolled 91 hepatitis C virus-positive patients with histologically proven chronic liver disease: 77 patients were included in our study; of these, 10 had NASH. For each patient, various clinical and serological variables were collected. Different algorithms combining squamous cell carcinoma antigen-immunoglobulin-M (SCCA-IgM) levels with other common clinical data were created to provide the probability of having NASH. Our analysis revealed a statistically significant correlation between the histological presence of NASH and SCCA-IgM, insulin, homeostasis model assessment, haemoglobin, high-density lipoprotein and ferritin levels, and smoke. Compared to the use of a single marker, algorithms that combined four, six or seven variables identified NASH with higher accuracy. The best diagnostic performance was obtained with the logistic regression combination, which included all seven variables correlated with NASH. The combination of SCCA-IgM with common clinical data shows promising diagnostic performance for the detection of NASH in hepatitis C virus patients.

  7. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH).

    PubMed

    Younossi, Zobair M; Jarrar, Mohammed; Nugent, Clare; Randhawa, Manpreet; Afendy, Mariam; Stepanova, Maria; Rafiq, Nila; Goodman, Zachary; Chandhoke, Vikas; Baranova, Ancha

    2008-11-01

    Within the spectrum of nonalcoholic fatty liver disease (NAFLD), only patients with nonalcoholic steatohepatitis (NASH) show convincing evidence for progression. To date, liver biopsy remains the gold standard for the diagnosis of NASH; however, liver biopsy is expensive and associated with a small risk, emphasizing the urgent need for noninvasive diagnostic biomarkers. Recent findings suggest a role for apoptosis and adipocytokines in the pathogenesis of NASH. The aim of this study was to develop a noninvasive diagnostic biomarker for NASH. The study included 101 patients with liver biopsies who were tested with enzyme-linked immunosorbent assay (ELISA)-based assays. Of these, 69 were included in the biomarker development set and 32 were included in the biomarker validation set. Clinical data and serum samples were collected at the time of biopsy. Fasting serum samples were assayed for adiponectin, resistin, insulin, glucose, TNF-alpha, IL-6, IL-8, cytokeratin CK-18 (M65 antigen), and caspase-cleaved CK-18 (M30 antigen). Data analysis revealed that the levels of M30 antigen (cleaved CK-18) predicted histological NASH with 70% sensitivity and 83.7% specificity and area under the curve (AUC) = 0.711, p < 10(-4), whereas the predictive value of the levels of intact CK-18 (M65) was higher (63.6% sensitivity and 89.4% specificity and AUC = 0.814, p < 10(-4)). Histological NASH could be predicted by a combination of Cleaved CK-18, a product of the subtraction of Cleaved CK-18 level from intact CK-18 level, serum adiponectin, and serum resistin with a sensitivity of 95.45% sensitivity, specificity of 70.21%, and AUC of 0.908 (p < 10(-4)). Blinded validation of this model confirmed its reliability for separating NASH from simple steatosis. Four ELISA-based tests were combined to form a simple diagnostic biomarker for NASH.

  8. The Nash Equilibrium Revisited: Chaos and Complexity Hidden in Simplicity

    NASA Astrophysics Data System (ADS)

    Fellman, Philip V.

    The Nash Equilibrium is a much discussed, deceptively complex, method for the analysis of non-cooperative games (McLennan and Berg, 2005). If one reads many of the commonly available definitions the description of the Nash Equilibrium is deceptively simple in appearance. Modern research has discovered a number of new and important complex properties of the Nash Equilibrium, some of which remain as contemporary conundrums of extraordinary difficulty and complexity (Quint and Shubik, 1997). Among the recently discovered features which the Nash Equilibrium exhibits under various conditions are heteroclinic Hamiltonian dynamics, a very complex asymptotic structure in the context of two-player bi-matrix games and a number of computationally complex or computationally intractable features in other settings (Sato, Akiyama and Farmer, 2002). This paper reviews those findings and then suggests how they may inform various market prediction strategies.

  9. Non-Alcoholic Steatohepatitis (NASH): Risk Factors in Morbidly Obese Patients

    PubMed Central

    Losekann, Alexandre; Weston, Antonio C.; de Mattos, Angelo A.; Tovo, Cristiane V.; de Carli, Luis A.; Espindola, Marilia B.; Pioner, Sergio R.; Coral, Gabriela P.

    2015-01-01

    The aim was to investigate the prevalence of non-alcoholic steatohepatitis (NASH) and risk factors for hepatic fibrosis in morbidly obese patients submitted to bariatric surgery. This retrospective study recruited all patients submitted to bariatric surgery from January 2007 to December 2012 at a reference attendance center of Southern Brazil. Clinical and biochemical data were studied as a function of the histological findings of liver biopsies done during the surgery. Steatosis was present in 226 (90.4%) and NASH in 176 (70.4%) cases. The diagnosis of cirrhosis was established in four cases (1.6%) and fibrosis in 108 (43.2%). Risk factors associated with NASH at multivariate analysis were alanine aminotransferase (ALT) >1.5 times the upper limit of normal (ULN); glucose ≥ 126 mg/dL and triglycerides ≥ 150 mg/dL. All patients with ALT ≥1.5 times the ULN had NASH. When the presence of fibrosis was analyzed, ALT > 1.5 times the ULN and triglycerides ≥ 150 mg/dL were risk factors, furthermore, there was an increase of 1% in the prevalence of fibrosis for each year of age increase. Not only steatosis, but NASH is a frequent finding in MO patients. In the present study, ALT ≥ 1.5 times the ULN identifies all patients with NASH, this finding needs to be further validated in other studies. Moreover, the presence of fibrosis was associated with ALT, triglycerides and age, identifying a subset of patients with more severe disease. PMID:26512661

  10. Controversies in the Diagnosis and Management of NAFLD and NASH.

    PubMed

    Rinella, Mary E; Loomba, Rohit; Caldwell, Stephen H; Kowdley, Kris; Charlton, Michael; Tetri, Brent; Harrison, Stephen A

    2014-04-01

    Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of chronic liver disease in the United States. Nonalcoholic steatohepatitis (NASH) occurs in a subset of patients with NAFLD and is characterized by the presence of hepa-tocellular injury, which is progressive in a substantial proportion of cases and can lead to cirrhosis and all of its complications. Although the diagnosis of NAFLD can be made through imaging studies or liver biopsy, the diagnosis of NASH still requires histologic confirmation. Liver biopsy should be performed in the presence of risk factors for advanced disease. Measures aimed at promoting weight loss, a healthier lifestyle, and optimization of metabolic risk factors remain the cornerstone of management of NAFLD. Therapeutic agents that are presently considered the most promising in NAFLD are effective in less than 50% of patients. Among patients with biopsy-proven NASH, treatment with pharmacologic agents should be considered; however, the role of specific agents in NASH still needs further study. Despite a wealth of research over the past 15 years, many controversies remain with respect to the diagnosis and management of NAFLD and NASH as well as the influence of alcohol on liver disease progression in these patients.

  11. Nash Receives 2004 David Perlman Award for Excellence in Science Writing

    NASA Astrophysics Data System (ADS)

    Elmer-DeWitt, Philip; Nash, J. Madeleine

    2004-07-01

    J. Madeleine Nash received the David Perlman Award for Excellence in Science Writing at the AGU Joint Assembly Honors Ceremony, which was held on 19 May 2004, in Montreal, Canada. Nash was honored for ``Fireproofing the Forests,'' an article that appeared in the 18 August 2003 edition of Time Magazine. ``It is an honor to present AGU's 2004 David Perlman Award to Madeleine Nash, a senior contributor to Time Magazine and, if I may say so, one of the great science writers of her generation.''

  12. A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH).

    PubMed

    Srivastava, Jyoti; Robertson, Chadia L; Ebeid, Kareem; Dozmorov, Mikhail; Rajasekaran, Devaraja; Mendoza, Rachel; Siddiq, Ayesha; Akiel, Maaged A; Jariwala, Nidhi; Shen, Xue-Ning; Windle, Jolene J; Subler, Mark A; Mukhopadhyay, Nitai D; Giashuddin, Shah; Ghosh, Shobha; Lai, Zhao; Chen, Yidong; Fisher, Paul B; Salem, Aliasger K; Sanyal, Arun J; Sarkar, Devanand

    2017-08-01

    Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established, mandating more in-depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of astrocyte elevated gene-1(AEG-1)/metadherin in NASH using a transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) and a conditional hepatocyte-specific AEG-1 knockout mouse (AEG-1 ΔHEP ). Alb/AEG-1 mice developed spontaneous NASH whereas AEG-1 ΔHEP mice were protected from high-fat diet (HFD)-induced NASH. Intriguingly, AEG-1 overexpression was observed in livers of NASH patients and wild-type (WT) mice that developed steatosis upon feeding HFD. In-depth molecular analysis unraveled that inhibition of peroxisome proliferator-activated receptor alpha activity resulting in decreased fatty acid β-oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased nuclear factor kappa B-mediated inflammation act in concert to mediate AEG-1-induced NASH. Therapeutically, hepatocyte-specific nanoparticle-delivered AEG-1 small interfering RNA provided marked protection from HFD-induced NASH in WT mice. AEG-1 might be a key molecule regulating initiation and progression of NASH. AEG-1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. (Hepatology 2017;66:466-480). © 2017 by the American Association for the Study of Liver Diseases.

  13. Uniqueness of Nash equilibrium in vaccination games.

    PubMed

    Bai, Fan

    2016-12-01

    One crucial condition for the uniqueness of Nash equilibrium set in vaccination games is that the attack ratio monotonically decreases as the vaccine coverage level increasing. We consider several deterministic vaccination models in homogeneous mixing population and in heterogeneous mixing population. Based on the final size relations obtained from the deterministic epidemic models, we prove that the attack ratios can be expressed in terms of the vaccine coverage levels, and also prove that the attack ratios are decreasing functions of vaccine coverage levels. Some thresholds are presented, which depend on the vaccine efficacy. It is proved that for vaccination games in homogeneous mixing population, there is a unique Nash equilibrium for each game.

  14. Mixed Nash equilibria in Eisert-Lewenstein-Wilkens (ELW) games

    NASA Astrophysics Data System (ADS)

    Bolonek-Lasoń, Katarzyna; Kosiński, Piotr

    2017-01-01

    The classification of all mixed Nash equilibria for the original ELW game is presented. It is based on the quaternionic form of the game proposed by Landsburg (Proc. Am. Math. Soc. 139 (2011), 4423; Rochester Working Paper No 524 (2006); Wiley Encyclopedia of Operations Research and Management Science (Wiley and Sons, New York, (2011)). This approach allows to reduce the problem of finding the Nash equilibria to relatively simple analysis of the extrema of certain quadratic forms.

  15. A Tribute to Gary Nash

    ERIC Educational Resources Information Center

    Jason-Fives, Alli

    2009-01-01

    In this article, the author gives tribute to Gary Nash, a brilliant scholar, an award-winning professor, a prolific writer, a true humanitarian, and a revered historian. She honors him for his work with public school teachers. He has provided the educational support, encouragement, and motivation behind the importance of teaching history. Here,…

  16. Serum uric acid concentrations and fructose consumption are independently associated with NASH in children and adolescents.

    PubMed

    Mosca, Antonella; Nobili, Valerio; De Vito, Rita; Crudele, Annalisa; Scorletti, Eleonora; Villani, Alberto; Alisi, Anna; Byrne, Christopher D

    2017-05-01

    Recent research has suggested that dietary fructose intake may increase serum uric acid (UA) concentrations. Both UA concentration and fructose consumption maybe also increase in NAFLD. It is not known whether dietary fructose consumption and UA concentration are independently associated with non-alcoholic steatohepatitis (NASH). Our aim was to investigate the factors associated with NASH in children and adolescents with proven NAFLD, and to test whether UA concentrations and fructose consumption are independently associated with NASH. Obese children with NAFLD were studied (n=271). NASH was diagnosed by a NAFLD activity score ⩾5 and the fatty liver inhibition of progression (FLIP) algorithm. Fructose consumption (g/day) was assessed by food frequency questionnaire, and UA (mg/dl) was measured in serum. Binary logistic regression with adjustment for covariates and potential confounders was undertaken to test factors independently associated with NASH. NASH occurred in 37.6% of patients. Hyperuricaemia (UA ⩾5.9mg/dl) was present in 47% of patients with NASH compared with 29.7% of non-NASH patients (p=0.003). Both UA concentration (OR=2.488, 95% CI: 1.87-2.83, p=0.004) and fructose consumption (OR=1.612, 95% CI 1.25-1.86, p=0.001) were independently associated with NASH, after adjustment for multiple (and all) measured confounders. Fructose consumption was independently associated with hyperuricaemia (OR=2.021, 95% CI: 1.66-2.78, p=0.01). These data were confirmed using the FLIP algorithm. Both dietary fructose consumption and serum UA concentrations are independently associated with NASH. Fructose consumption was the only factor independently associated with serum UA concentration. Currently, it is not known whether dietary fructose consumption and uric acid (UA) concentration are linked with non-alcoholic steatohepatitis (NASH) in children and adolescents. Our aim was to test whether UA concentrations and fructose consumption are independently associated with

  17. NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications

    PubMed Central

    van Rooyen, Derrick; Gan, Lay; Chitturi, Shivrakumar

    2012-01-01

    While non-alcoholic fatty liver disease (NAFLD) is highly prevalent (15% to 45%) in modern societies, only 10% to 25% of cases develop hepatic fibrosis leading to cirrhosis, end-stage liver disease or hepatocellular carcinoma. Apart from pre-existing fibrosis, the strongest predictor of fibrotic progression in NAFLD is steatohepatitis or non-alcoholic steatohepatitis (NASH). The critical features other than steatosis are hepatocellular degeneration (ballooning, Mallory hyaline) and mixed inflammatory cell infiltration. While much is understood about the relationship of steatosis to metabolic factors (over-nutrition, insulin resistance, hyperglycemia, metabolic syndrome, hypoadiponectinemia), less is known about inflammatory recruitment, despite its importance for the perpetuation of liver injury and fibrogenesis. In this review, we present evidence that liver inflammation has prognostic significance in NAFLD. We then consider the origins and components of liver inflammation in NASH. Hepatocytes injured by toxic lipid molecules (lipotoxicity) play a central role in the recruitment of innate immunity involving Toll-like receptors (TLRs), Kupffer cells (KCs), lymphocytes and neutrophils and possibly inflammasome. The key pro-inflammatory signaling pathways in NASH are nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). The downstream effectors include adhesion molecules, chemokines, cytokines and the activation of cell death pathways leading to apoptosis. The upstream activators of NF-κB and JNK are more contentious and may depend on the experimental model used. TLRs are strong contenders. It remains possible that inflammation in NASH originates outside the liver and in the gut microbiota that prime KC/TLR responses, inflamed adipose tissue and circulating inflammatory cells. We briefly review these mechanistic considerations and project their implications for the effective treatment of NASH. PMID:22570745

  18. Gender difference in NASH susceptibility: Roles of hepatocyte Ikkβ and Sult1e1

    PubMed Central

    Matsushita, Noriko; Hassanein, Mohamed T.; Martinez-Clemente, Marcos; Lazaro, Raul; French, Samuel W.; Xie, Wen; Lai, Keane; Karin, Michael; Tsukamoto, Hidekazu

    2017-01-01

    Myeloid cell and hepatocyte IKKβ may mediate the genesis of obesity and insulin resistance in mice fed high fat diet. However, their gender-specific roles in the pathogenesis of non-alcoholic steatohepatitis (NASH) are not known. Here we demonstrate myeloid IKKβ deficiency prevents Western diet-induced obesity and visceral adiposity in females but not in males, and attenuates hyperglycemia, global IR, and NASH in both genders. In contrast, all metabolic sequela including NASH are aggravated by hepatocyte IKKβ deficiency (IkbkbΔhep) in male but not female mice. Gene profiling identifies sulfotransferase family 1E (Sult1e1), which encodes a sulfotransferase E1 responsible for inactivation of estrogen, as a gene upregulated in NASH in both genders and most conspicuously in male IkbkbΔhep mice having worst NASH and lowest plasma estradiol levels. LXRα is enriched to LXRE on Sult1e1 promoter in male WT and IkbkbΔhep mice with NASH, and a Sult1e1 promoter activity is increased by LXRα and its ligand and augmented by expression of a S32A mutant of IκBα. These results demonstrate striking gender differences in regulation by IKKβ of high cholesterol saturated fat diet-induced metabolic changes including NASH and suggest hepatocyte IKKβ is protective in male due at least in part to its ability to repress LXR-induced Sult1e1. Our findings also raise a caution for systemic IKK inhibition for the treatment of NASH as it may exacerbate the disease in male patients. PMID:28797077

  19. On Nash-Equilibria of Approximation-Stable Games

    NASA Astrophysics Data System (ADS)

    Awasthi, Pranjal; Balcan, Maria-Florina; Blum, Avrim; Sheffet, Or; Vempala, Santosh

    One reason for wanting to compute an (approximate) Nash equilibrium of a game is to predict how players will play. However, if the game has multiple equilibria that are far apart, or ɛ-equilibria that are far in variation distance from the true Nash equilibrium strategies, then this prediction may not be possible even in principle. Motivated by this consideration, in this paper we define the notion of games that are approximation stable, meaning that all ɛ-approximate equilibria are contained inside a small ball of radius Δ around a true equilibrium, and investigate a number of their properties. Many natural small games such as matching pennies and rock-paper-scissors are indeed approximation stable. We show furthermore there exist 2-player n-by-n approximation-stable games in which the Nash equilibrium and all approximate equilibria have support Ω(log n). On the other hand, we show all (ɛ,Δ) approximation-stable games must have an ɛ-equilibrium of support O(Δ^{2-o(1)}/ɛ2{log n}), yielding an immediate n^{O(Δ^{2-o(1)}/ɛ^2log n)}-time algorithm, improving over the bound of [11] for games satisfying this condition. We in addition give a polynomial-time algorithm for the case that Δ and ɛ are sufficiently close together. We also consider an inverse property, namely that all non-approximate equilibria are far from some true equilibrium, and give an efficient algorithm for games satisfying that condition.

  20. Nonalcoholic steatohepatitis (NASH) after pancreaticoduodenectomy: association of pancreatic exocrine deficiency and infection.

    PubMed

    Murata, Yasuhiro; Mizuno, Shugo; Kato, Hiroyuki; Kishiwada, Masashi; Ohsawa, Ichiro; Hamada, Takashi; Usui, Masanobu; Sakurai, Hiroyuki; Tabata, Masami; Nishimura, Keisuke; Fukutome, Kazuo; Isaji, Shuji

    2011-08-01

    Previous clinical study has demonstrated that 30-40% of patients undergoing pancreaticoduodenectomy (PD) developed hepatic steatosis. However, nonalcoholic steatohepatitis (NASH) is a little-known complication after PD. Recently we encountered two patients with PD who later developed NASH diagnosed by liver biopsy. Case 1 was a 79-year-old woman who underwent PD for intraductal papillary mucinous neoplasm (IPMN). She had postoperative severe diarrhea due to pseudomembranous enterocolitis. Severe liver dysfunction was observed on the 31st postoperative day. Abdominal computed tomography (CT) on the 32nd day showed remarkably decreased hepatic CT value of 6 HU. Immediate liver biopsy revealed NASH (Brunt criteria: grade 2, stage 2). Case 2 was a 71-year-old woman who underwent PD for IPMN. Liver biopsy on 70th postoperative day, which was performed for assessment of moderate liver dysfunction and decreased hepatic CT value of 44 HU, demonstrated simple steatosis. In the 21st postoperative month, she developed severe urinary tract infection together with marked liver dysfunction. Immediate liver biopsy revealed NASH (Brunt criteria: grade 1, stage 1). For each patient, treatment of infection and high-dose pancreatic enzyme supplements improved liver dysfunction and liver steatosis. Clinical features of our cases seem to support the current leading hypothesis of the pathogenesis of NASH, i.e., the two-hit theory.

  1. Water extract of Vitis coignetiae Pulliat leaves attenuates oxidative stress and inflammation in progressive NASH rats.

    PubMed

    Pak, Wing; Takayama, Fusako; Hasegawa, Azusa; Mankura, Mitsumasa; Egashira, Toru; Ueki, Keiji; Nakamoto, Kazuo; Kawasaki, Hiromu; Mori, Akitane

    2012-01-01

    This study aimed to investigate the therapeutic effects of the water extract of leaves of Vitis coignetiae Pulliat (VCPL) on nonalcoholic steatohepatitis (NASH) with advanced fibrosis, as our previous study exhibited its preventive effect on NASH. The NASH animal model [PCT/JP2007/52477] was prepared by loading recurrent and intermittent hypoxemia stress to a rat with fatty liver, which resembled the condition occurring in patients with obstructive sleep apnea (OSA) and fatty liver, who have a high incidence of NASH. Intermittent hypoxemia stress is regarded as a condition similar to warm ischemia followed by re-oxygenation, which induces oxidative stress (OS). The daily 100 or 300 mg/kg VCPL administrations were performed for 3 weeks perorally beginning at the time of detection of advanced liver fibrosis. The therapeutic efficacy of VCPL on NASH was demonstrated by the reduction of the leakage of hepato-biliary enzymes and the amelioration of liver fibrosis. The OS elevation in NASH rats was measured based on the derivation of reactive oxygen species from liver mitochondrial energy metabolism and on the decrease in plasma SOD-like activity. The aggravation of inflammatory responses was demonstrated by the neutrophil infiltration (elevated myeloperoxidase activity) and the progression of fibrosis in the livers of NASH rats. In addition, the NASH rats without VCPL treatment also exhibited activation of nuclear factor-κB, a key factor in the link between oxidative stress and inflammation. All of these changes were reduced dose-dependently by the VCPL administration. These findings indicate that VCPL may improve hepatic fibrosis or at least suppress the progression of NASH, by breaking the crosstalk between OS and inflammation.

  2. Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH.

    PubMed

    Caballero, Francisco; Fernández, Anna; De Lacy, Antonio M; Fernández-Checa, Jose C; Caballería, Juan; García-Ruiz, Carmen

    2009-04-01

    Non-alcoholic fatty liver disease (NAFLD) pathogenesis remains unknown. Due to the emerging role of free cholesterol (FC) in NAFLD, our aim was to examine the correlation between FC accumulation in patients with NAFLD and the expression of enzymes that regulate cholesterol homeostasis. Filipin staining, indicative of FC accumulation, and real-time PCR analyses were performed in 31 NAFLD patients and in seven controls. All NASH patients (n=14) and 4 out of 17 patients with steatosis exhibited filipin staining compared to controls (0 out of 7 subjects with normal liver histology and BMI). Sterol regulatory element-binding protein-2 (SREBP-2) mRNA levels were 7- and 3-fold higher in NASH and steatosis patients, respectively, compared to controls. Since hydroxymethylglutaryl-CoA (HMG-CoA) reductase is the key enzyme in cholesterol synthesis and transcriptionally controlled by SREBP-2 we measured its mRNA levels, being 3- to 4-fold higher in NAFLD compared to controls, without any difference between NASH and steatosis patients. Fatty acid synthase (FAS) and SREBP-1c expression were not significantly induced in NAFLD, while ATP-binding cassette sub-family G member 1 (ABCG1), a transporter involved in cholesterol egress, and acyl-CoA-cholesterol acyltransferase mRNA levels were modestly increased (1.5- to 2.5-fold, p<0.05), regardless of fibrosis. Interestingly, mRNA levels of steroidogenic acute regulatory protein (StAR), a mitochondrial-cholesterol transporting polypeptide, increased 7- and 15-fold in steatosis and NASH patients, respectively, compared to controls. FC increases in NASH and correlates with SREBP-2 induction. Moreover, StAR overexpression in NASH suggests that mitochondrial FC may be a player in disease progression and a novel target for intervention.

  3. Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity.

    PubMed

    Lim, Andrea; Zhou, Jin; Sinha, Rohit A; Singh, Brijesh K; Ghosh, Sujoy; Lim, Kiat-Hon; Chow, Pierce Kah-Hoe; Woon, Esther C Y; Yen, Paul M

    2016-10-21

    Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NASH due to lack of understanding of its molecular etiology. In the present study, we demonstrate that the expression of fat mass and obesity associated gene (FTO) is significantly increased in the livers of NASH patients and in a rodent model of NASH. Furthermore, using human hepatic cells, we show that genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis in vitro. Taken together, our results show that FTO may have a deleterious role in hepatic cells during lipotoxic conditions, and strongly suggest that up-regulation of FTO may contribute to the increased liver damage in NASH. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Overexpression of the Vitronectin V10 Subunit in Patients with Nonalcoholic Steatohepatitis: Implications for Noninvasive Diagnosis of NASH.

    PubMed

    Del Ben, Maria; Overi, Diletta; Polimeni, Licia; Carpino, Guido; Labbadia, Giancarlo; Baratta, Francesco; Pastori, Daniele; Noce, Valeria; Gaudio, Eugenio; Angelico, Francesco; Mancone, Carmine

    2018-02-18

    Nonalcoholic steatohepatitis (NASH) is the critical stage of nonalcoholic fatty liver disease (NAFLD). The persistence of necroinflammatory lesions and fibrogenesis in NASH is the leading cause of liver cirrhosis and, ultimately, hepatocellular carcinoma. To date, the histological examination of liver biopsies, albeit invasive, remains the means to distinguish NASH from simple steatosis (NAFL). Therefore, a noninvasive diagnosis by serum biomarkers is eagerly needed. Here, by a proteomic approach, we analysed the soluble low-molecular-weight protein fragments flushed out from the liver tissue of NAFL and NASH patients. On the basis of the assumption that steatohepatitis leads to the remodelling of the liver extracellular matrix (ECM), NASH-specific fragments were in silico analysed for their involvement in the ECM molecular composition. The 10 kDa C-terminal fragment of the ECM protein vitronectin (VTN) was then selected as a promising circulating biomarker in discriminating NASH. The analysis of sera of patients provided these major findings: the circulating VTN fragment (i) is overexpressed in NASH patients and positively correlates with the NASH activity score (NAS); (ii) originates from the disulfide bond reduction between the V10 and the V65 subunits. In conclusion, V10 determination in the serum could represent a reliable tool for the noninvasive discrimination of NASH from simple steatosis.

  5. Nash equilibrium and multi criterion aerodynamic optimization

    NASA Astrophysics Data System (ADS)

    Tang, Zhili; Zhang, Lianhe

    2016-06-01

    Game theory and its particular Nash Equilibrium (NE) are gaining importance in solving Multi Criterion Optimization (MCO) in engineering problems over the past decade. The solution of a MCO problem can be viewed as a NE under the concept of competitive games. This paper surveyed/proposed four efficient algorithms for calculating a NE of a MCO problem. Existence and equivalence of the solution are analyzed and proved in the paper based on fixed point theorem. Specific virtual symmetric Nash game is also presented to set up an optimization strategy for single objective optimization problems. Two numerical examples are presented to verify proposed algorithms. One is mathematical functions' optimization to illustrate detailed numerical procedures of algorithms, the other is aerodynamic drag reduction of civil transport wing fuselage configuration by using virtual game. The successful application validates efficiency of algorithms in solving complex aerodynamic optimization problem.

  6. Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation

    PubMed Central

    Peverill, William; Powell, Lawrie W.; Skoien, Richard

    2014-01-01

    Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future. PMID:24830559

  7. Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

    PubMed Central

    Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M.; Coelho, A.M.M.; Xerfan, M.P.; Cogliati, B.; Barbeiro, D.F.; Mazo, D.F.C.; Kubrusly, M.S.; D'Albuquerque, L.A.C.; Souza, H.P.; Carrilho, F.J.; Oliveira, C.P.

    2015-01-01

    Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg-1·day-1 by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH. PMID:25714891

  8. Gary Nash: Repairing a Necessary Connection

    ERIC Educational Resources Information Center

    Bender, Thomas

    2009-01-01

    In this essay, the author comments on the life and the contributions of author Gary Nash. Everyone is thanking him for his remarkable engagement with the schools, as a writer of outstanding textbooks and materials for teachers developed through his work as director of the Center for Teaching History in the Schools, and, of course, the National…

  9. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice.

    PubMed

    Mridha, Auvro R; Wree, Alexander; Robertson, Avril A B; Yeh, Matthew M; Johnson, Casey D; Van Rooyen, Derrick M; Haczeyni, Fahrettin; Teoh, Narci C-H; Savard, Christopher; Ioannou, George N; Masters, Seth L; Schroder, Kate; Cooper, Matthew A; Feldstein, Ariel E; Farrell, Geoffrey C

    2017-05-01

    NOD-like receptor protein 3 (NLRP3) inflammasome activation occurs in Non-alcoholic fatty liver disease (NAFLD). We used the first small molecule NLRP3 inhibitor, MCC950, to test whether inflammasome blockade alters inflammatory recruitment and liver fibrosis in two murine models of steatohepatitis. We fed foz/foz and wild-type mice an atherogenic diet for 16weeks, gavaged MCC950 or vehicle until 24weeks, then determined NAFLD phenotype. In mice fed an methionine/choline deficient (MCD) diet, we gavaged MCC950 or vehicle for 6weeks and determined the effects on liver fibrosis. In vehicle-treated foz/foz mice, hepatic expression of NLRP3, pro-IL-1β, active caspase-1 and IL-1β increased at 24weeks, in association with cholesterol crystal formation and NASH pathology; plasma IL-1β, IL-6, MCP-1, ALT/AST all increased. MCC950 treatment normalized hepatic caspase 1 and IL-1β expression, plasma IL-1β, MCP-1 and IL-6, lowered ALT/AST, and reduced the severity of liver inflammation including designation as NASH pathology, and liver fibrosis. In vitro, cholesterol crystals activated Kupffer cells and macrophages to release IL-1β; MCC950 abolished this, and the associated neutrophil migration. MCD diet-fed mice developed fibrotic steatohepatitis; MCC950 suppressed the increase in hepatic caspase 1 and IL-1β, lowered numbers of macrophages and neutrophils in the liver, and improved liver fibrosis. MCC950, an NLRP3 selective inhibitor, improved NAFLD pathology and fibrosis in obese diabetic mice. This is potentially attributable to the blockade of cholesterol crystal-mediated NLRP3 activation in myeloid cells. MCC950 reduced liver fibrosis in MCD-fed mice. Targeting NLRP3 is a logical direction in pharmacotherapy of NASH. Fatty liver disease caused by being overweight with diabetes and a high risk of heart attack, termed non-alcoholic steatohepatitis (NASH), is the most common serious liver disease with no current treatment. There could be several causes of inflammation

  10. Grace Nash: Nine Decades of Graceful Teaching.

    ERIC Educational Resources Information Center

    Cole, Judith

    2000-01-01

    Provides information on the life of Grace Nash, an influential educator and pioneer of Orff Schulwerk in the United States, focusing on issues such as her young life, experience as a prisoner-of-war, development of her interest in the Orff, Kodaly, and Laban methods, and her own work. Offers selected resources. (CMK)

  11. Memories of Gary Nash over Five Decades

    ERIC Educational Resources Information Center

    Mellor, Ronald

    2009-01-01

    It is as a longtime client, softball teammate, colleague, traveling companion, and friend that the author writes this article to honor Gary Nash. He has known him in varied guises in five different decades, and on five continents, with Africa coming in 2009. In this article, the author recalls some of his memories of Gary over five decades.

  12. Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome.

    PubMed

    Van Rooyen, Derrick M; Gan, Lay T; Yeh, Matthew M; Haigh, W Geoffrey; Larter, Claire Z; Ioannou, George; Teoh, Narci C; Farrell, Geoffrey C

    2013-07-01

    We have recently showed that hyperinsulinemia promotes hepatic free cholesterol (FC) accumulation in obese, insulin-resistant Alms1 mutant (foz/foz) mice with NASH. Here we tested whether cholesterol-lowering drugs reduce stress-activated c-Jun N-terminal kinase (JNK) activation, hepatocyte injury/apoptosis, inflammation, and fibrosis in this metabolic syndrome NASH model. Female foz/foz and WT mice were fed HF (0.2% cholesterol) 16 weeks, before adding ezetimibe (5 mg/kg), atorvastatin (20 mg/kg), or both to diet, another 8 weeks. Hepatic lipidomic analysis, ALT, liver histology, Sirius Red morphometry, hepatic mRNA and protein expression and immunohistochemistry (IHC) for apoptosis (M30), macrophages (F4/80), and polymorphs (myeloperoxidase) were determined. In mice with NASH, ezetimibe/atorvastatin combination normalized hepatic FC but did not alter saturated free fatty acids (FFA) and had minimal effects on other lipids; ezetimibe and atorvastatin had similar but less profound effects. Pharmacological lowering of FC abolished JNK activation, improved serum ALT, apoptosis, liver inflammation/NAFLD activity score, designation as "NASH", macrophage chemotactic protein-1 expression, reduced macrophage and polymorph populations, and liver fibrosis. Cholesterol lowering with ezetimibe/atorvastatin combination reverses hepatic FC but not saturated FFA accumulation. This dampens JNK activation, ALT release, hepatocyte apoptosis, and inflammatory recruitment, with reversal of steatohepatitis pathology and liver fibrosis. Ezetimibe/statin combination is a potent, mechanism-based treatment that could reverse NASH and liver fibrosis. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  13. Beyond Reasonable Doubt: Who Is the Culprit in Lipotoxicity in NAFLD/NASH?

    PubMed Central

    Arteel, Gavin E.

    2016-01-01

    BACKGROUND & AIMS Type 2 diabetes and nonalcoholic steatohepatitis (NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to the pathogenesis of NASH. METHODS Alms1 mutant (foz/foz) and wild-type NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. RESULTS Hepatic cholesterol accumulation was attributed to up-regulation of low-density lipoprotein receptor via activation of sterol regulatory element binding protein 2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and low-density lipoprotein receptor and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol levels exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. CONCLUSIONS In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis to NASH. PMID:22422583

  14. Single non-invasive model to diagnose non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

    PubMed

    Otgonsuren, Munkhzul; Estep, Michael J; Hossain, Nayeem; Younossi, Elena; Frost, Spencer; Henry, Linda; Hunt, Sharon; Fang, Yun; Goodman, Zachary; Younossi, Zobair M

    2014-12-01

    Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD). A liver biopsy is considered the "gold standard" for diagnosing/staging NASH. Identification of NAFLD/NASH using non-invasive tools is important for intervention. The study aims were to: develop/validate the predictive performance of a non-invasive model (index of NASH [ION]); assess the performance of a recognized non-invasive model (fatty liver index [FLI]) compared with ION for NAFLD diagnosis; determine which non-invasive model (FLI, ION, or NAFLD fibrosis score [NFS]) performed best in predicting age-adjusted mortality. From the National Health and Nutrition Examination Survey III database, anthropometric, clinical, ultrasound, laboratory, and mortality data were obtained (n = 4458; n = 861 [19.3%] NAFLD by ultrasound) and used to develop the ION model, and then to compare the ION and FLI models for NAFLD diagnosis. For validation and diagnosis of NASH, liver biopsy data were used (n = 152). Age-adjusted Cox proportional hazard modeling estimated the association among the three non-invasive tests (FLI, ION, and NFS) and mortality. FLI's threshold score > 60 and ION's threshold score > 22 had similar specificity (FLI = 80% vs ION = 82%) for NAFLD diagnosis; FLI < 30 (80% sensitivity) and ION < 11 (81% sensitivity) excluded NAFLD. An ION score > 50 predicted histological NASH (92% specificity); the FLI model did not predict NASH or mortality. The ION model was best in predicting cardiovascular/diabetes-related mortality; NFS predicted overall or diabetes-related mortality. The ION model was superior in predicting NASH and mortality compared with the FLI model. Studies are needed to validate ION. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  15. Congestion schemes and Nash equilibrium in complex networks

    NASA Astrophysics Data System (ADS)

    Almendral, Juan A.; López, Luis; Cholvi, Vicent; Sanjuán, Miguel A. F.

    2005-09-01

    Whenever a common resource is scarce, a set of rules are needed to share it in a fairly way. However, most control schemes assume that users will behave in a cooperative way, without taking care of guaranteeing that they will not act in a selfish manner. Then, a fundamental issue is to evaluate the impact of cheating. From the point of view of game theory, a Nash equilibrium implies that nobody can take advantage by unilaterally deviating from this stable state, even in the presence of selfish users. In this paper we prove that any efficient Nash equilibrium strongly depends on the number of users, if the control scheme policy does not record their previous behavior. Since this is a common pattern in real situations, this implies that the system would be always out of equilibrium. Consequently, this result proves that, in practice, oblivious control schemes must be improved to cope with selfish users.

  16. Distributed Nash Equilibrium Seeking for Generalized Convex Games with Shared Constraints

    NASA Astrophysics Data System (ADS)

    Sun, Chao; Hu, Guoqiang

    2018-05-01

    In this paper, we deal with the problem of finding a Nash equilibrium for a generalized convex game. Each player is associated with a convex cost function and multiple shared constraints. Supposing that each player can exchange information with its neighbors via a connected undirected graph, the objective of this paper is to design a Nash equilibrium seeking law such that each agent minimizes its objective function in a distributed way. Consensus and singular perturbation theories are used to prove the stability of the system. A numerical example is given to show the effectiveness of the proposed algorithms.

  17. Long term highly saturated fat diet does not induce NASH in Wistar rats

    PubMed Central

    Romestaing, Caroline; Piquet, Marie-Astrid; Bedu, Elodie; Rouleau, Vincent; Dautresme, Marianne; Hourmand-Ollivier, Isabelle; Filippi, Céline; Duchamp, Claude; Sibille, Brigitte

    2007-01-01

    Background Understanding of nonalcoholic steatohepatitis (NASH) is hampered by the lack of a suitable model. Our aim was to investigate whether long term high saturated-fat feeding would induce NASH in rats. Methods 21 day-old rats fed high fat diets for 14 weeks, with either coconut oil or butter, and were compared with rats feeding a standard diet or a methionine choline-deficient (MCD) diet, a non physiological model of NASH. Results MCDD fed rats rapidly lost weight and showed NASH features. Rats fed coconut (86% of saturated fatty acid) or butter (51% of saturated fatty acid) had an increased caloric intake (+143% and +30%). At the end of the study period, total lipid ingestion in term of percentage of energy intake was higher in both coconut (45%) and butter (42%) groups than in the standard (7%) diet group. No change in body mass was observed as compared with standard rats at the end of the experiment. However, high fat fed rats were fattier with enlarged white and brown adipose tissue (BAT) depots, but they showed no liver steatosis and no difference in triglyceride content in hepatocytes, as compared with standard rats. Absence of hepatic lipid accumulation with high fat diets was not related to a higher lipid oxidation by isolated hepatocytes (unchanged ketogenesis and oxygen consumption) or hepatic mitochondrial respiration but was rather associated with a rise in BAT uncoupling protein UCP1 (+25–28% vs standard). Conclusion Long term high saturated fat feeding led to increased "peripheral" fat storage and BAT thermogenesis but did not induce hepatic steatosis and NASH. PMID:17313679

  18. Gary Nash: Preeminent Scholar and Committed Educator

    ERIC Educational Resources Information Center

    Symcox, Linda

    2009-01-01

    The author has known Gary Nash as a friend since 1969, but she only began to work with him as a colleague in 1989, when he invited her to join the National Center for History in the Schools (NCHS) as it was just forming. During the seven years she spent as Assistant and then Associate Director of the NCHS, they shared the extraordinary experience…

  19. Nash Equilibria in Noncooperative Predator-Prey Games

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ramos, Angel Manuel; Roubicek, Tomas

    2007-09-15

    A noncooperative game governed by a distributed-parameter predator-prey system is considered, assuming that two players control initial conditions for predator and prey, respectively. Existence of a Nash equilibrium is shown under the condition that the desired population profiles and the environmental carrying capacity for the prey are sufficiently small. A conceptual approximation algorithm is proposed and analyzed. Finally, numerical simulations are performed, too.

  20. Approximation of Nash equilibria and the network community structure detection problem

    PubMed Central

    2017-01-01

    Game theory based methods designed to solve the problem of community structure detection in complex networks have emerged in recent years as an alternative to classical and optimization based approaches. The Mixed Nash Extremal Optimization uses a generative relation for the characterization of Nash equilibria to identify the community structure of a network by converting the problem into a non-cooperative game. This paper proposes a method to enhance this algorithm by reducing the number of payoff function evaluations. Numerical experiments performed on synthetic and real-world networks show that this approach is efficient, with results better or just as good as other state-of-the-art methods. PMID:28467496

  1. Progression and Regression of Hepatic Lesions in a Mouse Model of NASH Induced by Dietary Intervention and Its Implications in Pharmacotherapy.

    PubMed

    Ding, Zhi-Ming; Xiao, Yue; Wu, Xikun; Zou, Haixia; Yang, Shurong; Shen, Yiyun; Xu, Juehua; Workman, Heather C; Usborne, Amy L; Hua, Haiqing

    2018-01-01

    Understanding of the temporal changes of hepatic lesions in the progression and regression of non-alcoholic steatohepatitis (NASH) is vital to elucidation of the pathogenesis of NASH, and critical to the development of a strategy for NASH pharmacotherapy. There are challenges in studying hepatic lesion progression and regression in NASH patients due to the slow development of NASH in humans, one being the requirement for multiple biopsies during the longitudinal follow-up. Here we studied lesion progression and regression in the diet-induced animal model of NASH by application or removal of the pathogenic diet for multiple time periods. Male C57BL/6 mice fed Western diet developed progressive hepatic steatosis/macrovesicular vacuolation, inflammation, and hepatocyte degeneration, as well as perisinusoidal fibrosis and occasionally portal fibrosis as early as 2 months after initiation of the Western diet. In the same period, the mice exhibited elevated ALT (alanine aminotransferase) and AST (aspartate aminotransferase) enzyme activities, CK18 (cytokeratin-18), PIIINP (N-terminal propeptide of type III collagen), and TIMP-1 (tissue inhibitor of metalloproteinase-1). Hepatic steatosis diminished rapidly when the Western diet was replaced by normal rodent chow diet and hepatic inflammation and hepatocyte degeneration were also reduced. Interestingly, perisinusoidal fibrosis and portal fibrosis regressed 8 months after chow diet replacement. To understand pharmacotherapy for NASH, mice with established NASH hepatic lesions were treated with either FXR agonist obeticholic acid (Ocaliva), or CCR2/5 antagonist Cenicriviroc. Similar to the diet replacement, metabolic modulator Ocaliva markedly reduced steatosis/macrovesicular vacuolation, hepatic inflammation, and hepatocyte degeneration effectively, but exhibited no significant effect on liver fibrosis. Anti-inflammation drug Cenicriviroc, on the other hand, markedly decreased inflammation and hepatocyte degeneration, and

  2. Gut microbiome composition in lean patients with NASH is associated with liver damage independent of caloric intake: A prospective pilot study.

    PubMed

    Duarte, S M B; Stefano, J T; Miele, L; Ponziani, F R; Souza-Basqueira, M; Okada, L S R R; de Barros Costa, F G; Toda, K; Mazo, D F C; Sabino, E C; Carrilho, F J; Gasbarrini, A; Oliveira, C P

    2018-04-01

    The aim of the study was to compare the gut microbiomes from obese and lean patients with or without NASH to outline phenotypic differences. We performed a cross-sectional pilot study comprising biopsy-proven NASH patients grouped according to BMI. Microbiome DNA was extracted from stool samples, and PCR amplification was performed using primers for the V4 region of the 16S rRNA gene. The amplicons were sequenced using the Ion PGM Torrent platform, and data were analyzed using QIIME software. Macronutrient consumption was analyzed by a 7-day food record. Liver fibrosis ≥ F2 was associated with increased abundance of Lactobacilli (p = 0.0007). NASH patients showed differences in Faecalibacterium, Ruminococcus, Lactobacillus and Bifidobacterium abundance compared with the control group. Lean NASH patients had a 3-fold lower abundance of Faecalibacterium and Ruminococcus (p = 0.004), obese NASH patients were enriched in Lactobacilli (p = 0.002), and overweight NASH patients had reduced Bifidobacterium (p = 0.018). Moreover, lean NASH patients showed a deficiency in Lactobacillus compared with overweight and obese NASH patients. This group also appeared similar to the control group with regard to gut microbiome alpha diversity. Although there were qualitative differences between lean NASH and overweight/obese NASH, they were not statistically significant (p = 0.618). The study limitations included a small sample size, a food questionnaire that collected only qualitative and semi-quantitative data, and variations in group gender composition that may influence differences in FXR signaling, bile acids metabolism and the composition of gut microbiota. Our preliminary finding of a different pathogenetic process in lean NASH patients needs to be confirmed by larger studies, including those with patient populations stratified by sex and dietary habits. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the

  3. Nash equilibrium in differential games and the construction of the programmed iteration method

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Averboukh, Yurii V

    This work is devoted to the study of nonzero-sum differential games. The set of payoffs in a situation of Nash equilibrium is examined. It is shown that the set of payoffs in a situation of Nash equilibrium coincides with the set of values of consistent functions which are fixed points of the program absorption operator. A condition for functions to be consistent is given in terms of the weak invariance of the graph of the functions under a certain differential inclusion. Bibliography: 18 titles.

  4. Surviving History: Gary Nash and the National Standards

    ERIC Educational Resources Information Center

    Bingham, Marjorie

    2009-01-01

    In this article, the author recalls the first time she met Gary Nash. He came to speak at a Bradley Commission meeting and she was rather surprised to see him appear and to find out that he, along with Charlotte Crabtree, was involved in a National Center for History. She gives three reasons for her surprise which she thinks may tell aspects of…

  5. A Graphical Analysis of the Cournot-Nash and Stackelberg Models.

    ERIC Educational Resources Information Center

    Fulton, Murray

    1997-01-01

    Shows how the Cournot-Nash and Stackelberg equilibria can be represented in the familiar supply-demand graphical framework, allowing a direct comparison with the monopoly, competitive, and industrial organization models. This graphical analysis is represented throughout the article. (MJP)

  6. Factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Tasneem, Abbas Ali; Luck, Nasir Hassan; Majid, Zain

    2018-04-01

    Introduction To determine the factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Methodology All patients aged >18 years and having a fatty liver on abdominal ultrasound (US), presenting from January 2011 to January 2017, were included. A liver biopsy was performed on all the patients. Results Of 96 patients undergoing liver biopsy for non-alcoholic fatty liver disease (NAFLD), 76 (79.2%) were men. On liver US, diffuse fatty liver (DFL) was noted in 68 (70.8%) patients. Liver biopsy showed non-alcoholic steatohepatitis (NASH) in 78 (81.3%) patients. Factors associated with NASH were male gender, body mass index (BMI) > 27 kg/m 2 , DFL and raised alanine aminotransferase (ALT). A GULAB score (based on gender, US liver findings, lipid (fasting) levels, ALT level and BMI) of ≥5 predicted NASH with 82.05% sensitivity. Factors associated with advanced fibrosis in NAFLD were age >40 years, diabetes mellitus, AST/ALT ratio > 1 and raised GGT. Conclusion NASH is common in patients with male gender, high BMI, DFL on liver US, raised ALT and GULAB score ≥5.

  7. Critical Realism and Statistical Methods--A Response to Nash

    ERIC Educational Resources Information Center

    Scott, David

    2007-01-01

    This article offers a defence of critical realism in the face of objections Nash (2005) makes to it in a recent edition of this journal. It is argued that critical and scientific realisms are closely related and that both are opposed to statistical positivism. However, the suggestion is made that scientific realism retains (from statistical…

  8. Follow-up CT findings of tamoxifen-induced non-alcoholic steatohepatitis (NASH) of breast cancer patients treated with bezafibrate.

    PubMed

    Ogawa, Yasuhiro; Murata, Yoriko; Saibara, Toshiji; Nishioka, Akihito; Kariya, Shinji; Yoshida, Shoji

    2003-01-01

    One-third of the breast cancer patients who underwent tamoxifen intake showed less than 0.9 of their liver/spleen CT (computed tomography) ratio on their annual CT study, and were diagnosed as having fatty liver (hepatic steatosis). Among them, patients who showed a lower liver/spleen CT ratio of less than 0.5 were recommended to undergo needle biopsy of the liver in order to obtain histopathological confirmation of non-alcoholic steatohepatitis (NASH), with 15 patients undergoing needle biopsy of the liver. As a result, 14 out of the 15 patients were diagnosed as having NASH, and these patients were additionally administered bezafibrate in order to prevent possible progressive changes of NASH into liver cirrhosis. In this study, we show the changes of follow-up CT findings of 6 patients with histopathologically-proven NASH who continued to undergo bezafibrate intake after the diagnosis of NASH. Two patients showed almost complete improvement as indicated by the liver/spleen CT ratio several months after completion of a tamoxifen intake of 5 years, and another 3 showed partial improvement on their liver/spleen CT ratio by bezafibrate intake in spite of continuing tamoxifen intake. Another patient with diabetes mellitus (type II) showed a continually decreasing liver/spleen CT ratio during adjuvant tamoxifen in spite of bezafibrate intake. Therefore, we concluded that the progression of NASH could be prevented by bezafibrate without any interruption of adjuvant tamoxifen treatment. For patients with diabetes mellitus, critical follow-up using CT study and laboratory tests is considered essential.

  9. Kupffer Cells Undergo Fundamental Changes during the Development of Experimental NASH and Are Critical in Initiating Liver Damage and Inflammation

    PubMed Central

    Reid, D. T.; Reyes, J. L.; McDonald, B. A.; Vo, T.; Reimer, R. A.; Eksteen, B.

    2016-01-01

    Non-alcoholic fatty liver disease has become the leading liver disease in North America and is associated with the progressive inflammatory liver disease non-alcoholic steatohepatitis (NASH). Considerable effort has been made to understand the role of resident and recruited macrophage populations in NASH however numerous questions remain. Our goal was to characterize the dynamic changes in liver macrophages during the initiation of NASH in a murine model. Using the methionine-choline deficient diet we found that liver-resident macrophages, Kupffer cells were lost early in disease onset followed by a robust infiltration of Ly-6C+ monocyte-derived macrophages that retained a dynamic phenotype. Genetic profiling revealed distinct patterns of inflammatory gene expression between macrophage subsets. Only early depletion of liver macrophages using liposomal clodronate prevented the development of NASH in mice suggesting that Kupffer cells are critical for the orchestration of inflammation during experimental NASH. Increased understanding of these dynamics may allow us to target potentially harmful populations whilst promoting anti-inflammatory or restorative populations to ultimately guide the development of effective treatment strategies. PMID:27454866

  10.  The product of triglycerides and glucose as biomarker for screening simple steatosis and NASH in asymptomatic women.

    PubMed

    Simental-Mendía, Luis E; Simental-Mendía, Esteban; Rodríguez-Hernández, Heriberto; Rodríguez-Morán, Martha; Guerrero-Romero, Fernando

    2016-01-01

     Introduction and aim. Given that early identification of non-alcoholic fatty liver disease (NAFLD) is an important issue for primary prevention of hepatic disease, the objectives of this study were to evaluate the efficacy of the product of triglyceride and glucose levels (TyG) for screening simple steatosis and non-alcoholic steatohepatitis (NASH) in asymptomatic women, and to compare its efficacy vs. other biomarkers for recognizing NAFLD. Asymptomatic women aged 20 to 65 years were enrolled into a cross-sectional study. The optimal values of TyG, for screening simple steatosis and NASH were established on a Receiver Operating Characteristic scatter plot; the sensitivity, specificity, and likelihood ratios of TyG index were estimated versus liver biopsy. According sensitivity and specificity, the efficacy of TyG was compared versus the well-known clinical biomarkers for recognizing NAFLD. A total of 50 asymptomatic women were enrolled. The best cutoff point of TyG for screening simple steatosis was 4.58 (sensitivity 0.94, specificity 0.69); in addition, the best cutoff point of TyG index for screening NASH was 4.59 (sensitivity 0.87, specificity 0.69). The positive and negative likelihood ratios were 3.03 and 0.08 for simple steatosis, and 2.80 and 0.18 for NASH. As compared versus SteatoTest, NashTest, Fatty liver index, and Algorithm, the TyG showed to be the best test for screening. TyG has high sensitivity and low negative likelihood ratio; as compared with other clinical biomarkers, the TyG showed to be the best test for screening simple steatosis and NASH.

  11. Information Structures in Nash and Leader-Follower Strategies.

    DTIC Science & Technology

    1981-01-01

    OICkASSIPICATION/ OOWNGRAOING IS. OISTNIIIUTION STATEMINT (ao tD. esPort ) * Approved for public release; distribution unlimited. 17. DISTRIBUTION STATEMENT...problems and two market models of duopoly ith this type of information structure are extensively analyzed and examined. DO jAN7, 1473 EDIION OF NV SS IS...information 3 structure is employed in both Nash games and optimal coordination problems and two market models of duopoly with this type of information

  12. On Nash Equilibrium and Evolutionarily Stable States That Are Not Characterised by the Folk Theorem

    PubMed Central

    Li, Jiawei; Kendall, Graham

    2015-01-01

    In evolutionary game theory, evolutionarily stable states are characterised by the folk theorem because exact solutions to the replicator equation are difficult to obtain. It is generally assumed that the folk theorem, which is the fundamental theory for non-cooperative games, defines all Nash equilibria in infinitely repeated games. Here, we prove that Nash equilibria that are not characterised by the folk theorem do exist. By adopting specific reactive strategies, a group of players can be better off by coordinating their actions in repeated games. We call it a type-k equilibrium when a group of k players coordinate their actions and they have no incentive to deviate from their strategies simultaneously. The existence and stability of the type-k equilibrium in general games is discussed. This study shows that the sets of Nash equilibria and evolutionarily stable states have greater cardinality than classic game theory has predicted in many repeated games. PMID:26288088

  13. Remediating Language Deficient/Dyslexic College Students: An Interview with Robert Nash.

    ERIC Educational Resources Information Center

    Lundquist, Arlene J.; Nash, Robert

    1988-01-01

    Robert Nash responds to questions concerning his personal and professional background, the Simultaneous Multisensory Instructional Procedure for Teaching the Complete Sound Structure of the Language, problems associated with dyslexia, the social/emotional impact of learning disabilities, and the University of Wisconsin's Project Success for…

  14. 77 FR 10553 - Match-E-Be-Nash-She-Wish Band of Pottawatomi Indians (Gun Lake)-Amendment to Liquor Beverage...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-22

    ... DEPARTMENT OF THE INTERIOR Bureau of Indian Affairs Match-E-Be-Nash-She-Wish Band of Pottawatomi Indians (Gun Lake)-- Amendment to Liquor Beverage Control Ordinance AGENCY: Bureau of Indian Affairs, Interior. ACTION: Notice SUMMARY: This notice publishes the amendments to the Match-E-Be-Nash- She-Wish...

  15. Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH.

    PubMed

    Ioannou, George N; Van Rooyen, Derrick M; Savard, Christopher; Haigh, W Geoffrey; Yeh, Matthew M; Teoh, Narci C; Farrell, Geoffrey C

    2015-02-01

    Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant (foz/foz) mice were a fed high-fat (23%) diet containing 0.2% cholesterol for 16 weeks and then assigned to four intervention groups for 8 weeks: a) vehicle control, b) ezetimibe (5 mg/kg/day), c) atorvastatin (20 mg/kg/day), or d) ezetimibe and atorvastatin. Livers of vehicle-treated mice developed fibrosing NASH with abundant cholesterol crystallization within lipid droplets calculated to extend over 3.3% (SD, 2.2%) of liver surface area. Hepatocyte lipid droplets with prominent cholesterol crystallization were surrounded by TNFα-positive (activated) KCs forming CLSs (≥ 3 per high-power field). KCs that formed CLSs stained positive for NLRP3, implicating activation of the NLRP3 inflammasome in response to cholesterol crystals. In contrast, foz/foz mice treated with ezetimibe and atorvastatin showed near-complete resolution of cholesterol crystals [0.01% (SD, 0.02%) of surface area] and CLSs (0 per high-power field), with amelioration of fibrotic NASH. Ezetimibe or atorvastatin alone had intermediate effects on cholesterol crystallization, CLSs, and NASH. These findings are consistent with a causative link between exposure of hepatocytes and KCs to cholesterol crystals and with the development of NASH possibly mediated by NLRP3 activation.

  16. Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in HIV.

    PubMed

    Rockstroh, Jürgen Kurt

    2017-04-01

    Abnormal liver enzymes (LE) are common in patients infected with the human immunodeficiency virus (HIV) even in the absence of viral hepatitis or alcohol abuse. With availability of antiretroviral combination therapy, life expectancy has improved dramatically and as a consequence the spectrum of liver disease is changing. Increased reports on the development of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) in HIV coinfected patients raise questions around prevalence, clinical manifestations, and clinical outcome of these liver diseases in HIV coinfection. Moreover, the potential impact of combination antiretroviral therapy as well as direct HIV effects on the emergence of non-alcoholic fatty liver disease needs to be explored. This review summarizes the recent literature on NAFLD and NASH in HIV.

  17. Optimization, Monotonicity and the Determination of Nash Equilibria — An Algorithmic Analysis

    NASA Astrophysics Data System (ADS)

    Lozovanu, D.; Pickl, S. W.; Weber, G.-W.

    2004-08-01

    This paper is concerned with the optimization of a nonlinear time-discrete model exploiting the special structure of the underlying cost game and the property of inverse matrices. The costs are interlinked by a system of linear inequalities. It is shown that, if the players cooperate, i.e., minimize the sum of all the costs, they achieve a Nash equilibrium. In order to determine Nash equilibria, the simplex method can be applied with respect to the dual problem. An introduction into the TEM model and its relationship to an economic Joint Implementation program is given. The equivalence problem is presented. The construction of the emission cost game and the allocation problem is explained. The assumption of inverse monotony for the matrices leads to a new result in the area of such allocation problems. A generalization of such problems is presented.

  18. NASH resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels.

    PubMed

    Corey, K E; Vuppalanchi, R; Wilson, L A; Cummings, O W; Chalasani, N

    2015-02-01

    Nonalcoholic steatohepatitis (NASH) is associated with dyslipidemia and cardiovascular disease (CVD). To determine the relationship between resolution of NASH and dyslipidemia. Individuals in the Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial with paired liver biopsies and fasting lipid levels were included (N = 222). In the PIVENS trial individuals were randomised to pioglitazone 30 mg, vitamin E 800 IU or placebo for 96 weeks. Change in lipid levels at 96 weeks was compared between those with and without NASH resolution. Dyslipidemia at baseline was frequent, with low high-density lipoprotein (HDL) (<40 mg/dL in men or <50 mg/dL in women) in 63%, hypertriglyceridaemia (≥150 mg/dL) in 46%, hypercholesterolaemia (≥200 mg/dL) in 47% and triglycerides (TG)/HDL >5.0 in 25%. Low-density lipoprotein (LD) ≥160 mg/dL was found in 16% and elevated non-HDL cholesterol (non-HDL-C) (≥130 mg/dL) in 73%. HDL increased with NASH resolution but decreased in those without resolution (2.9 mg/dL vs. -2.5 mg/dL, P < 0.001). NASH resolution was associated with significant decreases in TG and TG/HDL ratio compared to those without resolution (TG: -21.1 vs. -2.3 mg/dL, P = 0.03 and TG/HDL: -0.7 vs. 0.1, P = 0.003). Non-HDL-C, LDL and cholesterol decreased over 96 weeks in both groups, but there was no significant difference between groups. Treatment group did not impact lipids. NASH resolution is associated with improvements in TG and HDL but not in other cardiovascular disease risk factors including LDL and non-HDL-C levels. Individuals with resolution of NASH may still be at increased risk of cardiovascular disease. ClinicalTrials.gov identifier: NCT00063622. © 2014 John Wiley & Sons Ltd.

  19. Efficacy of docosahexaenoic acid-choline-vitamin E in paediatric NASH: a randomized controlled clinical trial.

    PubMed

    Zöhrer, Evelyn; Alisi, Anna; Jahnel, Jörg; Mosca, Antonella; Della Corte, Claudia; Crudele, Annalisa; Fauler, Günter; Nobili, Valerio

    2017-09-01

    Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease, is one of the most common hepatic diseases in children. We conducted a randomized controlled clinical trial on children with biopsy-proven NASH based on a combinatorial nutritional approach compared with placebo. Participants were assigned to lifestyle modification plus placebo or lifestyle modification plus a mix containing docosahexaenoic acid, choline, and vitamin E (DHA-CHO-VE). Forty children and adolescents participated in the entire trial. The primary outcome was the improvement of liver hyperechogenicity. Secondary outcomes included alterations of alanine aminotransferase (ALT) and other metabolic parameters. Furthermore, changes of serum bile acids (BA) and plasma fibroblast growth factor 19 (FGF19) levels were evaluated as inverse biomarkers of disease severity. At the end of the study, we observed a significant decrease in severe steatosis in the treatment group (50% to 5%, p = 0.001). Furthermore, although the anthropometric and biochemical measurements in the placebo and DHA-CHO-VE groups were comparable at baseline, at the end of the study ALT and fasting glucose levels improved only in the treatment group. Finally, we found that BA levels were not influenced whereas FGF19 levels were significantly increased by DHA-CHO-VE. The results suggest that a combination of DHA, VE, and CHO could improve steatosis and reduce ALT and glucose levels in children with NASH. However, further studies are needed to assess the impact of a DHA and VE combination on repair of liver damage in paediatric NASH.

  20. The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α.

    PubMed

    Ren, Tingting; Zhu, Juanjuan; Zhu, Lili; Cheng, Mingliang

    2017-02-27

    Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets ( p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models ( p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) ( p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3

  1. TLR9 is up-regulated in human and murine NASH: pivotal role in inflammatory recruitment and cell survival.

    PubMed

    Mridha, Auvro R; Haczeyni, Fahrettin; Yeh, Matthew M; Haigh, W Geoffrey; Ioannou, George N; Barn, Vanessa; Ajamieh, Hussam; Adams, Leon; Hamdorf, Jeffrey M; Teoh, Narci C; Farrell, Geoffrey C

    2017-08-15

    Background and aims : TLR9 deletion protects against steatohepatitis due to choline-amino acid depletion and high-fat diet. We measured TLR9 in human non-alcoholic steatohepatitis (NASH) livers, and tested whether TLR9 mediates inflammatory recruitment in three murine models of non-alcoholic fatty liver disease (NAFLD). Methods : We assayed TLR mRNA in liver biopsies from bariatric surgery patients. Wild-type ( Wt ), appetite-dysregulated Alms1 mutant (foz/foz), Tlr9 -/- , and Tlr9 -/- foz/foz C57BL6/J mice and bone marrow (BM) chimeras were fed 0.2% cholesterol, high-fat, high sucrose (atherogenic[Ath]) diet or chow, and NAFLD activity score (NAS)/NASH pathology, macrophage/neutrophil infiltration, cytokines/chemokines, and cell death markers measured in livers. Results : Hepatic TLR9 and TLR4 mRNA were increased in human NASH but not simple steatosis, and in Ath-fed foz/foz mice with metabolic syndrome-related NASH. Ath-fed Tlr9 -/- mice showed simple steatosis and less Th1 cytokines than Wt. Tlr9 -/- foz/foz mice were obese and diabetic, but necroinflammatory changes were less severe than Tlr9 +/+ .foz/foz mice. TLR9-expressing myeloid cells were critical for Th1 cytokine production in BM chimeras. BM macrophages from Tlr9 -/- mice showed M2 polarization, were resistant to M1 activation by necrotic hepatocytes/other pro-inflammatory triggers, and provoked less neutrophil chemotaxis than Wt Livers from Ath-fed Tlr9 -/- mice appeared to exhibit more markers of necroptosis [receptor interacting protein kinase (RIP)-1, RIP-3, and mixed lineage kinase domain-like protein (MLKL)] than Wt , and ∼25% showed portal foci of mononuclear cells unrelated to NASH pathology. Our novel clinical data and studies in overnutrition models, including those with diabetes and metabolic syndrome, clarify TLR9 as a pro-inflammatory trigger in NASH. This response is mediated via M1-macrophages and neutrophil chemotaxis. © 2017 The Author(s). Published by Portland Press Limited on

  2. Nash equilibrium strategy in the deregulated power industry and comparing its lost welfare with Iran wholesale electricity market

    NASA Astrophysics Data System (ADS)

    Mousavi, Seyed Hosein; Nazemi, Ali; Hafezalkotob, Ashkan

    2016-09-01

    With the increasing use of different types of auctions in market designing, modeling of participants' behaviors to evaluate the market structure is one of the main discussions in the studies related to the deregulated power industries. In this article, we apply an approach of the optimal bidding behavior to the Iran wholesale electricity market as a restructured electric power industry and model how the participants of the market bid in the spot electricity market. The problem is formulated analytically using the Nash equilibrium concept composed of large numbers of players having discrete and very large strategy spaces. Then, we compute and draw supply curve of the competitive market in which all generators' proposed prices are equal to their marginal costs and supply curve of the real market in which the pricing mechanism is pay-as-bid. We finally calculate the lost welfare or inefficiency of the Nash equilibrium and the real market by comparing their supply curves with the competitive curve. We examine 3 cases on November 24 (2 cases) and July 24 (1 case), 2012. It is observed that in the Nash equilibrium on November 24 and demand of 23,487 MW, there are 212 allowed plants for the first case (plants are allowed to choose any quantity of generation except one of them that should be equal to maximum Power) and the economic efficiency or social welfare of Nash equilibrium is 2.77 times as much as the real market. In addition, there are 184 allowed plants for the second case (plants should offer their maximum power with different prices) and the efficiency or social welfare of Nash equilibrium is 3.6 times as much as the real market. On July 24 and demand of 42,421 MW, all 370 plants should generate maximum energy due to the high electricity demand that the economic efficiency or social welfare of the Nash equilibrium is about 2 times as much as the real market.

  3. Geometry of Cournot-Nash Equilibrium with Application to Commons and Anticommons

    ERIC Educational Resources Information Center

    D'Agata, Antonio

    2010-01-01

    The author develops a simple geometric analysis of Cournot-Nash equilibrium in the price-quantity space by exploiting the economic content of the first-order condition. The approach makes it clear that strategic interdependency in oligopoly originates from externalities among producers. This explains why cartels are unstable and casts oligopoly…

  4. Challenges and Management of Liver Cirrhosis: Practical Issues in the Therapy of Patients with Cirrhosis due to NAFLD and NASH.

    PubMed

    Traussnigg, Stefan; Kienbacher, Christian; Halilbasic, Emina; Rechling, Christian; Kazemi-Shirazi, Lili; Hofer, Harald; Munda, Petra; Trauner, Michael

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and comprises a liver disease spectrum ranging from steatosis to nonalcoholic steatohepatitis (NASH) with risk of progression to liver cirrhosis and hepatocellular carcinoma (HCC). Associated metabolic conditions and comorbidities such as obesity, diabetes and cardiovascular diseases are common and require concerted management. Adiponutrin (PNPLA3) variants may help to identify NAFLD patients at higher risk for liver disease progression towards advanced fibrosis and HCC. The therapeutic options in NAFLD/NASH include lifestyle modification, pharmacological treatment, bariatric surgery for patients with morbid obesity and treatment of complications of liver cirrhosis and HCC, including liver transplantation. Insulin sensitizers and antioxidative treatment strategies with vitamin E are among the best-established pharmacological approaches, but both drugs have long-term safety issues and there is limited evidence in cirrhotic patients. Treatment of concomitant/underlying metabolic conditions with statins or metformin may also have beneficial effects on portal hypertension, complications of liver cirrhosis and HCC prevention. The bile acid receptor FXR may be a promising novel therapeutic target for the treatment of NAFLD/NASH, fibrosis and portal hypertension, but the prognostic implications of associated changes in low- and high-density lipoprotein cholesterol require further studies. Morbidly obese NASH patients can benefit from bariatric surgery which may reduce liver fibrosis but carries a risk of decompensation in patients with advanced liver cirrhosis. When carefully selected, patients with NASH cirrhosis undergoing liver transplantation have a good outcome. This review summarizes recent progress in the management of patients with liver cirrhosis due to NASH. © 2015 S. Karger AG, Basel.

  5. Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH

    PubMed Central

    Ioannou, George N.; Van Rooyen, Derrick M.; Savard, Christopher; Haigh, W. Geoffrey; Yeh, Matthew M.; Teoh, Narci C.; Farrell, Geoffrey C.

    2015-01-01

    Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant (foz/foz) mice were a fed high-fat (23%) diet containing 0.2% cholesterol for 16 weeks and then assigned to four intervention groups for 8 weeks: a) vehicle control, b) ezetimibe (5 mg/kg/day), c) atorvastatin (20 mg/kg/day), or d) ezetimibe and atorvastatin. Livers of vehicle-treated mice developed fibrosing NASH with abundant cholesterol crystallization within lipid droplets calculated to extend over 3.3% (SD, 2.2%) of liver surface area. Hepatocyte lipid droplets with prominent cholesterol crystallization were surrounded by TNFα-positive (activated) KCs forming CLSs (≥3 per high-power field). KCs that formed CLSs stained positive for NLRP3, implicating activation of the NLRP3 inflammasome in response to cholesterol crystals. In contrast, foz/foz mice treated with ezetimibe and atorvastatin showed near-complete resolution of cholesterol crystals [0.01% (SD, 0.02%) of surface area] and CLSs (0 per high-power field), with amelioration of fibrotic NASH. Ezetimibe or atorvastatin alone had intermediate effects on cholesterol crystallization, CLSs, and NASH. These findings are consistent with a causative link between exposure of hepatocytes and KCs to cholesterol crystals and with the development of NASH possibly mediated by NLRP3 activation. PMID:25520429

  6. Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD

    PubMed Central

    Bazick, Jessica; Donithan, Michele; Neuschwander-Tetri, Brent A.; Kleiner, David; Brunt, Elizabeth M.; Wilson, Laura; Doo, Ed; Lavine, Joel; Tonascia, James

    2015-01-01

    OBJECTIVE Approximately 18 million people in the U.S. have coexisting type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). It is not known who among these patients has nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Therefore, we aimed to determine factors that are associated with both NASH and advanced fibrosis in patients with diabetes and NAFLD in order to identify who should be prioritized for referral to a hepatologist for further diagnostic evaluation and treatment. RESEARCH DESIGN AND METHODS This study was derived from the NASH Clinical Research Network studies and included 1,249 patients with biopsy-proven NAFLD (including a model development cohort of 346 patients and an independent validation cohort of 100 patients with type 2 diabetes as defined by the American Diabetes Association criteria). Outcome measures were presence of NASH or advanced fibrosis (stage 3 or 4) using cross-validated, by jackknife method, multivariable-adjusted area under the receiver operating characteristic curve (AUROC) and 95% CI. RESULTS The mean ± SD age and BMI of patients with diabetes and NAFLD was 52.5 ± 10.3 years and 35.8 ± 6.8 kg/m2, respectively. The prevalence of NASH and advanced fibrosis was 69.2% and 41.0%, respectively. The model for NASH included white race, BMI, waist, alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, HbA1c, HOMA of insulin resistance, and ferritin with an AUROC of 0.80 (95% CI 0.75–0.84, P = 0.007). The specificity, sensitivity, negative predictive values (NPVs), and positive predictive values (PPVs) were 90.0%, 56.8%, 47.7%, and 93.2%, respectively, and the model correctly classified 67% of patients as having NASH. The model for predicting advanced fibrosis included age, Hispanic ethnicity, BMI, waist-to-hip ratio, hypertension, ALT-to-AST ratio, alkaline phosphatase, isolated abnormal alkaline phosphatase, bilirubin (total and direct), globulin, albumin, serum insulin, hematocrit

  7. Characterizing the Nash equilibria of three-player Bayesian quantum games

    NASA Astrophysics Data System (ADS)

    Solmeyer, Neal; Balu, Radhakrishnan

    2017-05-01

    Quantum games with incomplete information can be studied within a Bayesian framework. We analyze games quantized within the EWL framework [Eisert, Wilkens, and Lewenstein, Phys Rev. Lett. 83, 3077 (1999)]. We solve for the Nash equilibria of a variety of two-player quantum games and compare the results to the solutions of the corresponding classical games. We then analyze Bayesian games where there is uncertainty about the player types in two-player conflicting interest games. The solutions to the Bayesian games are found to have a phase diagram-like structure where different equilibria exist in different parameter regions, depending both on the amount of uncertainty and the degree of entanglement. We find that in games where a Pareto-optimal solution is not a Nash equilibrium, it is possible for the quantized game to have an advantage over the classical version. In addition, we analyze the behavior of the solutions as the strategy choices approach an unrestricted operation. We find that some games have a continuum of solutions, bounded by the solutions of a simpler restricted game. A deeper understanding of Bayesian quantum game theory could lead to novel quantum applications in a multi-agent setting.

  8. Role of white adipose lipolysis in the development of NASH induced by methionine-and choline-deficient diet

    PubMed Central

    Tanaka, Naoki; Takahashi, Shogo; Fang, Zhong-Ze; Matsubara, Tsutomu; Krausz, Kristopher W.; Qu, Aijuan; Gonzalez, Frank J.

    2014-01-01

    Methionine- and choline-deficient diet (MCD) is a model for nonalcoholic steatohepatitis (NASH) in rodents. However, the mechanism of NASH development by dietary methionine/choline deficiency remains undetermined. To elucidate the early metabolic changes associated with MCD-NASH, serum metabolomic analysis was performed using mice treated with MCD and control diet for three days and one week, revealing significant increases in oleic and linoleic acids after MCD treatment. These increases were correlated with reduced body weight and white adipose tissue (WAT) mass, increased phosphorylation of hormone-sensitive lipase, and up-regulation of genes encoding carboxylesterase 3 and β2-adrenergic receptor in WAT, indicating accelerated lipolysis in adipocytes. The changes in serum fatty acids and WAT by MCD treatment were reversed by methionine supplementation, and similar alterations were detected in mice fed a methionine-deficient diet (MD), thus demonstrating that dietary methionine deficiency enhances lipolysis in WAT. MD treatment decreased glucose and increased fibroblast growth factor 21 in serum, thus exhibiting a similar metabolic phenotype as the fasting response. Comparison between MCD and choline-deficient diet (CD) treatments suggested that the addition of MD-induced metabolic alterations, such as WAT lipolysis, to CD-induced hepatic steatosis promotes liver injury. Collectively, these results demonstrate an important role for dietary methionine deficiency and WAT lipolysis in the development of MCD-NASH. PMID:25178843

  9. The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

    PubMed Central

    Ren, Tingting; Zhu, Juanjuan; Zhu, Lili; Cheng, Mingliang

    2017-01-01

    Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets (p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models (p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) (p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3 pathway

  10. A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition.

    PubMed

    Krishnan, Anuradha; Abdullah, Tasduq Sheikh; Mounajjed, Taofic; Hartono, Stella; McConico, Andrea; White, Thomas; LeBrasseur, Nathan; Lanza, Ian; Nair, Sreekumaran; Gores, Gregory; Charlton, Michael

    2017-06-01

    The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13-276 pmol·s -1 ·ml -1 per unit citrate synthase) than SC mice (17-394 pmol·s -1 ·ml -1 per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of

  11. Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD.

    PubMed

    Bazick, Jessica; Donithan, Michele; Neuschwander-Tetri, Brent A; Kleiner, David; Brunt, Elizabeth M; Wilson, Laura; Doo, Ed; Lavine, Joel; Tonascia, James; Loomba, Rohit

    2015-07-01

    Approximately 18 million people in the U.S. have coexisting type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). It is not known who among these patients has nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Therefore, we aimed to determine factors that are associated with both NASH and advanced fibrosis in patients with diabetes and NAFLD in order to identify who should be prioritized for referral to a hepatologist for further diagnostic evaluation and treatment. This study was derived from the NASH Clinical Research Network studies and included 1,249 patients with biopsy-proven NAFLD (including a model development cohort of 346 patients and an independent validation cohort of 100 patients with type 2 diabetes as defined by the American Diabetes Association criteria). Outcome measures were presence of NASH or advanced fibrosis (stage 3 or 4) using cross-validated, by jackknife method, multivariable-adjusted area under the receiver operating characteristic curve (AUROC) and 95% CI. The mean ± SD age and BMI of patients with diabetes and NAFLD was 52.5 ± 10.3 years and 35.8 ± 6.8 kg/m(2), respectively. The prevalence of NASH and advanced fibrosis was 69.2% and 41.0%, respectively. The model for NASH included white race, BMI, waist, alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, HbA1c, HOMA of insulin resistance, and ferritin with an AUROC of 0.80 (95% CI 0.75-0.84, P = 0.007). The specificity, sensitivity, negative predictive values (NPVs), and positive predictive values (PPVs) were 90.0%, 56.8%, 47.7%, and 93.2%, respectively, and the model correctly classified 67% of patients as having NASH. The model for predicting advanced fibrosis included age, Hispanic ethnicity, BMI, waist-to-hip ratio, hypertension, ALT-to-AST ratio, alkaline phosphatase, isolated abnormal alkaline phosphatase, bilirubin (total and direct), globulin, albumin, serum insulin, hematocrit, international normalized ratio, and platelet count with

  12. A long-acting FGF21 alleviates hepatic steatosis and inflammation in NASH mice partly through an FGF21- adiponectin- IL17A axis.

    PubMed

    Bao, Lichen; Yin, Jun; Gao, Wen; Wang, Qun; Yao, Wenbing; Gao, Xiangdong

    2018-06-02

    NASH is the most severe form of NAFLD and is a serious public health problem around the world. There are currently no approved treatments for NASH. FGF21 has recently emerged as a promising drug candidate for metabolic diseases. However, the challenges in developing FGF21 as a novel medicine include its short plasma half-life and poor drug-like properties. Here, we explored the therapeutic effects of PsTag600-FGF21, an engineered long-acting FGF21 fusion protein, in NASH mice and revealed some of the mechanisms responsible for this activity. A long-acting FGF21 was prepared by genetic fusion with a 600 residues polypeptide (PsTag600). We conducted our studies using a choline-deficient high-fat diet (CD-HFD) induced NASH mouse model. In NASH mice, the effects on body weight, insulin sensitivity, inflammation and levels of hormones and metabolites were studied first. We further investigated whether PsTag600-FGF21 attenuated inflammation through the Th17-IL17A axis and the associated mechanisms. PsTag600-FGF21 dose-dependently reduced body weight, blood glucose, insulin and lipid levels and reversed hepatic steatosis. PsTag600-FGF21 enhanced fatty acid activation and mitochondrial β-oxidation in the liver. The profound reduction in hepatic inflammation in NASH mice was associated with PsTag600-FGF21 inhibition of IL17A expression in Th17 cells. Furthermore, PsTag600-FGF21 depended on adiponectin to exert its suppression effects on Th17 cell differentiation and IL17A expression. Our data begin to uncover the indirect mechanism by which PsTag600-FGF21 suppresses hepatic inflammation and further suggest that PsTag600-FGF21 could be an effective approach in NASH treatment. This article is protected by copyright. All rights reserved.

  13. Nash Equilibria in Theory of Reasoned Action

    NASA Astrophysics Data System (ADS)

    Almeida, Leando; Cruz, José; Ferreira, Helena; Pinto, Alberto Adrego

    2009-08-01

    Game theory and Decision Theory have been applied to many different areas such as Physics, Economics, Biology, etc. In its application to Psychology, we introduce, in the literature, a Game Theoretical Model of Planned Behavior or Reasoned Action by establishing an analogy between two specific theories. In this study we take in account that individual decision-making is an outcome of a process where group decisions can determine individual probabilistic behavior. Using Game Theory concepts, we describe how intentions can be transformed in behavior and according to the Nash Equilibrium, this process will correspond to the best individual decision/response taking in account the collective response. This analysis can be extended to several examples based in the Game Theoretical Model of Planned Behavior or Reasoned Action.

  14. Nash Equilibrium of Social-Learning Agents in a Restless Multiarmed Bandit Game.

    PubMed

    Nakayama, Kazuaki; Hisakado, Masato; Mori, Shintaro

    2017-05-16

    We study a simple model for social-learning agents in a restless multiarmed bandit (rMAB). The bandit has one good arm that changes to a bad one with a certain probability. Each agent stochastically selects one of the two methods, random search (individual learning) or copying information from other agents (social learning), using which he/she seeks the good arm. Fitness of an agent is the probability to know the good arm in the steady state of the agent system. In this model, we explicitly construct the unique Nash equilibrium state and show that the corresponding strategy for each agent is an evolutionarily stable strategy (ESS) in the sense of Thomas. It is shown that the fitness of an agent with ESS is superior to that of an asocial learner when the success probability of social learning is greater than a threshold determined from the probability of success of individual learning, the probability of change of state of the rMAB, and the number of agents. The ESS Nash equilibrium is a solution to Rogers' paradox.

  15. Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.

    PubMed

    Boursier, J; Anty, R; Vonghia, L; Moal, V; Vanwolleghem, T; Canivet, C M; Michalak, S; Bonnafous, S; Michielsen, P; Oberti, F; Iannelli, A; Van Gaal, L; Patouraux, S; Blanchet, O; Verrijken, A; Gual, P; Rousselet, M-C; Driessen, A; Hunault, G; Bertrais, S; Tran, A; Calès, P; Francque, S

    2018-05-01

    The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) ("fibrotic NASH") is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved. To develop a new blood test specifically dedicated for this new diagnostic target of interest. Eight Hundred and forty-six biopsy-proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets. The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK-3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut-offs were calculated. In the validation set, MACK-3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut-offs (36.0% of the patients), MACK-3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well-classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%. The new blood test MACK-3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved. © 2018 John Wiley & Sons Ltd.

  16. Design and rationale for a real-world observational cohort of patients with nonalcoholic fatty liver disease: The TARGET-NASH study.

    PubMed

    Barritt, A S; Gitlin, Norman; Klein, Samuel; Lok, Anna S; Loomba, Rohit; Malahias, Laura; Powell, Margaret; Vos, Miriam B; Weiss, L Michael; Cusi, Kenneth; Neuschwander-Tetri, Brent A; Sanyal, Arun

    2017-10-01

    Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. NAFLD comprises the spectrum from simple steatosis (nonalcoholic fatty liver, NAFL), to steatosis with inflammation (nonalcoholic steatohepatitis, NASH). Current primary therapy recommended for NAFLD is weight loss induced by lifestyle modification. The difficulty in achieving this has led to robust pharmacological therapy development. While new drugs may show efficacy in selected phase II/III clinical trial populations, their real-world effectiveness is unknown. TARGET-NASH is a 5-year, longitudinal, observational study of patients with NAFLD designed to evaluate the effectiveness of clinical practice interventions and provide practical information unobtainable in registration trials. A biological specimen repository is included in TARGET-NASH for translational studies of genomics and biomarkers of disease activity. Patients are enrolling at adult and pediatric sites representing multiple specialties. All patients being managed for NAFLD are eligible, whereas those in other NASH registries or clinical trials will be excluded. Enrolled patients range in age from 6 and up and will have 3years of clinical data reviewed. Patient comorbidities, concomitant medications, disease progression and off-label interventions will be assessed, and adverse outcomes, monitored. Confirming the use, safety and effectiveness of NAFLD interventions in children and adults and establishing pragmatic methods of assessing disease progression under real-world conditions are key study outcomes. Ultimately, TARGET-NASH will establish a large, diverse registry of NAFLD patients at academic and community practices to be leveraged to improve health and reduce development of cirrhosis and hepatocellular carcinoma. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. HCV genotype 3 and squamous cell carcinoma antigen (SCCA)-IgM are independently associated with histological features of NASH in HCV-infected patients.

    PubMed

    Martini, A; Fattovich, G; Guido, M; Bugianesi, E; Biasiolo, A; Ieluzzi, D; Gallotta, A; Fassina, G; Merkel, C; Gatta, A; Negro, F; Pontisso, P

    2015-10-01

    Nonalcoholic steatohepatitis (NASH) enhances the risk of progressive liver disease. In chronic hepatitis C (CHC), liver steatosis is frequent, especially in genotype 3, but its clinical significance is debated. As squamous cell carcinoma antigen (SCCA)-IgM has been associated with advanced liver disease and risk of tumour development, we evaluated its occurrence in CHC and the possible relation with NASH at liver biopsy. Using a validated ELISA, serum SCCA-IgM was measured in 91 patients with CHC at the time of liver biopsy performed before antiviral treatment, at the end of treatment and 6 months thereafter, and in 93 HCV-negative patients with histological diagnosis of nonalcoholic fatty liver disease, as controls. SCCA-IgM was detected in 33% of CHC patients and in 4% of controls. This biomarker was found more elevated in CHC patients with histological NASH, and at multivariate analysis, SCCA-IgM and HCV genotype 3 were independently associated with NASH [OR (95% CI): 6.94 (1.21-40) and 27.02 (4.44-166.6)]. As predictors of NASH, HCV genotype 3 and SCCA-IgM had a specificity and a sensitivity of 97% and 44%, and of 95% and 27%, respectively. PPV and NPV were 80% and 86% for HCV genotype 3 vs 73% and 72% for SCCA-IgM. In patients with sustained virologic response to therapy, SCCA-IgM levels decreased significantly, while these remained unchanged in nonresponders. In conclusion, SCCA-IgM is detectable in one-third of patients with CHC and significantly correlates with histological NASH. © 2015 John Wiley & Sons Ltd.

  18. Obeticholic acid raises LDL-cholesterol and reduces HDL-cholesterol in the Diet-Induced NASH (DIN) hamster model.

    PubMed

    Briand, François; Brousseau, Emmanuel; Quinsat, Marjolaine; Burcelin, Rémy; Sulpice, Thierry

    2018-01-05

    The use of rat and mouse models limits the translation to humans for developing novel drugs targeting nonalcoholic steatohepatitis (NASH). Obeticholic acid (OCA) illustrates this limitation since its dyslipidemic effect in humans cannot be observed in these rodents. Conversely, Golden Syrian hamsters have a lipoprotein metabolism mimicking human dyslipidemia since it does express the cholesteryl ester transfer protein (CETP). We therefore developed a Diet-Induced NASH (DIN) hamster model and evaluated the impact of OCA. Compared with chow fed controls, hamsters fed for 20 weeks with a free-choice (FC) diet, developed obesity, insulin resistance, dyslipidemia and NASH (microvesicular steatosis, inflammation, hepatocyte ballooning and perisinusoidal to bridging fibrosis). After 20 weeks of diet, FC fed hamsters were treated without or with obeticholic acid (15mg/kg/day) for 5 weeks. Although a non-significant trend towards higher dietary caloric intake was observed, OCA significantly lowered body weight after 5 weeks of treatment. OCA significantly increased CETP activity and LDL-C levels by 20% and 27%, and reduced HDL-C levels by 20%. OCA blunted hepatic gene expression of Cyp7a1 and Cyp8b1 and reduced fecal bile acids mass excretion by 64% (P < 0.05). Hamsters treated with OCA showed a trend towards higher scavenger receptor Class B type I (SR-BI) and lower LDL-receptor hepatic protein expression. OCA reduced NAS score for inflammation (P < 0.01) and total NAS score, although not significantly. Compared to mouse and rat models, the DIN hamster replicates benefits and side effects of OCA as observed in humans, and should be useful for evaluating novel drugs targeting NASH. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine.

    PubMed

    Panasevich, M R; Meers, G M; Linden, M A; Booth, F W; Perfield, J W; Fritsche, K L; Wankhade, Umesh D; Chintapalli, Sree V; Shankar, K; Ibdah, J A; Rector, R S

    2018-01-01

    Pediatric obesity and nonalcoholic steatohepatitis (NASH) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal models. Here, we examined the effects of high-fat, high-fructose corn syrup, high-cholesterol Western-style diet (WD)-induced obesity on NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Juvenile female Ossabaw swine (5 wk old) were fed WD (43.0% fat; 17.8% high-fructose corn syrup; 2% cholesterol) or low-fat diet (CON/lean; 10.5% fat) for 16 wk ( n = 6 each) or 36 wk ( n = 4 each). WD-fed pigs developed obesity, dyslipidemia, and systemic insulin resistance compared with CON pigs. In addition, obese WD-fed pigs developed severe NASH, with hepatic steatosis, hepatocyte ballooning, inflammatory cell infiltration, and fibrosis after 16 wk, with further exacerbation of histological inflammation and fibrosis after 36 wk of WD feeding. WD feeding also resulted in robust cecal microbiota changes including increased relative abundances of families and genera in Proteobacteria ( P < 0.05) (i.e., Enterobacteriaceae, Succinivibrionaceae, and Succinivibrio) and LPS-containing Desulfovibrionaceae and Desulfovibrio and a greater ( P < 0.05) predicted microbial metabolic function for LPS biosynthesis, LPS biosynthesis proteins, and peptidoglycan synthesis compared with CON-fed pigs. Overall, juvenile Ossabaw swine fed a high-fat, high-fructose, high-cholesterol diet develop obesity and severe microbiota dysbiosis with a proinflammatory signature and a NASH phenotype directly relevant to the pediatric/adolescent and young adult population.

  20. Foraging swarms as Nash equilibria of dynamic games.

    PubMed

    Özgüler, Arif Bülent; Yildiz, Aykut

    2014-06-01

    The question of whether foraging swarms can form as a result of a noncooperative game played by individuals is shown here to have an affirmative answer. A dynamic game played by N agents in 1-D motion is introduced and models, for instance, a foraging ant colony. Each agent controls its velocity to minimize its total work done in a finite time interval. The game is shown to have a unique Nash equilibrium under two different foraging location specifications, and both equilibria display many features of a foraging swarm behavior observed in biological swarms. Explicit expressions are derived for pairwise distances between individuals of the swarm, swarm size, and swarm center location during foraging.

  1. Transforming the Ordinary into Extraordinary: Gary Nash and the Visions of History

    ERIC Educational Resources Information Center

    Vigilante, David

    2009-01-01

    Through his long career, Gary Nash has been a pioneer in opening the often-stuffy chambers of academia. He has shown a devotion to K-12 teachers throughout the nation and has ventured into their classrooms to observe, to teach, and, yes, to learn. It is all too rare for a noted historian, famous for his many seminal works, to roll up his sleeves…

  2. A Differential Evolution Algorithm Based on Nikaido-Isoda Function for Solving Nash Equilibrium in Nonlinear Continuous Games

    PubMed Central

    He, Feng; Zhang, Wei; Zhang, Guoqiang

    2016-01-01

    A differential evolution algorithm for solving Nash equilibrium in nonlinear continuous games is presented in this paper, called NIDE (Nikaido-Isoda differential evolution). At each generation, parent and child strategy profiles are compared one by one pairwisely, adapting Nikaido-Isoda function as fitness function. In practice, the NE of nonlinear game model with cubic cost function and quadratic demand function is solved, and this method could also be applied to non-concave payoff functions. Moreover, the NIDE is compared with the existing Nash Domination Evolutionary Multiplayer Optimization (NDEMO), the result showed that NIDE was significantly better than NDEMO with less iterations and shorter running time. These numerical examples suggested that the NIDE method is potentially useful. PMID:27589229

  3. High prevalence of normal serum albumin in NASH patients with ascites: a retrospective analysis.

    PubMed

    Sourianarayanane, Achuthan; O'Shea, Robert S; Barnes, David S; McCullough, Arthur J

    2013-06-01

    Ascites usually occurs in the setting of end-stage liver disease and low serum albumin and is associated with increased mortality. However, some patients develop ascites despite normal serum albumin (NSA), when a higher portal pressure and/or enhanced renal sodium retention would be expected. This study investigated the relationship between the hepatic venous pressure gradient (HVPG) and serum albumin in ascitic patients with different etiologies of cirrhosis and mortality. Records of all patients with non-malignant ascites who underwent HVPG measurement from 2005 to 2009 were reviewed. One hundred and thirty-eight 138 patients met inclusion criteria; 18.8% had NSA. No difference in sodium excretion or diuretic use was noted in patients with and without NSA. NASH patients were more likely to have a NSA (34.2% vs 12.4%; P=0.001) as well as lower HVPG (15 vs 17.9 mmHg; P=0.009) compared to other etiologies. MELD and HVPG predicted overall survival. However, mortality did not differ by disease etiology, though NASH patients had lower CTP (7.6 vs 8.5; P<0.001) and MELD (15.6 vs 18.1; P=0.09) scores, particularly among patients who died. In patients with ascites and NSA, there were no increase in HVPG or urinary sodium retention. NASH patients with ascites had lower HVPG and a higher prevalence of NSA. They also had a higher mortality relative to MELD and CTP scores in other patients. In these patients, mechanisms other than portal and oncotic pressures and sodium retention play a role in ascites development, and increase mortality rate when complicated by low albumin. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  4. Role of adipose tissue in methionine-choline-deficient model of non-alcoholic steatohepatitis (NASH).

    PubMed

    Jha, Pooja; Knopf, Astrid; Koefeler, Harald; Mueller, Michaela; Lackner, Carolin; Hoefler, Gerald; Claudel, Thierry; Trauner, Michael

    2014-07-01

    Methionine-choline-deficient (MCD) diet is a widely used dietary model of non-alcoholic steatohepatitis (NASH) in rodents. However, the contribution of adipose tissue to MCD-induced steatosis, and inflammation as features of NASH are not fully understood. The goal of this study was to elucidate the role of adipose tissue fatty acid (FA) metabolism, adipogenesis, lipolysis, inflammation and subsequent changes in FA profiles in serum and liver in the pathogenesis of steatohepatitis. We therefore fed ob/ob mice with control or MCD diet for 5 weeks. MCD-feeding increased adipose triglyceride lipase and hormone sensitive lipase activities in all adipose depots which may be attributed to increased systemic FGF21 levels. The highest lipase enzyme activity was exhibited by visceral WAT. Non-esterified fatty acid (NEFA)-18:2n6 was the predominantly elevated FA species in serum and liver of MCD-fed ob/ob mice, while overall serum total fatty acid (TFA) composition was reduced. In contrast, an overall increase of all FA species from TFA pool was found in liver, reflecting the combined effects of increased FA flux to liver, decreased FA oxidation and decrease in lipase activity in liver. NAFLD activity score was increased in liver, while WAT showed no changes and BAT showed even reduced inflammation. This study demonstrates a key role for adipose tissue lipases in the pathogenesis of NASH and provides a comprehensive lipidomic profiling of NEFA and TFA homeostasis in serum and liver. Our findings provide novel mechanistic insights for the role of WAT in progression of MCD-induced liver injury. Copyright © 2014. Published by Elsevier B.V.

  5. Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPAR{alpha} with clofibrate

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Donthamsetty, Shashikiran; Bhave, Vishakha S.; Mitra, Mayurranjan S.

    2008-08-01

    The objective was to investigate if the hepatotoxic sensitivity in nonalcoholic steatohepatitic mice to acetaminophen (APAP) is due to downregulation of nuclear receptor PPAR{alpha} via lower cell division and tissue repair. Male Swiss Webster mice fed methionine and choline deficient diet for 31 days exhibited NASH. On the 32nd day, a marginally toxic dose of APAP (360 mg/kg, ip) yielded 70% mortality in steatohepatitic mice, while all non steatohepatitic mice receiving the same dose survived. {sup 14}C-APAP covalent binding, CYP2E1 protein, and enzyme activity did not differ from the controls, obviating increased APAP bioactivation as the cause of amplified APAPmore » hepatotoxicity. Liver injury progressed only in steatohepatitic livers between 6 and 24 h. Cell division and tissue repair assessed by {sup 3}H-thymidine incorporation and PCNA were inhibited only in the steatohepatitic mice given APAP suggesting that higher sensitivity of NASH liver to APAP-induced hepatotoxicity was due to lower tissue repair. The hypothesis that impeded liver tissue repair in steatohepatitic mice was due to downregulation of PPAR{alpha} was tested. PPAR{alpha} was downregulated in NASH. To investigate whether downregulation of PPAR{alpha} in NASH is the critical mechanism of compromised liver tissue repair, PPAR{alpha} was induced in steatohepatitic mice with clofibrate (250 mg/kg for 3 days, ip) before injecting APAP. All clofibrate pretreated steatohepatitic mice receiving APAP exhibited lower liver injury, which did not progress and the mice survived. The protection was not due to lower bioactivation of APAP but due to higher liver tissue repair. These findings suggest that inadequate PPAR{alpha} expression in steatohepatitic mice sensitizes them to APAP hepatotoxicity.« less

  6. Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice.

    PubMed

    Honda, Takashi; Ishigami, Masatoshi; Luo, Fangqiong; Lingyun, Ma; Ishizu, Yoji; Kuzuya, Teiji; Hayashi, Kazuhiko; Nakano, Isao; Ishikawa, Tetsuya; Feng, Guo-Gang; Katano, Yoshiaki; Kohama, Tomoya; Kitaura, Yasuyuki; Shimomura, Yoshiharu; Goto, Hidemi; Hirooka, Yoshiki

    2017-04-01

    For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (P<0.05). Moreover, hepatic total and free cholesterol of CDHF-BCAA was significantly lower than those of CDHF-control. BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Induction of steatohepatitis (NASH) with insulin resistance in wildtype B6 mice by a western-type diet containing soybean oil and cholesterol.

    PubMed

    Henkel, Janin; Coleman, Charles Dominic; Schraplau, Anne; Jӧhrens, Korinna; Weber, Daniela; Castro, José Pedro; Hugo, Martin; Schulz, Tim Julius; Krämer, Stephanie; Schürmann, Annette; Püschel, Gerhard Paul

    2017-03-21

    Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g. high-fat diets) or overweight and insulin resistance (e.g. methionine-choline-deficient diets) or they are based on monogenetic defects (e.g. ob/ob mice). In the current study, a western-type diet containing soybean oil with high n 6-PUFA and 0.75% cholesterol (SOD+Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast a soybean oil-containing western-type diet without cholesterol (SOD) induced only mild steatosis but neither hepatic inflammation nor fibrosis, weight gain or insulin resistance. Another high-fat diet mainly consisting of lard and supplemented with fructose in drinking water (LAD+Fru) resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD+Cho but livers were devoid of inflammation and fibrosis. Although both LAD+Fru- and SOD+Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD+Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. Summarizing, dietary cholesterol in SOD+Cho diet may trigger hepatic inflammation and fibrosis. SOD+Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.

  8. 75 FR 41518 - Match-E-Be-Nash-She-Wish (Gun Lake) Tribe Liquor Control Ordinance

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-16

    ... ethyl alcohol, hydrated oxide of ethyl, or spirit of wine, commonly produced by the fermentation or... benefit of the Tribe. (j) ``Tribe'' means the Match-E-Be-Nash-She-Wish Band of Pottawatomi Indians of... and wine shall be purchased from distributors licensed by the Michigan Liquor Control Commission. (f...

  9. Navigable networks as Nash equilibria of navigation games.

    PubMed

    Gulyás, András; Bíró, József J; Kőrösi, Attila; Rétvári, Gábor; Krioukov, Dmitri

    2015-07-03

    Common sense suggests that networks are not random mazes of purposeless connections, but that these connections are organized so that networks can perform their functions well. One function common to many networks is targeted transport or navigation. Here, using game theory, we show that minimalistic networks designed to maximize the navigation efficiency at minimal cost share basic structural properties with real networks. These idealistic networks are Nash equilibria of a network construction game whose purpose is to find an optimal trade-off between the network cost and navigability. We show that these skeletons are present in the Internet, metabolic, English word, US airport, Hungarian road networks, and in a structural network of the human brain. The knowledge of these skeletons allows one to identify the minimal number of edges, by altering which one can efficiently improve or paralyse navigation in the network.

  10. Navigable networks as Nash equilibria of navigation games

    PubMed Central

    Gulyás, András; Bíró, József J.; Kőrösi, Attila; Rétvári, Gábor; Krioukov, Dmitri

    2015-01-01

    Common sense suggests that networks are not random mazes of purposeless connections, but that these connections are organized so that networks can perform their functions well. One function common to many networks is targeted transport or navigation. Here, using game theory, we show that minimalistic networks designed to maximize the navigation efficiency at minimal cost share basic structural properties with real networks. These idealistic networks are Nash equilibria of a network construction game whose purpose is to find an optimal trade-off between the network cost and navigability. We show that these skeletons are present in the Internet, metabolic, English word, US airport, Hungarian road networks, and in a structural network of the human brain. The knowledge of these skeletons allows one to identify the minimal number of edges, by altering which one can efficiently improve or paralyse navigation in the network. PMID:26138277

  11. Genetic Predisposition in NAFLD and NASH: Impact on Severity of Liver Disease and Response to Treatment

    PubMed Central

    Dongiovanni, Paola; Anstee, Quentin M; Valenti, Luca

    2013-01-01

    Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome. PMID:23394097

  12. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial.

    PubMed

    Argo, Curtis K; Patrie, James T; Lackner, Carolin; Henry, Thomas D; de Lange, Eduard E; Weltman, Arthur L; Shah, Neeral L; Al-Osaimi, Abdullah M; Pramoonjago, Patcharin; Jayakumar, Saumya; Binder, Lukas P; Simmons-Egolf, Winsor D; Burks, Sandra G; Bao, Yongde; Taylor, Ann Gill; Rodriguez, Jessica; Caldwell, Stephen H

    2015-01-01

    This study's aim was to assess the histological and metabolic effects of n-3 polyunsaturated fatty acids (PUFAs) vs. placebo while adjusting for the impact of age and weight change in NASH patients. (ClinicalTrials.gov: NCT00681408). Forty-one subjects with non-cirrhotic NASH were enrolled, and 34 completed the study. 17 received n-3 fish oil 3000 mg/day and 17 received placebo daily for 1 year with typical counselling on caloric intake and physical activity for all subjects. N-3- and placebo-treated groups showed no significant difference for the primary end point of NASH activity score (NAS) reduction ⩾ 2 points without fibrosis progression after adjustment for known covariates (n-3, 4/17 (23.5%); placebo, 3/17, (17.6%), p = 0.99). Among subjects with increased or stable weight, n-3 subjects showed a larger decrease in liver fat content by MRI than placebo-treated subjects (p = 0.014 for 2nd quartile, p = 0.003 for 3rd quartile of weight change). N-3 treatment showed significant fat reduction on the paired analysis of image-assisted fat morphometry regardless of weight loss or gain. Exercise capacity remained markedly reduced in all subjects. No independent effects on markers of hepatocyte injury or insulin sensitivity indices were observed. N-3 PUFAs at 3000 mg/day for one year did not lead to an improvement in the primary outcome of histological activity in NASH patients (⩾ 2 point NAS reduction). N-3 led to reduced liver fat by multiple measures. Other metabolic effects were not seen, although no detrimental effects were apparent. Whether longer duration, higher dose, or different composition of n-3 therapy would lead to additional benefits is uncertain. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  13. Modulatory role of Co-enzyme Q10 on methionine and choline deficient diet-induced non-alcoholic steatohepatitis (NASH) in albino rats.

    PubMed

    Saleh, Dalia O; Ahmed, Rania F; Amin, Mohamed M

    2017-03-01

    The present study aimed to evaluate the hepato-protective and neuro-protective activity of Co-enzyme Q10 (CoQ10) on non-alcoholic steatohepatitis (NASH) in albino rats induced by methionine and choline-deficient (MCD) diet. Rats were fed an MCD diet for 8 weeks to induce non-alcoholic steatohepatitis. CoQ10 (10 mg/(kg·day) -1 ) was orally administered for 2 consecutive weeks. Twenty-four hours after the last dose of the drug, the behavioral test, namely the activity cage test, was performed and the activity counts were recorded. Serum alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, total/direct bilirubin, and albumin were valued to assess liver function. Moreover, hepatic cytokines interleukin-6 as well as its modulator nuclear factor kappa-light-chain-enhancer of activated B cells were determined. In addition, brain biomarkers, viz ammonia, nitric oxide, and brain-derived neurotrophic factor (BDNF), were measured as they are reliable indices to assess brain damage. Histopathological and immunohistochemical examination of brain proliferating cell nuclear antigen in brain and liver tissues were also evaluated. Results revealed that MCD-induced NASH showed impairment in the liver functions with an increase in the liver inflammatory markers. Moreover, NASH resulted in pronounced brain dysfunction as evidenced by hyper-locomotor activity, a decrease in the BDNF level, as well as an increase in the brain nitric oxide and ammonia contents. Oral treatment of MCD-diet-fed rats with CoQ10 for 14 days showed a marked improvement in all the assigned parameters. Finally, it can be concluded that CoQ10 has a hepatoprotective and neuroprotective role in MCD-diet-induced NASH in rats.

  14. Iterative algorithms for computing the feedback Nash equilibrium point for positive systems

    NASA Astrophysics Data System (ADS)

    Ivanov, I.; Imsland, Lars; Bogdanova, B.

    2017-03-01

    The paper studies N-player linear quadratic differential games on an infinite time horizon with deterministic feedback information structure. It introduces two iterative methods (the Newton method as well as its accelerated modification) in order to compute the stabilising solution of a set of generalised algebraic Riccati equations. The latter is related to the Nash equilibrium point of the considered game model. Moreover, we derive the sufficient conditions for convergence of the proposed methods. Finally, we discuss two numerical examples so as to illustrate the performance of both of the algorithms.

  15. Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype.

    PubMed

    Farrell, Geoffrey C; Mridha, Auvro R; Yeh, Matthew M; Arsov, Todor; Van Rooyen, Derrick M; Brooling, John; Nguyen, Tori; Heydet, Deborah; Delghingaro-Augusto, Viviane; Nolan, Christopher J; Shackel, Nicholas A; McLennan, Susan V; Teoh, Narci C; Larter, Claire Z

    2014-08-01

    Obese Alms1 mutant (foz/foz) NOD.B10 mice develop diabetes and fibrotic NASH when fed high-fat(HF) diet. To establish whether diabetes or obesity is more closely associated with NASH fibrosis, we compared diabetic foz/foz C57BL6/J with non-diabetic foz/foz BALB/c mice. We also determined hepatic cytokines, growth factors and related profibrotic pathways. Male and female foz/foz BALB/c and C57BL6/J mice were fed HF or chow for 24 weeks before determining metabolic indices, liver injury, cytokines, growth factors, pathology/fibrosis and matrix deposition pathways. All foz/foz mice were obese. Hepatomegaly, hyperinsulinemia, hyperglycaemia and hypoadiponectinaemia occurred only in foz/foz C57BL6/J mice, whereas foz/foz BALB/c formed more adipose. Serum ALT, steatosis, ballooning, liver inflammation and NAFLD activity score were worse in C57BL6/J mice. In HF-fed mice, fibrosis was severe in foz/foz C57BL6/J, appreciable in WT C57BL6/J, but absent in foz/foz BALB/c mice. Hepatic mRNA expression of TNF-α, IL-12, IL-4, IL-10 was increased (but not IFN-γ, IL-1β, IL-17A), and IL-4:IFN-γ ratio (indicating Th-2 predominance) was higher in HF-fed foz/foz C57BL6/J than BALB/c mice. In livers of HF-fed foz/foz C57BL6/J mice, TGF-β was unaltered but PDGFα and CTGF were increased in association with enhanced α-SMA, CD147and MMP activity. In mice with equivalent genetic/dietary obesity, NASH development is linked to strain differences in hyperinsulinaemia and hyperglycaemia inversely related to lipid partitioning between adipose and liver. Diabetes-mediated CTGF-regulation of MMPs as well as cytokines/growth factors (Th-2 cytokine predominant, PDGFα, not TGF-β) mobilized in the resultant hepatic necroinflammatory change may contribute to strain differences in NASH fibrosis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice.

    PubMed

    Jung, Kwang Hwa; Yoo, Wonbeak; Stevenson, Heather L; Deshpande, Dipti; Shen, Hong; Gagea, Mihai; Yoo, Suk-Young; Wang, Jing; Eckols, T Kris; Bharadwaj, Uddalak; Tweardy, David J; Beretta, Laura

    2017-09-15

    Purpose: The incidence of hepatocellular carcinoma is increasing in the United States, and liver cancer is the second leading cause of cancer-related mortality worldwide. Nonalcoholic steatohepatitis (NASH) is becoming an important risk for hepatocellular carcinoma, and most patients with hepatocellular carcinoma have underlying liver cirrhosis and compromised liver function, which limit treatment options. Thus, novel therapeutic strategies to prevent or treat hepatocellular carcinoma in the context of NASH and cirrhosis are urgently needed. Experimental Design: Constitutive activation of STAT3 is frequently detected in hepatocellular carcinoma tumors. STAT3 signaling plays a pivotal role in hepatocellular carcinoma survival, growth, angiogenesis, and metastasis. We identified C188-9, a novel small-molecule STAT3 inhibitor using computer-aided rational drug design. In this study, we evaluated the therapeutic potential of C188-9 for hepatocellular carcinoma treatment and prevention. Results: C188-9 showed antitumor activity in vitro in three hepatocellular carcinoma cell lines. In mice with hepatocyte-specific deletion of Pten (Hep Pten - mice), C188-9 treatment blocked hepatocellular carcinoma tumor growth, reduced tumor development, and reduced liver steatosis, inflammation, and bile ductular reactions, resulting in improvement of the pathological lesions of NASH. Remarkably, C188-9 also greatly reduced liver injury in these mice as measured by serum aspartate aminotransferase and alanine transaminase levels. Analysis of gene expression showed that C188-9 treatment of Hep Pten - mice resulted in inhibition of signaling pathways downstream of STAT3, STAT1, TREM-1, and Toll-like receptors. In contrast, C188-9 treatment increased liver specification and differentiation gene pathways. Conclusions: Our results suggest that C188-9 should be evaluated further for the treatment and/or prevention of hepatocellular carcinoma. Clin Cancer Res; 23(18); 5537-46. ©2017 AACR

  17. Midkine Increases Diagnostic Yield in AFP Negative and NASH-Related Hepatocellular Carcinoma

    PubMed Central

    Vongsuvanh, Roslyn; van der Poorten, David; Iseli, Tristan; Strasser, Simone I.; McCaughan, Geoffrey W.; George, Jacob

    2016-01-01

    Robust biomarkers for population-level hepatocellular carcinoma (HCC) surveillance are lacking. We compared serum midkine (MDK), dickkopf-1 (DKK1), osteopontin (OPN) and AFP for HCC diagnosis in 86 HCC patients matched to 86 cirrhotics, 86 with chronic liver disease (CLD) and 86 healthy controls (HC). Based on the performance of each biomarker, we assessed a separate longitudinal cohort of 28 HCC patients, at and before cancer diagnosis. Serum levels of MDK and OPN were higher in HCC patients compared to cirrhosis, CLD and HC groups. DKK1 was not different between cases and controls. More than half of HCC patients had normal AFP. In this AFP-negative HCC cohort, 59.18% (n = 29/49) had elevated MDK, applying the optimal cut-off of 0.44 ng/ml. Using AFP ≥ 20 IU/ml or MDK ≥ 0.44 ng/ml, a significantly greater number (76.7%; n = 66/86) of HCC cases were detected. The area under the receiver operating curve for MDK was superior to AFP and OPN in NASH-HCC diagnosis. In the longitudinal cohort, MDK was elevated in 15/28 (54%) of HCC patients at diagnosis, of whom 67% had elevated MDK 6 months prior. Conclusion: AFP and MDK have a complementary role in HCC detection. MDK increases the diagnostic yield in AFP-negative HCC and has greater diagnostic performance than AFP, OPN and DKK-1 in the diagnosis of NASH-HCC. Additionally, MDK has a promising role in the pre-clinical diagnosis of HCC. PMID:27219517

  18. High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine

    USDA-ARS?s Scientific Manuscript database

    Pediatric obesity and nonalcoholic steatohepatitis (NASH) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal models. Here, we examined the effects of high-fat, high-fructose corn syrup, high-cho...

  19. Spontaneous Time Symmetry Breaking in System with Mixed Strategy Nash Equilibrium: Evidences in Experimental Economics Data

    NASA Astrophysics Data System (ADS)

    Wang, Zhijian; Xu, Bin; Zhejiang Collaboration

    2011-03-01

    In social science, laboratory experiment with human subjects' interaction is a standard test-bed for studying social processes in micro level. Usually, as in physics, the processes near equilibrium are suggested as stochastic processes with time-reversal symmetry (TRS). To the best of our knowledge, near equilibrium, the breaking time symmetry, as well as the existence of robust time anti-symmetry processes, has not been reported clearly in experimental economics till now. By employing Markov transition method to analysis the data from human subject 2x2 Games with wide parameters and mixed Nash equilibrium, we study the time symmetry of the social interaction process near Nash equilibrium. We find that, the time symmetry is broken, and there exists a robust time anti-symmetry processes. We also report the weight of the time anti-symmetry processes in the total processes of each the games. Evidences in laboratory marketing experiments, at the same time, are provided as one-dimension cases. In these cases, time anti-symmetry cycles can also be captured. The proposition of time anti-symmetry processes is small, but the cycles are distinguishable.

  20. Quantitative imaging of fibrotic and morphological changes in liver of non-alcoholic steatohepatitis (NASH) model mice by second harmonic generation (SHG) and auto-fluorescence (AF) imaging using two-photon excitation microscopy (TPEM).

    PubMed

    Yamamoto, Shin; Oshima, Yusuke; Saitou, Takashi; Watanabe, Takao; Miyake, Teruki; Yoshida, Osamu; Tokumoto, Yoshio; Abe, Masanori; Matsuura, Bunzo; Hiasa, Yoichi; Imamura, Takeshi

    2016-12-01

    Non-alcoholic steatohepatitis (NASH) is a common liver disorder caused by fatty liver. Because NASH is associated with fibrotic and morphological changes in liver tissue, a direct imaging technique is required for accurate staging of liver tissue. For this purpose, in this study we took advantage of two label-free optical imaging techniques, second harmonic generation (SHG) and auto-fluorescence (AF), using two-photon excitation microscopy (TPEM). Three-dimensional ex vivo imaging of tissues from NASH model mice, followed by image processing, revealed that SHG and AF are sufficient to quantitatively characterize the hepatic capsule at an early stage and parenchymal morphologies associated with liver disease progression, respectively.

  1. Mixed-strategy Nash equilibrium for a discontinuous symmetric N-player game

    NASA Astrophysics Data System (ADS)

    Hilhorst, H. J.; Appert-Rolland, C.

    2018-03-01

    We consider a game in which each player must find a compromise between more daring strategies that carry a high risk for him to be eliminated, and more cautious ones that, however, reduce his final score. For two symmetric players this game was originally formulated in 1961 by Dresher, who modeled a duel between two opponents. The game has also been of interest in the description of athletic competitions. We extend here the two-player game to an arbitrary number N of symmetric players. We show that there is a mixed-strategy Nash equilibrium and find its exact analytic expression, which we analyze in particular in the limit of large N, where mean-field behavior occurs. The original game with N  =  2 arises as a singular limit of the general case.

  2. The Mathematics of Aggregation, Interdependence, Organizations and Systems of Nash Equilibria (NE): A Replacement for Game Theory

    DTIC Science & Technology

    2011-06-01

    there a free-market economist in the House?, American Journal of Economics and Sociology, 66(2): 309-334. Jasny, B. R., Zahn, L.M., & Marshall, E...1   The Mathematics of Aggregation, Interdependence, Organizations and Systems of Nash equilibria (NE): A replacement for Game Theory...level data to group, organization and systems levels, making it one of social science’s biggest challenges, if not the most important (Giles, 2011). For

  3. CHIP−/−-Mouse Liver: Adiponectin-AMPK-FOXO-Activation Overrides CYP2E1-Elicited JNK1-Activation, Delaying Onset of NASH: Therapeutic Implications

    PubMed Central

    Kim, Sung-Mi; Grenert, James P.; Patterson, Cam; Correia, Maria Almira

    2016-01-01

    Genetic ablation of C-terminus of Hsc70-interacting protein (CHIP) E3 ubiquitin-ligase impairs hepatic cytochrome P450 CYP2E1 degradation. Consequent CYP2E1 gain of function accelerates reactive O2 species (ROS) production, triggering oxidative/proteotoxic stress associated with sustained activation of c-Jun NH2-terminal kinase (JNK)-signaling cascades, pro-inflammatory effectors/cytokines, insulin resistance, progressive hepatocellular ballooning and microvesicular steatosis. Despite this, little evidence of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) was found in CHIP−/−-mice over the first 8–9-months of life. We herein document that this lack of tissue injury is largely due to the concurrent up-regulation and/or activation of the adiponectin-5′-AMP-activated protein kinase (AMPK)-forkhead box O (FOXO)-signaling axis stemming from at the least three synergistic features: Up-regulated expression of adipose tissue adiponectin and its hepatic adipoR1/adipoR2 receptors, stabilization of hepatic AMPKα1-isoform, identified herein for the first time as a CHIP-ubiquitination substrate (unlike its AMPKα2-isoform), as well as nuclear stabilization of FOXOs, well-known CHIP-ubiquitination targets. Such beneficial predominance of the adiponectin-AMPK-FOXO-signaling axis over the sustained JNK-elevation and injurious insulin resistance in CHIP−/−-livers apparently counteracts/delays rapid progression of the hepatic microvesicular steatosis to the characteristic macrovesicular steatosis observed in clinical NASH and/or rodent NASH-models. PMID:27406999

  4. Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice.

    PubMed

    Du, Xianhong; Wu, Zhuanchang; Xu, Yong; Liu, Yuan; Liu, Wen; Wang, Tixiao; Li, Chunyang; Zhang, Cuijuan; Yi, Fan; Gao, Lifen; Liang, Xiaohong; Ma, Chunhong

    2018-05-07

    As an immune checkpoint, Tim-3 plays roles in the regulation of both adaptive and innate immune cells including macrophages and is greatly involved in chronic liver diseases. However, the precise roles of Tim-3 in nonalcoholic steatohepatitis (NASH) remain unstated. In the current study, we analyzed Tim-3 expression on different subpopulations of liver macrophages and further investigated the potential roles of Tim-3 on hepatic macrophages in methionine and choline-deficient diet (MCD)-induced NASH mice. The results of flow cytometry demonstrated the significantly increased expression of Tim-3 on all detected liver macrophage subsets in MCD mice, including F4/80 + CD11b + , F4/80 + CD68 + , and F4/80 + CD169 + macrophages. Remarkably, Tim-3 knockout (KO) significantly accelerated MCD-induced liver steatosis, displaying higher serum ALT, larger hepatic vacuolation, more liver lipid deposition, and more severe liver fibrosis. Moreover, compared with wild-type C57BL/6 mice, Tim-3 KO MCD mice demonstrated an enhanced expression of NOX2, NLRP3, and caspase-1 p20 together with increased generation of IL-1β and IL-18 in livers. In vitro studies demonstrated that Tim-3 negatively regulated the production of reactive oxygen species (ROS) and related downstream pro-inflammatory cytokine secretion of IL-1β and IL-18 in macrophages. Exogenous administration of N-Acetyl-L-cysteine (NAC), a small molecular inhibitor of ROS, remarkably suppressed caspase-1 p20 expression and IL-1β and IL-18 production in livers of Tim-3 KO mice, thus significantly reducing the severity of steatohepatitis induced by MCD. In conclusion, Tim-3 is a promising protector in MCD-induced steatohepatitis by controlling ROS and the associated pro-inflammatory cytokine production in macrophages.

  5. Development, Testing, and Psychometric Qualities of the Nash Duty to Care Scale for Disaster Response.

    PubMed

    Nash, Tracy Jeanne

    2017-08-01

    Although nurses struggle with the decision to report for work during disaster events, there are no instruments to measure nurses' duty to care for disaster situations. The purpose of this study was to describe the development, testing, and psychometric qualities of the Nash Duty to Care Scale. A convenience sample of 409 registered nurses were recruited from 3 universities in the United States. Exploratory factor analysis resulted in a 19-item, 4-factor model explaining 67.34% of the variance. Internal consistency reliability was supported by Cronbach's alpha ranging from .81 to .91 for the 4-factor subscales and .92 for the total scale. The psychometrically sound instrument for measuring nurses' perceived duty to care for disasters is applicable to contemporary nursing practice, institutional disaster management plans, and patient health outcomes worldwide.

  6. Strategic trade between two regions with partial local consumer protection - General setup and nash equilibria

    NASA Astrophysics Data System (ADS)

    Iordanov, Iordan V.; Vassilev, Andrey A.

    2017-12-01

    We construct a model of the trade relations between two regions for the case when the trading entities (consumers) compete for a scarce good and there is an element of strategic interdependence in the trading process. Additionally, local consumers enjoy partial protection in the form of guaranteed access to a part of the locally-supplied quantity of the good. The model is formulated for the general asymmetric case, where the two regions differ in terms of parameters such as income, size of the local market supply, degree of protection and transportation costs. For this general model we establish the existence of Nash equilibria and obtain their form as a function of the model parameters, producing a typology of the equilibria. This is a required step in order to rigorously study various types of price dynamics for the model.

  7. The Effect of Metformin and Standard Therapy Versus Standard Therapy Alone in Nondiabetic Patients with Insulin Resistance and Nonalcoholic Steatohepatitis (NASH): A Pilot Trial

    DTIC Science & Technology

    2009-01-01

    histology in nondiabetic patients with insulin resistance and NASH. Decrease in BMI through diet and exercise significantly improved HOMA - IR scores, serum...BMI through diet and exercise significantly improved HOMA - IR scores, serum aminotransferases and liver histology. 15. SUBJECT TERMS 16. SECURITY...insulin resistance (or HOMA - IR ) score was calculated using the formula: fasting insulin (mIU/ml) fasting glu- cose (mg/dl)/405 [Matthews et al. 1985

  8. From rationality to cooperativeness: The totally mixed Nash equilibrium in Markov strategies in the iterated Prisoner's Dilemma.

    PubMed

    Menshikov, Ivan S; Shklover, Alexsandr V; Babkina, Tatiana S; Myagkov, Mikhail G

    2017-01-01

    In this research, the social behavior of the participants in a Prisoner's Dilemma laboratory game is explained on the basis of the quantal response equilibrium concept and the representation of the game in Markov strategies. In previous research, we demonstrated that social interaction during the experiment has a positive influence on cooperation, trust, and gratefulness. This research shows that the quantal response equilibrium concept agrees only with the results of experiments on cooperation in Prisoner's Dilemma prior to social interaction. However, quantal response equilibrium does not explain of participants' behavior after social interaction. As an alternative theoretical approach, an examination was conducted of iterated Prisoner's Dilemma game in Markov strategies. We built a totally mixed Nash equilibrium in this game; the equilibrium agrees with the results of the experiments both before and after social interaction.

  9. MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice

    PubMed Central

    Dulai, Parambir S.; Sirlin, Claude B.; Loomba, Rohit

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents one of the most common causes of chronic liver disease, and its prevalence is rising worldwide. The occurrence of nonalcoholic steatohepatitis (NASH) is associated with a substantial increase in disease related morbidity and mortality. Accordingly, there has been a surge of innovation surrounding drug development in an effort to off-set the natural progression and long-term risks of this disease. Disease assessment within clinical trials and clinical practice for NAFLD is currently done with liver biopsies. Liver biopsy-based assessments, however, remain imprecise and are not without cost or risk. This carries significant implications for the feasibility and costs of bringing therapeutic interventions to market. A need therefore arises for reliable and highly accurate surrogate end-points that can be used in phase 2 and 3 clinical trials to reduce trial size requirements and costs, while improving feasibility and ease of implementation in clinical practice. Significant advances have now been made in magnetic resonance technology, and magnetic resonance imaging (MRI) and elastrography (MRE) have been demonstrated to be highly accurate diagnostic tools for the detection of hepatic steatosis and fibrosis. In this review article, we will summarize the currently available evidence regarding the use of MRI and MRE among NAFLD patients, and the evolving role these surrogate biomarkers will play in the rapidly advancing arena of clinical trials in NASH and hepatic fibrosis. Furthermore, we will highlight how these tools can be readily applied to routine clinical practice, where the growing burden of NAFLD will need to be met with enhanced monitoring algorithms. PMID:27312947

  10. On the Fair Division of Multiple Stochastic Pies to Multiple Agents within the Nash Bargaining Solution

    PubMed Central

    Karmperis, Athanasios C.; Aravossis, Konstantinos; Tatsiopoulos, Ilias P.; Sotirchos, Anastasios

    2012-01-01

    The fair division of a surplus is one of the most widely examined problems. This paper focuses on bargaining problems with fixed disagreement payoffs where risk-neutral agents have reached an agreement that is the Nash-bargaining solution (NBS). We consider a stochastic environment, in which the overall return consists of multiple pies with uncertain sizes and we examine how these pies can be allocated with fairness among agents. Specifically, fairness is based on the Aristotle’s maxim: “equals should be treated equally and unequals unequally, in proportion to the relevant inequality”. In this context, fairness is achieved when all the individual stochastic surplus shares which are allocated to agents are distributed in proportion to the NBS. We introduce a novel algorithm, which can be used to compute the ratio of each pie that should be allocated to each agent, in order to ensure fairness within a symmetric or asymmetric NBS. PMID:23024752

  11. A Bidding Methodology by Nash Equilibrium for Finite Generators Participating in Imperfect Electricity Markets

    NASA Astrophysics Data System (ADS)

    Satyaramesh, P. V.

    2014-01-01

    This paper presents an application of finite n-person non-cooperative game theory for analyzing bidding strategies of generators in a deregulated energy marketplace with Pool Bilateral contracts so as to maximize their net profits. A new methodology to build bidding methodology for generators participating in oligopoly electricity market has been proposed in this paper. It is assumed that each generator bids a supply function. This methodology finds out the coefficients in the supply function of generators in order to maximize benefits in an environment of competing rival bidders. A natural choice for developing strategies is Nash Equilibrium (NE) model incorporating mixed strategies, for solving the bidding problem of electrical market. Associated optimal profits are evaluated for a combination of set of pure strategies of bidding of generators, and payoff matrix has been constructed. The optimal payoff is calculated by using NE. An attempt has also been made to minimize the gap between the optimal payoff and the payoff obtained by a possible mixed strategies combination. The algorithm is coded in MATLAB. A numerical example is used to illustrate the essential features of the approach and the results are proved to be the optimal values.

  12. Gd-EOB-DTPA-enhanced-MR imaging in the inflammation stage of nonalcoholic steatohepatitis (NASH) in mice.

    PubMed

    Yamada, Tomomi; Obata, Atsushi; Kashiwagi, Yuto; Rokugawa, Takemi; Matsushima, Shuuichi; Hamada, Tadateru; Watabe, Hiroshi; Abe, Kohji

    2016-07-01

    The purpose of this study is to investigate the correlation between the liver kinetics of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) and liver histopathology in a mouse model of NASH by using dynamic contrast-enhanced MRI. Twenty male C57/BL6 mice aged 8weeks were fed a methionine-choline-deficient (MCD) diet for 2, 4 and 6weeks (MCD groups: MCD 2w, 4w, or 6w). Gd-EOB-DTPA-enhanced MR imaging of the liver was performed at 2, 4 and 6weeks after the MCD feeding. The signal intensity of the liver was obtained from dynamic MR images and relative enhancement (RE), and the time to maximum RE (Tmax) and half-life of elimination RE (T1/2) were calculated. After MRI scan, histopathological scores of hepatic steatosis and inflammation and blood biochemistry data, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were obtained. Plasma AST and ALT levels were significantly increased in mice fed MCD. Histopathological scores indicated that steatohepatitis progressed with the MCD feeding period from 2 to 6weeks, but significant fibrosis was observed only in mice fed MCD for 6weeks. Gd-EOB-DTPA-enhanced MRI showed that Tmax was significantly prolonged in the livers of the 6-week group compared to the control group (control, 4.0±0.7min; MCD 6w, 12.1±1.6min), although there was no alteration in the 2- and 4-week groups. T1/2 was significantly prolonged in mice fed MCD for 4 and 6weeks compared to the control group (control, 19.9±2.0min; MCD 4w, 46.7±8.7min; MCD 6w, 65.4±8.8min). The parameters of Gd-EOB-DTPA kinetics (Tmax and T1/2) in the liver were positively correlated with the liver histopathological score (steatosis vs Tmax, rho=0.69, P=0.0007; inflammation vs Tmax, rho=0.66, P=0.00155; steatosis vs T1/2, rho=0.77, P<0.0001; inflammation vs T1/2, rho=0.73, P=0.0003). The liver kinetics of Gd-EOB-DTPA correlated well with the inflammation score in the mouse model of NASH, suggesting the possibility of

  13. From rationality to cooperativeness: The totally mixed Nash equilibrium in Markov strategies in the iterated Prisoner’s Dilemma

    PubMed Central

    Myagkov, Mikhail G.

    2017-01-01

    In this research, the social behavior of the participants in a Prisoner's Dilemma laboratory game is explained on the basis of the quantal response equilibrium concept and the representation of the game in Markov strategies. In previous research, we demonstrated that social interaction during the experiment has a positive influence on cooperation, trust, and gratefulness. This research shows that the quantal response equilibrium concept agrees only with the results of experiments on cooperation in Prisoner’s Dilemma prior to social interaction. However, quantal response equilibrium does not explain of participants’ behavior after social interaction. As an alternative theoretical approach, an examination was conducted of iterated Prisoner's Dilemma game in Markov strategies. We built a totally mixed Nash equilibrium in this game; the equilibrium agrees with the results of the experiments both before and after social interaction. PMID:29190280

  14. Evolution of wealth in a non-conservative economy driven by local Nash equilibria.

    PubMed

    Degond, Pierre; Liu, Jian-Guo; Ringhofer, Christian

    2014-11-13

    We develop a model for the evolution of wealth in a non-conservative economic environment, extending a theory developed in Degond et al. (2014 J. Stat. Phys. 154, 751-780 (doi:10.1007/s10955-013-0888-4)). The model considers a system of rational agents interacting in a game-theoretical framework. This evolution drives the dynamics of the agents in both wealth and economic configuration variables. The cost function is chosen to represent a risk-averse strategy of each agent. That is, the agent is more likely to interact with the market, the more predictable the market, and therefore the smaller its individual risk. This yields a kinetic equation for an effective single particle agent density with a Nash equilibrium serving as the local thermodynamic equilibrium. We consider a regime of scale separation where the large-scale dynamics is given by a hydrodynamic closure with this local equilibrium. A class of generalized collision invariants is developed to overcome the difficulty of the non-conservative property in the hydrodynamic closure derivation of the large-scale dynamics for the evolution of wealth distribution. The result is a system of gas dynamics-type equations for the density and average wealth of the agents on large scales. We recover the inverse Gamma distribution, which has been previously considered in the literature, as a local equilibrium for particular choices of the cost function. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  15. Nash points, Ky Fan inequality and equilibria of abstract economies in Max-Plus and -convexity

    NASA Astrophysics Data System (ADS)

    Briec, Walter; Horvath, Charles

    2008-05-01

    -convexity was introduced in [W. Briec, C. Horvath, -convexity, Optimization 53 (2004) 103-127]. Separation and Hahn-Banach like theorems can be found in [G. Adilov, A.M. Rubinov, -convex sets and functions, Numer. Funct. Anal. Optim. 27 (2006) 237-257] and [W. Briec, C.D. Horvath, A. Rubinov, Separation in -convexity, Pacific J. Optim. 1 (2005) 13-30]. We show here that all the basic results related to fixed point theorems are available in -convexity. Ky Fan inequality, existence of Nash equilibria and existence of equilibria for abstract economies are established in the framework of -convexity. Monotone analysis, or analysis on Maslov semimodules [V.N. Kolokoltsov, V.P. Maslov, Idempotent Analysis and Its Applications, Math. Appl., volE 401, Kluwer Academic, 1997; V.P. Litvinov, V.P. Maslov, G.B. Shpitz, Idempotent functional analysis: An algebraic approach, Math. Notes 69 (2001) 696-729; V.P. Maslov, S.N. Samborski (Eds.), Idempotent Analysis, Advances in Soviet Mathematics, Amer. Math. Soc., Providence, RI, 1992], is the natural framework for these results. From this point of view Max-Plus convexity and -convexity are isomorphic Maslov semimodules structures over isomorphic semirings. Therefore all the results of this paper hold in the context of Max-Plus convexity.

  16. Potential of vetiver (vetiveria zizanioides (L.) Nash) for phytoremediation of petroleum hydrocarbon-contaminated soils in Venezuela.

    PubMed

    Brandt, Regine; Merkl, Nicole; Schultze-Kraft, Rainer; Infante, Carmen; Broll, Gabriele

    2006-01-01

    Venezuela is one of the largest oil producers in the world. For the rehabilitation of oil-contaminated sites, phytoremediation represents a promising technology whereby plants are used to enhance biodegradation processes in soil. A greenhouse study was conducted to determine the tolerance of vetiver (Vetiveria zizanioides (L.) Nash) to a Venezuelan heavy crude oil in soil. Additionally, the plant's potential for stimulating the biodegradation processes of petroleum hydrocarbons was tested under the application of two fertilizer levels. In the presence of contaminants, biomass and plant height were significantly reduced. As for fertilization, the lower fertilizer level led to higher biomass production. The specific root surface area was reduced under the effects of petroleum. However, vetiver was found to tolerate crude-oil contamination in a concentration of 5% (w/w). Concerning total oil and grease content in soil, no significant decrease under the influence of vetiver was detected when compared to the unplanted control. Thus, there was no evidence of vetiver enhancing the biodegradation of crude oil in soil under the conditions of this trial. However, uses of vetiver grass in relation to petroleum-contaminated soils are promising for amelioration of slightly polluted sites, to allow other species to get established and for erosion control.

  17. Epilepsy management in older people: Lessons from National Audit of Seizure management in Hospitals (NASH).

    PubMed

    Ziso, B; Dixon, P A; Marson, A G

    2017-08-01

    Epilepsy is the third most common diagnosis in older people, however management in this group remains variable. National Audit of Seizure management in Hospitals (NASH) set out to assess care provided to patients attending hospitals in England following a seizure. 154 Emergency Departments (EDs) across the UK took part. 1256 patients aged 60 years or over were included for analysis (median age 74 years, 54% men). 51% were known to have epilepsy, 17% had history of previous seizure or blackout and 32% presented with a suspected first seizure. 14% of older patients with epilepsy were not on treatment, 59% were on monotherapy. Sodium valproate was the most commonly used antiepileptic, 28%. 35% of patients with epilepsy, aged 60 and over, had a CT during admission compared to only 17% of those under 60. 80% of patients aged 60 and over presenting with a likely first seizure were admitted to hospital, compared to 65% of those under 60. 34% of those with suspected first seizure were referred to a neurologist on discharge compared to 68% of patients under the age of 60. 52% of 60-69year olds with a suspected first seizure were referred to neurology compared to 25% of patients aged 80-89. Older patients presenting with seizures are more likely to be admitted to hospital and have imaging. They are less likely to be referred to specialist services on discharge. There appears to be significant disparity in patient age and rate of referral. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  18. Nash and integrated solutions in a just-in-time seller-buyer supply chain with buyer's ordering cost reductions

    NASA Astrophysics Data System (ADS)

    Lou, Kuo-Ren; Wang, Lu

    2016-05-01

    The seller frequently offers the buyer trade credit to settle the purchase amount. From the seller's prospective, granting trade credit increases not only the opportunity cost (i.e., the interest loss on the buyer's purchase amount during the credit period) but also the default risk (i.e., the rate that the buyer will be unable to pay off his/her debt obligations). On the other hand, granting trade credit increases sales volume and revenue. Consequently, trade credit is an important strategy to increase seller's profitability. In this paper, we assume that the seller uses trade credit and number of shipments in a production run as decision variables to maximise his/her profit, while the buyer determines his/her replenishment cycle time and capital investment as decision variables to reduce his/her ordering cost and achieve his/her maximum profit. We then derive non-cooperative Nash solution and cooperative integrated solution in a just-in-time inventory system, in which granting trade credit increases not only the demand but also the opportunity cost and default risk, and the relationship between the capital investment and the ordering cost reduction is logarithmic. Then, we use a software to solve and compare these two distinct solutions. Finally, we use sensitivity analysis to obtain some managerial insights.

  19. Advanced oil recovery technologies for improved recovery from slope basin clastic reservoirs, Nash Draw Brushy Canyon Pool, Eddy County, NM. Second annual technical progress report, October 1, 1996--September 30, 1997

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    NONE

    1998-09-01

    The Nash Draw Brushy Canyon Pool in Eddy County, New Mexico is a field demonstration in the US Department of Energy Class III Program. Advanced reservoir characterization techniques are being used at the Nash Draw project to develop reservoir management strategies for optimizing oil recovery from this Delaware reservoir. Analysis, interpretation, and integration of recently acquired geological, geophysical, and engineering data revealed that the initial reservoir description was too simplistic to capture the critical features of this complex formation. As a result of the analysis, a proposed pilot area was reconsidered. Comparison of seismic data and engineering data have shownmore » evidence of discontinuities in the area surrounding the proposed injector. Analysis of the 3-D seismic has shown that wells in the proposed pilot are in an area of poor quality amplitude development. The implication is that since amplitude attenuation is a function of porosity, then this is not the best area to be attempting a pilot pressure maintenance project. Because the original pilot area appears to be compartmentalized, the lateral continuity between the pilot wells could be reduced. The 3-D seismic interpretation indicates other areas may be better suited for the initial pilot area. Therefore, the current focus has shifted more to targeted drilling, and the pilot injection will be considered in a more continuous area of the NDP in the future. Results of reservoir simulation studies indicate that pressure maintenance should be started early when reservoir pressure is still high.« less

  20. Fracture propagation through a layered shale and limestone sequence at Nash Point, South Wales: Implications on the development of fracture networks in layered sequences

    NASA Astrophysics Data System (ADS)

    Forbes Inskip, N.; Meredith, P. G.; Gudmundsson, A.

    2017-12-01

    While considerable effort has been expended on the study of fracture propagation in rocks in recent years, our understanding of how fractures propagate through sedimentary rocks composed of layers with different mechanical and elastic properties remains poor. Yet the mechanical layering is a key parameter controlling the propagation of fractures in sedimentary sequences. Here we report measurements of the contrasting properties of the Lower Lias at Nash Point, South Wales, which comprises a sequence of interbedded shale and limestone layers, and how those properties influence fracture propagation. The static Young's modulus (Estat) of both rock types has been measured parallel and normal to bedding. The shale is highly anisotropic, with Estat varying from 2.4 GPa, in the bedding-normal orientation, to 7.9 GPa, in the bedding-parallel orientation, yielding an anisotropy of 107%. By contrast the limestone has a very low anisotropy of 8%, with Estat values varying from 28.5 GPa, in the bedding-normal orientation, to 26.3 GPa in the bedding-parallel orientation. It follows that for a vertical fracture propagating in this sequence the modulus contrast is by a factor of about 12. This is important because the contrast in elastic properties is a key factor in controlling whether fractures arrest, deflect, or propagate across interfaces between layers in a sequence. Preliminary numerical modelling results (using a finite element modelling software) of induced fractures at Nash Point demonstrate a rotation of the maximum principal compressive stress across interfaces but also the concentration of tensile stress within the more competent (high Estat) limestone layers. The tensile strength (σT), using the Brazil-disk technique, and fracture toughness (KIc), using the semi-circular bend methodology, of both rock types have been measured. Measurements were made in the three principal orientations relative to bedding, Arrester, Divider, and Short-Transverse, and also at 15

  1. Efficient Nash Equilibrium Resource Allocation Based on Game Theory Mechanism in Cloud Computing by Using Auction

    PubMed Central

    Nezarat, Amin; Dastghaibifard, GH

    2015-01-01

    One of the most complex issues in the cloud computing environment is the problem of resource allocation so that, on one hand, the cloud provider expects the most profitability and, on the other hand, users also expect to have the best resources at their disposal considering the budget constraints and time. In most previous work conducted, heuristic and evolutionary approaches have been used to solve this problem. Nevertheless, since the nature of this environment is based on economic methods, using such methods can decrease response time and reducing the complexity of the problem. In this paper, an auction-based method is proposed which determines the auction winner by applying game theory mechanism and holding a repetitive game with incomplete information in a non-cooperative environment. In this method, users calculate suitable price bid with their objective function during several round and repetitions and send it to the auctioneer; and the auctioneer chooses the winning player based the suggested utility function. In the proposed method, the end point of the game is the Nash equilibrium point where players are no longer inclined to alter their bid for that resource and the final bid also satisfies the auctioneer’s utility function. To prove the response space convexity, the Lagrange method is used and the proposed model is simulated in the cloudsim and the results are compared with previous work. At the end, it is concluded that this method converges to a response in a shorter time, provides the lowest service level agreement violations and the most utility to the provider. PMID:26431035

  2. Efficient Nash Equilibrium Resource Allocation Based on Game Theory Mechanism in Cloud Computing by Using Auction.

    PubMed

    Nezarat, Amin; Dastghaibifard, G H

    2015-01-01

    One of the most complex issues in the cloud computing environment is the problem of resource allocation so that, on one hand, the cloud provider expects the most profitability and, on the other hand, users also expect to have the best resources at their disposal considering the budget constraints and time. In most previous work conducted, heuristic and evolutionary approaches have been used to solve this problem. Nevertheless, since the nature of this environment is based on economic methods, using such methods can decrease response time and reducing the complexity of the problem. In this paper, an auction-based method is proposed which determines the auction winner by applying game theory mechanism and holding a repetitive game with incomplete information in a non-cooperative environment. In this method, users calculate suitable price bid with their objective function during several round and repetitions and send it to the auctioneer; and the auctioneer chooses the winning player based the suggested utility function. In the proposed method, the end point of the game is the Nash equilibrium point where players are no longer inclined to alter their bid for that resource and the final bid also satisfies the auctioneer's utility function. To prove the response space convexity, the Lagrange method is used and the proposed model is simulated in the cloudsim and the results are compared with previous work. At the end, it is concluded that this method converges to a response in a shorter time, provides the lowest service level agreement violations and the most utility to the provider.

  3. Leaf gas exchange of Andropogon gerardii Vitman, Panicum virgatum L., and Sorghastrum nutans (L.) Nash in a tallgrass prairie

    NASA Technical Reports Server (NTRS)

    Polley, H. W.; Norman, J. M.; Arkebauer, T. J.; Walter-Shea, E. A.; Greegor, D. H., Jr.; Bramer, B.

    1992-01-01

    Net CO2 assimilation as a function of internal CO2 and stomatal conductance to water vapor were measured on blades of the C4 grasses Andropogon gerardii Vitman, Panicum virgatrum L., and Sorghastrum nutans (L.) Nash in northeast Kansas over two growing seasons to determine the comparative physiological responses of these dominant grasses of the tallgrass prairie to environmental variables. The response of dark respiration to temperature and of net assimilation to CO2 concentration and absorbed quantum flux differed little among species. A. gerardii had lower potential photosynthetic rates at internal CO2 concentrations below saturation than P. virgatum and S. nutans, but net assimilation under ambient conditions was similar in the three species. Net assimilation and both the initial slope of assimilation versus internal CO2 curves and the maximum potential assimilation rate decreased as leaf water potential declined in blades of A. gerardii and S. nutans. Changes in assimilation capacity were paralleled by changes in stomatal conductance that were similar in all three species. The strong correlations among processes regulating leaf CO2 assimilation and transpiration in A. gerardii, P. virgatum, and S. nutans suggest that the processes are tightly and similarly coupled in these grasses over a wide range of environmental conditions encountered in the tallgrass prairie.

  4. Aeromagnetic Surveying with a Rotary-Wing Unmanned Aircraft System: A Case Study from a Zinc Deposit in Nash Creek, New Brunswick, Canada

    NASA Astrophysics Data System (ADS)

    Cunningham, Michael; Samson, Claire; Wood, Alan; Cook, Ian

    2017-12-01

    Unmanned aircraft systems (UASs) have been under rapid development for applications in the mineral exploration industry, mainly for aeromagnetic surveying. They provide improved detection of smaller, deeper and weaker magnetic targets. A traditional system flying an altitude of 100 m above ground level (AGL) can detect a spherical ore body with a radius of 16 m and a magnetic susceptibility of 10-4 buried at a depth of 40 m. A UAS flying at an altitude of 50 or 2 m AGL would require the radius to be 11 or 5 m, respectively. A demonstration survey was performed using the SkyLance rotary-wing UAS instrumented with a cesium vapour magnetometer in Nash Creek, New Brunswick, Canada. The UAS flew over a zinc deposit featuring three magnetic anomalies. It acquired repeatable data that compared well with upward continuation maps of ground magnetic data. Dykes or faults that are dipping eastward at 25° and are approximately 1.5 m wide fit the observed response of the three anomalies captured on the UAS magnetic data.

  5. An optimized Nash nonlinear grey Bernoulli model based on particle swarm optimization and its application in prediction for the incidence of Hepatitis B in Xinjiang, China.

    PubMed

    Zhang, Liping; Zheng, Yanling; Wang, Kai; Zhang, Xueliang; Zheng, Yujian

    2014-06-01

    In this paper, by using a particle swarm optimization algorithm to solve the optimal parameter estimation problem, an improved Nash nonlinear grey Bernoulli model termed PSO-NNGBM(1,1) is proposed. To test the forecasting performance, the optimized model is applied for forecasting the incidence of hepatitis B in Xinjiang, China. Four models, traditional GM(1,1), grey Verhulst model (GVM), original nonlinear grey Bernoulli model (NGBM(1,1)) and Holt-Winters exponential smoothing method, are also established for comparison with the proposed model under the criteria of mean absolute percentage error and root mean square percent error. The prediction results show that the optimized NNGBM(1,1) model is more accurate and performs better than the traditional GM(1,1), GVM, NGBM(1,1) and Holt-Winters exponential smoothing method. Copyright © 2014. Published by Elsevier Ltd.

  6. Equivalent survival following liver transplantation in patients with non-alcoholic steatohepatitis compared with patients with other liver diseases.

    PubMed

    Kennedy, Christopher; Redden, David; Gray, Stephen; Eckhoff, Devin; Massoud, Omar; McGuire, Brendan; Alkurdi, Basem; Bloomer, Joseph; DuBay, Derek A

    2012-09-01

    Orthotopic liver transplantation (LT) in non-alcoholic steatohepatitis (NASH) is increasing in parallel with the obesity epidemic. This study retrospectively reviewed the clinical outcomes of LTs in NASH (n = 129) and non-NASH (n = 775) aetiologies carried out at a single centre between 1999 and 2009. Rates of 1-, 3- and 5-year overall survival in NASH (90%, 88% and 85%, respectively) were comparable with those in non-NASH (92%, 86% and 80%, respectively) patients. Mortality within 4 months of LT was twice as high in NASH as in non-NASH patients (8.5% vs. 4.2%; P = 0.04). Compared with non-NASH patients, post-LT mortality in NASH patients was more commonly caused by infectious (38% vs. 26%; P < 0.05) or cardiac (19% vs. 7%; P < 0.05) aetiologies. Five-year survival was lower in NASH patients with a high-risk phenotype (age >60 years, body mass index >30 kg/m(2), with hypertension and diabetes) than in NASH patients without these characteristics (72% vs. 87%; P = 0.02). Subgroup analyses revealed that 5-year overall survival in NASH was equivalent to that in Laennec's cirrhosis (85% vs. 80%; P 0.87), but lower than that in cirrhosis of cryptogenic aetiology (85% vs. 96%; P = 0.04). Orthotopic LT in NASH was associated with increased early postoperative mortality, but 1-, 3- and 5-year overall survival rates were equivalent to those in non-NASH patients. © 2012 International Hepato-Pancreato-Biliary Association.

  7. Photoinduced Electronic Energy Transfer: Theoretical and Experimental Issues for Light Harvesting Applications

    DTIC Science & Technology

    2013-10-21

    PHOTOINDUCED ELECTRONIC ENERGY TRANSFER - THEORETICAL AND EXPERIMENTAL ISSUES FOR LIGHT HARVESTING APPLICATIONS PAUL BRUMER UNIV OF TORONTO 10/21... Applications 5a. CONTRACT NUMBER 5b. GRANT NUMBER FA9550-10-1-0260 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...Harvesting Applications Grant Number: FA9550-10-1-0260 Program Manager: Dr. Tatjana Curcic, AFOSR Stated aims of the project

  8. Questionnaire survey on lifestyle of patients with nonalcoholic steatohepatitis

    PubMed Central

    Noto, Haruka; Tokushige, Katsutoshi; Hashimoto, Etsuko; Taniai, Makiko; Shiratori, Keiko

    2014-01-01

    Lack of exercise and excessive food intake are known to be the important causes of nonalcoholic steatohepatitis (NASH). To elucidate the relationship between lifestyle and NASH, we surveyed exercise and dietary habits, comparing them among 171 biopsy-proven NASH patients, 29 nonalcoholic fatty liver (NAFL) patients and 49 normal subjects. Dietary habits including the duration of dinner time, amount of rice at dinner, and weekly frequencies of meat, fries, Chinese noodles, sweets, and instant food consumption were significantly different in male NASH patients compared to normal male subjects. In women, differences were seen in the amount of rice at dinner, frequency of eating out, and proclivity for sweets. In male NASH patients, the frequency of physical exercise was significantly lower. The lifestyle tendencies of NASH were almost similar to those of NAFL. In the comparison between obese NASH and non-obese NASH, no clear lifestyle differences were found. In conclusion, the most striking result of this survey was that the lifestyle of males contributed significantly to the development of NASH. These results point to treatment of NASH in males. In female NASH patients, lifestyle differences were minimal, and the effects of other factors such as genetic background will need to be investigated. PMID:25411525

  9. Questionnaire survey on lifestyle of patients with nonalcoholic steatohepatitis.

    PubMed

    Noto, Haruka; Tokushige, Katsutoshi; Hashimoto, Etsuko; Taniai, Makiko; Shiratori, Keiko

    2014-11-01

    Lack of exercise and excessive food intake are known to be the important causes of nonalcoholic steatohepatitis (NASH). To elucidate the relationship between lifestyle and NASH, we surveyed exercise and dietary habits, comparing them among 171 biopsy-proven NASH patients, 29 nonalcoholic fatty liver (NAFL) patients and 49 normal subjects. Dietary habits including the duration of dinner time, amount of rice at dinner, and weekly frequencies of meat, fries, Chinese noodles, sweets, and instant food consumption were significantly different in male NASH patients compared to normal male subjects. In women, differences were seen in the amount of rice at dinner, frequency of eating out, and proclivity for sweets. In male NASH patients, the frequency of physical exercise was significantly lower. The lifestyle tendencies of NASH were almost similar to those of NAFL. In the comparison between obese NASH and non-obese NASH, no clear lifestyle differences were found. In conclusion, the most striking result of this survey was that the lifestyle of males contributed significantly to the development of NASH. These results point to treatment of NASH in males. In female NASH patients, lifestyle differences were minimal, and the effects of other factors such as genetic background will need to be investigated.

  10. Non-alcoholic fatty liver disease - histological scoring systems: a large cohort single-center, evaluation study.

    PubMed

    Rastogi, Archana; Shasthry, Saggere Muralikrishna; Agarwal, Ayushi; Bihari, Chhagan; Jain, Priyanka; Jindal, Ankur; Sarin, Shiv

    2017-11-01

    Non-alcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver disease. Till date, liver biopsy remains the gold standard for identification and quantification of the wide histological spectra of NAFLD. Histological scorings are very useful and widely applied for the diagnosis and management in clinical trials and follow-up studies of non-alcoholic steatohepatitis (NASH). However, in view of scarce published literature, there is a need to evaluate them in large cohort of NAFLD. This study was aimed to evaluate the two histological scoring systems (NAS-CRN, SAF) in the diagnosis of NAFLD and to assess the role of histological characteristics as injury markers in NAFLD. Retrospective histological study of liver biopsies of 1000 patients diagnosed as NAFLD, between 2010 and 2016, was conducted. Histopathologic evaluation and semiquantiative scoring based on NAS-CRN and SAF algorithm and their correlation with serum aminotransferase and fibrosis were performed. Liver biopsies were classified according to the NAS-CRN scoring, as NAS <3 (not NASH) in 72 (7.2%), NAS 3-4 (borderline NASH) in 310 (31%), and NAS ≥5 (definite NASH) in 618 (61.8%), and SAF classified 117 (11.7%) not NASH and 883 (88.3%) definite NASH. There was excellent concordance for definite NASH and not NASH; however, 88.06% of borderline NASH was classified as NASH by SAF. 76.39% by NAS and 78.63% by SAF algorithm who were diagnosed as not NASH showed the presence of fibrosis; however, higher stages of fibrosis were significantly more prevalent in definite NASH, excluding burnt-out cirrhosis. Serum ALT was significantly associated with increasing stages of fibrosis (p < 0.001) and the three categories (not NASH, borderline NASH, and definite NASH) when classified as with/without fibrosis (p < 0.001). Steatosis of higher grades, more ballooned cells, and more foci of Lobular Inflammation were found in significantly higher proportion of patients with NASH (p < 0

  11. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis.

    PubMed

    Molloy, Jeffrey W; Calcagno, Christopher J; Williams, Christopher D; Jones, Frances J; Torres, Dawn M; Harrison, Stephen A

    2012-02-01

    Coffee caffeine consumption (CC) is associated with reduced hepatic fibrosis in patients with chronic liver diseases, such as hepatitis C. The association of CC with nonalcoholic fatty liver disease (NAFLD) has not been established. The aim of this study was to correlate CC with the prevalence and severity of NAFLD. Patients involved in a previously published NAFLD prevalence study, as well as additional NASH patients identified in the Brooke Army Medical Center Hepatology clinic, were queried about their caffeine intake. A validated questionnaire for CC was utilized to assess for a relationship between caffeine and four groups: ultrasound negative (controls), bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4. A total of 306 patients responded to the CC questionnaire. Average milligrams of total caffeine/coffee CC per day in controls, bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4 were 307/228, 229/160, 351/255, and 252/152, respectively. When comparing patients with bland steatosis/not-NASH to those with NASH stage 0-1, there was a significant difference in CC between the two groups (P = 0.005). Additionally, when comparing patients with NASH stage 0-1 to those with NASH stage 2-4, there was a significant difference in coffee CC (P = 0.016). Spearman's rank correlation analysis further supported a negative relationship between coffee CC and hepatic fibrosis (r = -0.215; P = 0.035). Coffee CC is associated with a significant reduction in risk of fibrosis among NASH patients. Copyright © 2011 American Association for the Study of Liver Diseases.

  12. Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis.

    PubMed

    Ferslew, Brian C; Xie, Guoxiang; Johnston, Curtis K; Su, Mingming; Stewart, Paul W; Jia, Wei; Brouwer, Kim L R; Barritt, A Sidney

    2015-11-01

    The prevalence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal. Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial time points following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine. Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH 2595-3549 µM and healthy 1171-1458 µM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH 4444-5898 µM and healthy 2634-2829 µM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile. Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.

  13. Prevalence and predictors of nonalcoholic steatohepatitis in obese patients undergoing bariatric surgery: a Department of Defense experience.

    PubMed

    Reha, Jeffrey L; Lee, Sukhyung; Hofmann, Luke J

    2014-06-01

    Nonalcoholic steatohepatitis (NASH) is a silent liver disease that can lead to inflammation and subsequent scaring. If left untreated, cirrhosis may ensue. Morbidly obese patients are at an increased risk of NASH. We report the prevalence and predictors of NASH in patients undergoing morbid obesity surgery. A retrospective review was conducted on morbidly obese patients undergoing weight reduction surgery from September 2005 through December 2008. A liver biopsy was performed at the time of surgery. Patients who had a history of hepatitis infection or previous alcohol dependency were excluded. Prevalence of NASH was studied. Predictors of NASH among clinical and biochemical variables were analyzed using multivariate regression analysis. One hundred thirteen patients were analyzed (84% female; mean age, 42.6 ± 11.4 years; mean body mass index, 45.1 ± 5.7 kg/m(2)). Sixty-one patients had systemic hypertension (54%) and 35 patients had diabetes (31%). The prevalence of NASH in this study population was 35 per cent (40 of 113). An additional 59 patients (52%) had simple steatosis without NASH. Only 14 patients had normal liver histology. On multivariate analysis, only elevated aspartate aminotransferase (AST) (greater than 41 IU/L) was the independent predictor for NASH (odds ratio, 5.85; confidence interval, 1.06 to 32.41). Patient age, body mass index, hypertension, diabetes, hypercholesterolemia, and abnormal alanine aminotransferase did not predict NASH. NASH is a common finding in obese population. Abnormal AST was the only predictive factor for NASH.

  14. National Audit of Seizure management in Hospitals (NASH): results of the national audit of adult epilepsy in the UK

    PubMed Central

    Dixon, Peter A; Kirkham, Jamie J; Marson, Anthony G; Pearson, Mike G

    2015-01-01

    Objectives About 100 000 people present to hospitals each year in England with an epileptic seizure. How they are managed is unknown; thus, the National Audit of Seizure management in Hospitals (NASH) set out to assess prior care, management of the acute event and follow-up of these patients. This paper describes the data from the second audit conducted in 2013. Setting 154 emergency departments (EDs) across the UK. Participants Data from 4544 attendances (median age of 45 years, 57% men) showed that 61% had a prior diagnosis of epilepsy, 12% other neurological problems and 22% were first seizure cases. Each ED identified 30 consecutive adult cases presenting due to a seizure. Primary and secondary outcome measures Details were recorded of the patient's prior care, management at hospital and onward referral to neurological specialists onto an online database. Descriptive results are reported at national level. Results Of those with epilepsy, 498 (18%) were on no antiepileptic drug therapy and 1330 (48%) were on monotherapy. Assessments were often incomplete and witness histories were sought in only 759 (75%) of first seizure patients, 58% were seen by a senior doctor and 57% were admitted. For first seizure patients, advice on further seizure management was given to 264 (27%) and only 55% were referred to a neurologist or epilepsy specialist. For each variable, there was wide variability among sites that was not explicable. For the sites who partook in both audits, there was a trend towards better care in 2013, but this was small and dwarfed by the intersite variability. Conclusions These results have parallels with the Sentinel Audit of Stroke performed a decade earlier. There is wide intersite variability in care covering the entire care pathway, and a need for better organised and accessible care for these patients. PMID:25829372

  15. The effect of cocoa supplementation on hepatic steatosis, reactive oxygen species and LFABP in a rat model of NASH

    PubMed Central

    2011-01-01

    Background Non alcoholic steatohepatitis is hypothesised to develop via a mechanism involving fat accumulation and oxidative stress. The current study aimed to investigate if an increase in oxidative stress was associated with changes in the expression of liver fatty acid binding protein in a rat model of non alcoholic steatohepatitis and whether cocoa supplementation attenuated those changes. Methods Female Sprague Dawley rats were fed a high fat control diet, a high fat methionine choline deficient diet, or one of four 12.5% cocoa supplementation regimes in combination with the high fat methionine choline deficient diet. Results Liver fatty acid binding protein mRNA and protein levels were reduced in the liver of animals with fatty liver disease when compared to controls. Increased hepatic fat content was accompanied by higher levels of oxidative stress in animals with fatty liver disease when compared to controls. An inverse association was found between the levels of hepatic liver fatty acid binding protein and the level of hepatic oxidative stress in fatty liver disease. Elevated NADPH oxidase protein levels were detected in the liver of animals with increased severity in inflammation and fibrosis. Cocoa supplementation was associated with partial attenuation of these pathological changes, although the severity of liver disease induced by the methionine choline deficient diet prevented complete reversal of any disease associated changes. Red blood cell glutathione was increased by cocoa supplementation, whereas liver glutathione was reduced by cocoa compared to methionine choline deficient diet fed animals. Conclusion These findings suggest a potential role for liver fatty acid binding protein and NADPH oxidase in the development of non alcoholic steatohepatitis. Furthermore, cocoa supplementation may have be of therapeutic benefit in less sever forms of NASH. PMID:22081873

  16. [Prevalence of non-alcoholic fatty liver disease in a population with elevated transaminases and level of accuracy of the diagnosis in Primary Care].

    PubMed

    Samperio-González, María Amelia; Selvi-Blasco, Marta; Manzano-Montero, Mónica; Méndez-Gómez, Judit; Gil-Prades, Montserrat; Azagra, Rafael

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated transaminases in adults. Determine the prevalence of NASH in patients with sustained hypertransaminasemia, and Know the adequacy of the registered in Primary Care (AP) diagnosis. 1) Cross-sectional study with a random sample of patients with elevated alanine aminotransferase (ALT) held (ALT> 32 for ≥6 months), ruling out other causes of liver disease, according to clinical, laboratory and ultrasound scan criteria in AP and 2) cross-sectional description of all cases diagnosed with NASH recorded (K76 - ICD10) with diagnostic adequacy analysis according to standard criteria. 290 patients were analyzed: 76 were diagnosed as NASH (26.1%), 44 women (57.9%). Multivariate analysis adjusted for age and sex showed no association between NASH and male gender (OR: 0.5; CI95%: 0.3-0.9), diabetes mellitus (DM) (OR: 2.42; CI95%: 1.2-4.9) and hypertension blood pressure (HBP) (OR: 3.07; CI 95% 1.6-5.6). Of the 209 diagnosed with NASH record: 51 (24.4%) met the criteria for NASH. The rest had insufficient records. 53.1% lacked sustained hypertransaminasemia; 48% of viral serology; 11% supported and 53.1% abdominal ultrasound registration of alcohol. Severe NASH is frequent among patients with sustained hypertransaminasemia. The DM and hypertension significantly increase the risk of NASH. The diagnosis of NASH is recorded without considering all criteria and mainly NASH made by ultrasonography. They should unify diagnostic criteria in the register of NASH. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  17. Identification of novel noninvasive markers for diagnosing nonalcoholic steatohepatitis and related fibrosis by data mining.

    PubMed

    Yoshimura, Keito; Okanoue, Takeshi; Ebise, Hayao; Iwasaki, Tsuyoshi; Mizuno, Masayuki; Shima, Toshihide; Ichihara, Junji; Yamazaki, Kazuto

    2016-02-01

    It is important that patients with nonalcoholic steatohepatitis (NASH) are diagnosed and treated early to prevent serious complications, such as liver cirrhosis or hepatocellular carcinoma. However, current methods for NASH diagnosis are invasive given that they rely on liver biopsy, making early diagnosis difficult. In this study, we developed novel noninvasive markers for the diagnosis of NASH and NASH-related fibrosis. A total of 132 Japanese patients with nonalcoholic fatty liver disease were included in this study. Blood samples were collected, and 261 biomolecules were quantified in serum. Using cluster and pathway analyses, we identified biomolecule modules connected to biological events that occur with disease progression to NASH. The modules were used as variables for diagnosis, leading to a NASH diagnostic marker associated with two biological events, that is, protective response to hepatic steatosis and hepatitis-causing innate immune response. Regarding the NASH-related fibrosis marker, immunological responses to hepatocyte injury were identified as a biological event. To develop diagnostic markers for NASH and NASH-related fibrosis, specific biomolecules were selected from each biomolecule module. The former marker was obtained by averaging the levels of four biomolecules, whereas the latter was obtained by averaging the levels of two biomolecules. Both markers achieved a diagnostic accuracy of almost 0.9 of the area under the receiver operating characteristic curve, and the latter exhibited equivalent performance in an independent group of 62 prospectively recruited patients. We developed highly accurate markers for the diagnosis of both NASH and NASH-related fibrosis (i.e., FM-NASH index and FM-fibro index, respectively). These markers may be used as an alternative diagnostic tool to liver biopsy. © 2015 by the American Association for the Study of Liver Diseases.

  18. Prevalence and Outcome of Nonalcoholic Fatty Liver Disease in Adolescents and Young Adults Undergoing Weight Loss Surgery

    PubMed Central

    Corey, Kathleen E.; Stanley, Takara L.; Misdraji, Joseph; Scirica, Christina; Pratt, Janey; Hoppin, Alison; Misra, Madhusmita

    2014-01-01

    We evaluated the prevalence of NAFLD (nonalcoholic fatty liver disease) and NASH (nonalcoholic steatohepatitis) in 27 adolescents referred for weight loss surgery (WLS). On biopsy 18 patients (66.7%) had NAFLD, and of those, 10 patients (37.0%) had NASH and 11 (40.7%) had fibrosis. Insulin, HbA1C and homeostatic model assessment of insulin resistance (HOMA-IR) were significantly higher in patients with NASH than those without NASH. Following WLS, 40% of NASH patients had persistently elevated aminotransferase levels despite weight loss. We found that NASH is underdiagnosed in adolescents referred for WLS and hyperinsulinemia, HOMA-IR and HbA1c can aid in identifying high-risk patients. PMID:24677740

  19. Refractive Index Enhancement in Gases

    DTIC Science & Technology

    2012-02-29

    Associate Professor Deniz D. Yavuz Graduate Ph. D. Students: Nick Proite, Tyler Green, Dan Sikes, Zach Simmons, and Jared Miles Se. TASK NUMBER Sf...NUMBER OF PAGES 8 19a. NAME OF RESPONSIBLE PERSON Assoc. Prof. Deniz D. Yavuz 19b. TELEPHONE NUMBER (Include area code) Reset 608-263-9399...Refractive Index Enhancement in Gases Grant/Contract Number: FA9550-09-1-0124 Program Manager: Tatjana Curcic Principal Investigator: Deniz D. Yavuz Our

  20. Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice.

    PubMed

    Henning, Justin R; Graffeo, Christopher S; Rehman, Adeel; Fallon, Nina C; Zambirinis, Constantinos P; Ochi, Atsuo; Barilla, Rocky; Jamal, Mohsin; Deutsch, Michael; Greco, Stephanie; Ego-Osuala, Melvin; Bin-Saeed, Usama; Rao, Raghavendra S; Badar, Sana; Quesada, Juan P; Acehan, Devrim; Miller, George

    2013-08-01

    Nonalcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DCs) are antigen-presenting cells with an emerging role in hepatic inflammation. We postulated that DCs are important in the progression of NASH. We found that intrahepatic DCs expand and mature in NASH liver and assume an activated immune phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibroinflammation. Our mechanistic studies support a regulatory role for DCs in NASH by limiting sterile inflammation through their role in the clearance of apoptotic cells and necrotic debris. We found that DCs limit CD8(+) T-cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. Our findings support a role for DCs in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH. Copyright © 2013 American Association for the Study of Liver Diseases.

  1. Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy.

    PubMed

    Nagaya, Tadanobu; Tanaka, Naoki; Kimura, Takefumi; Kitabatake, Hiroyuki; Fujimori, Naoyuki; Komatsu, Michiharu; Horiuchi, Akira; Yamaura, Takahiro; Umemura, Takeji; Sano, Kenji; Gonzalez, Frank J; Aoyama, Toshifumi; Tanaka, Eiji

    2015-06-01

    It is recognized that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), may develop after pancreaticoduodenectomy (PD). However, the mechanism of NASH development remains unclear. This study aimed to examine the changes in gene expression associated with NASH occurrence following PD. The expression of genes related to fatty acid/triglyceride (FA/TG) metabolism and inflammatory signaling was examined using liver samples obtained from 7 post-PD NASH patients and compared with 6 healthy individuals and 32 conventional NASH patients. The livers of post-PD NASH patients demonstrated significant up-regulation of the genes encoding CD36, FA-binding proteins 1 and 4, acetyl-coenzyme A carboxylase α, diacylglycerol acyltransferase 2, and peroxisome proliferator-activated receptor (PPAR) γ compared with normal and conventional NASH livers. Although serum apolipoprotein B (ApoB) and TG were decreased in post-PD NASH patients, the mRNAs of ApoB and microsomal TG transfer protein were robustly increased, indicating impaired TG export from the liver as very-low-density lipoprotein (VLDL). Additionally, elevated mRNA levels of myeloid differentiation primary response 88 and superoxide dismutases in post-PD NASH livers suggested significant activation of innate immune response and augmentation of oxidative stress generation. Enhanced FA uptake into hepatocytes and lipogenesis, up-regulation of PPARγ, and disruption of VLDL excretion into the circulation are possible mechanisms of steatogenesis after PD. These results provide a basis for understanding the pathogenesis of NAFLD/NASH following PD.

  2. Expression of cytokine signaling genes in morbidly obese patients with non-alcoholic steatohepatitis and hepatic fibrosis.

    PubMed

    Estep, J Michael; Baranova, Ancha; Hossain, Noreen; Elariny, Hazem; Ankrah, Kathy; Afendy, Arian; Chandhoke, Vikas; Younossi, Zobair M

    2009-05-01

    White adipose tissue (WAT) from visceral adiposity plays an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Development of NASH and its progression to fibrosis is partially due to cytokines and adipokines produced by WAT. The aim of this study was to assess the association of hepatic fibrosis and NASH by evaluating the intrinsic differences in the inflammatory cytokine signaling in the visceral adipose tissue obtained from morbidly obese patients. We used targeted microarrays representing human genes involved in the inflammatory and fibrogenic reactions to profile visceral adipose samples of 15 well-matched NASH patients with and without fibrosis. Additionally, visceral adipose samples were subjected to real-time polymerase chain reaction profiling of 84 inflammations related genes. Eight genes (CCL2, CCL4, CCL18, CCR1, IL10RB, IL15RA, and LTB) were differentially expressed in NASH with fibrosis. Additionally, an overlapping but distinct list of the differentially expressed genes were found in NASH with type II diabetes (DM; IL8, BLR1, IL2RA, CD40LG, IL1RN, IL15RA, and CCL4) as compared to NASH without DM. Inflammatory cytokines are differentially expressed in the adipose tissue of NASH with fibrosis, as well in NASH with DM. These findings point at the interaction of adipose inflammatory cytokines, DM, hepatic fibrosis in NASH, and its progression to cirrhosis and end-stage liver disease.

  3. Paraoxonase 1 and oxidative stress in paediatric non-alcoholic steatohepatitis.

    PubMed

    Desai, Sonal; Baker, Susan S; Liu, Wensheng; Moya, Diana A; Browne, Richard W; Mastrandrea, Lucy; Baker, Robert D; Zhu, Lixin

    2014-01-01

    Non-alcoholic steatohepatitis (NASH) in children is a significant public health concern. Oxidative stress is an important component in the pathophysiology of NASH. Several enzymatic antioxidant mechanisms protect the liver from oxidative injury. Examination of the expression of these enzymes in NASH livers may provide insight on the roles for these antioxidant mechanisms in the pathophysiology of NASH. The mRNA expression of catalase, glutathione peroxidase 1 (GPX1), glutathione reductase (GSR), paraoxonase 1 (PON1) and other reactive oxygen species-related genes was evaluated by microarray and quantitative real-time PCR analyses. The PON1 protein levels were evaluated in liver and serum by Western blot analyses. Serum enzymatic activities of GPX, GSR and PON1 (paraoxonase and arylesterase activities) were examined. NASH livers exhibited elevated mRNA expression of catalase and PON1, but not GPX1 or GSR. No difference in serum GPX or GSR activity was detected between NASH patients and controls. Elevated expression of PON1 mRNA and protein was detected in NASH livers, but serum PON1 protein and activities were not elevated. Elevated expression of catalase and PON1 suggests protective roles for these antioxidants in NASH livers. Given the importance of oxidative stress in the pathophysiology of NASH, future studies focusing on these enzymes could identify important targets for therapeutic or preventive interventions for NASH patients. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Anisotropic and heterogeneous mechanical properties of a stratified shale/limestone sequence at Nash Point, South Wales: A case study for hydraulic fracture propagation through a layered medium

    NASA Astrophysics Data System (ADS)

    Forbes Inskip, Nathaniel; Meredith, Philip; Gudmundsson, Agust

    2016-04-01

    While considerable effort has been expended on the study of fracture propagation in rocks in recent years, our understanding of how fractures propagate through layered sedimentary rocks with different mechanical and elastic properties remains poorly constrained. Yet this is a key issue controlling the propagation of both natural and anthropogenic hydraulic fractures in layered sequences. Here we report measurements of the contrasting mechanical and elastic properties of the Lower Lias at Nash Point, South Wales, which comprises an interbedded sequence of shale and limestone layers, and how those properties may influence fracture propagation. Elastic properties of both materials have been characterised via ultrasonic wave velocity measurements as a function of azimuth on samples cored both normal and parallel to bedding. The shale is highly anisotropic, with P-wave velocities varying from 2231 to 3890 m s-1, giving an anisotropy of ~55%. By contrast, the limestone is essentially isotropic, with a mean P-wave velocity of 5828 m s-1 and an anisotropy of ~2%. The dynamic Young's modulus of the shale, calculated from P- and S-wave velocity data, is also anisotropic with a value of 36 GPa parallel to bedding and 12 GPa normal to bedding. The modulus of the limestone is again isotropic with a value of 80 GPa. It follows that for a vertical fracture propagating (i.e. normal to bedding) the modulus contrast is 6.6. This is important because the contrast in elastic properties is a key factor in controlling whether fractures arrest, deflect, or propagate across interfaces between layers in a sequence. There are three principal mechanisms by which a fracture may deflect across or along an interface, namely: Cook-Gordon debonding, stress barrier, and elastic mismatch. Preliminary numerical modelling results (using a Finite Element Modelling software) of induced fractures at Nash Point suggest that all three are important. The results demonstrate a rotation of the maximum

  5. Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients

    PubMed Central

    Chiappini, Franck; Coilly, Audrey; Kadar, Hanane; Gual, Philippe; Tran, Albert; Desterke, Christophe; Samuel, Didier; Duclos-Vallée, Jean-Charles; Touboul, David; Bertrand-Michel, Justine; Brunelle, Alain; Guettier, Catherine; Le Naour, François

    2017-01-01

    Nonalcoholic steatohepatitis (NASH) is a condition which can progress to cirrhosis and hepatocellular carcinoma. Markers for NASH diagnosis are still lacking. We performed a comprehensive lipidomic analysis on human liver biopsies including normal liver, nonalcoholic fatty liver and NASH. Random forests-based machine learning approach allowed characterizing a signature of 32 lipids discriminating NASH with 100% sensitivity and specificity. Furthermore, we validated this signature in an independent group of NASH patients. Then, metabolism dysregulations were investigated in both patients and murine models. Alterations of elongase and desaturase activities were observed along the fatty acid synthesis pathway. The decreased activity of the desaturase FADS1 appeared as a bottleneck, leading upstream to an accumulation of fatty acids and downstream to a deficiency of long-chain fatty acids resulting to impaired phospholipid synthesis. In NASH, mass spectrometry imaging on tissue section revealed the spreading into the hepatic parenchyma of selectively accumulated fatty acids. Such lipids constituted a highly toxic mixture to human hepatocytes. In conclusion, this study characterized a specific and sensitive lipid signature of NASH and positioned FADS1 as a significant player in accumulating toxic lipids during NASH progression. PMID:28436449

  6. Combined Adiponectin Deficiency and Resistance in Obese Patients: Can It Solve Part of the Puzzle in Nonalcoholic Steatohepatitis.

    PubMed

    Salman, Ahmed; Hegazy, Mona; AbdElfadl, Soheir

    2015-06-15

    Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, nonalcoholic steatohepatitis (NASH) and fibrosis in obese patients identifies the risk group with increased incidence of liver-related deaths. To clarify the role of serum adiponectin and its receptor liver gene expression in the progression of liver damage in NAFLD. Fifty four (54) obese patients with NAFLD preliminary diagnosed by liver ultra-sound were recruited. Full medical history, anthropometric measurement, biochemical studies, serum adiponectin level, liver biopsy for histological examination and NAS score to identify NASH patients, and assessment of adiponectin receptor gene expression by RT-PCR, were conducted for each patients. Fifteen ages matched average weight healthy adult had been chosen as a control for serum adiponectin level. According to NAS score, patients were divided into non- NASH (8 patients), and NASH (46 patients). Serum adiponectin level was significantly lower in NAFLD patients compared to normal participants (p < 0.004). Serum adiponectin level was lower in NASH patients (4.437 ± 2.569 ng/dl in NASH vs. 5.138 ± 2.841 ng/dl in non-NASH). Adiponectin receptor liver gene expression was lower in NASH patients (0.8459 ± 0.4671 vs. 1.0688 ± 0.3965 in non-NASH). Both adiponectin deficiency and resistance had a role in progression of simple liver steatosis to severe injury in obese patients.

  7. Potential for Dietary ω-3 Fatty Acids to Prevent Nonalcoholic Fatty Liver Disease and Reduce the Risk of Primary Liver Cancer123

    PubMed Central

    Jump, Donald B; Depner, Christopher M; Tripathy, Sasmita; Lytle, Kelli A

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity, and its prevalence is anticipated to increase as the obesity epidemic remains unabated. NAFLD is now the most common cause of chronic liver disease in developed countries and is defined as excessive lipid accumulation in the liver, that is, hepatosteatosis. NAFLD ranges in severity from benign fatty liver to nonalcoholic steatohepatitis (NASH), and NASH is characterized by hepatic injury, inflammation, oxidative stress, and fibrosis. NASH can progress to cirrhosis, and cirrhosis is a risk factor for primary hepatocellular carcinoma (HCC). The prevention of NASH will lower the risk of cirrhosis and NASH-associated HCC. Our studies have focused on NASH prevention. We developed a model of NASH by using mice with the LDL cholesterol receptor gene ablated fed the Western diet (WD). The WD induces a NASH phenotype in these mice that is similar to that seen in humans and includes robust induction of hepatic steatosis, inflammation, oxidative stress, and fibrosis. With the use of transcriptomic, lipidomic, and metabolomic approaches, we examined the capacity of 2 dietary ω-3 (n–3) polyunsaturated fatty acids, eicosapentaenoic acid (20:5ω-3; EPA) and docosahexaenoic acid (22:6ω-3; DHA), to prevent WD-induced NASH. Dietary DHA was superior to EPA at attenuating WD-induced changes in plasma lipids and hepatic injury and at reversing WD effects on hepatic metabolism, oxidative stress, and fibrosis. The outcome of these studies suggests that DHA may be useful in preventing NASH and reducing the risk of HCC. PMID:26567194

  8. Noninvasive Differentiation between Hepatic Steatosis and Steatohepatitis with MR Imaging Enhanced with USPIOs in Patients with Nonalcoholic Fatty Liver Disease: A Proof-of-Concept Study.

    PubMed

    Smits, Loek P; Coolen, Bram F; Panno, Maria D; Runge, Jurgen H; Nijhof, Wouter H; Verheij, Joanne; Nieuwdorp, Max; Stoker, Jaap; Beuers, Ulrich H; Nederveen, Aart J; Stroes, Erik S

    2016-03-01

    To (a) study the optimal timing and dosing for ultrasmall superparamagnetic iron oxide particle (USPIO)-enhanced magnetic resonance (MR) imaging of the liver in nonalcoholic fatty liver disease, (b) evaluate whether hepatic USPIO uptake is decreased in nonalcoholic steatohepatitis (NASH), and (c) study the diagnostic accuracy of USPIO-enhanced MR imaging to distinguish between NASH and simple steatosis. This prospective study was approved by the local institutional review board, and informed consent was obtained from all patients. Quantitative R2* MR imaging of the liver was performed at baseline and 72 hours after USPIO administration in patients with biopsy-proven NASH (n = 13), hepatic steatosis without NASH (n = 11), and healthy control subjects (n = 9). The hepatic USPIO uptake in the liver was quantified by the difference in R2* (ΔR2*) between the contrast material-enhanced images and baseline images. Between-group differences in mean ΔR2* were tested with the Student t test, and diagnostic accuracy was tested by calculating the area under the receiver operating characteristic curve. Patients with NASH had a significantly lower ΔR2* 72 hours after USPIO administration when compared with patients who had simple steatosis and healthy control subjects (mean ± standard deviation for patients with NASH, 37.0 sec(-1) ± 16.1; patients with simple steatosis, 61.0 sec(-1) ± 17.3; and healthy control subjects, 72.2 sec(-1) ± 22.0; P = .006 for NASH vs simple steatosis; P < .001 for NASH vs healthy control subjects). The area under the receiver operating characteristic curve to distinguish NASH from simple steatosis was 0.87 (95% confidence interval: 0.72, 1.00). This proof-of-concept study provides clues that hepatic USPIO uptake in patients with NASH is decreased and that USPIO MR imaging can be used to differentiate NASH from simple steatosis.

  9. Ability of Cytokeratin-18 Fragments and FIB-4 Index to Diagnose Overall and Mild Fibrosis Nonalcoholic Steatohepatitis in Japanese Nonalcoholic Fatty Liver Disease Patients.

    PubMed

    Kobayashi, Natsuko; Kumada, Takashi; Toyoda, Hidenori; Tada, Toshifumi; Ito, Takanori; Kage, Masayoshi; Okanoue, Takeshi; Kudo, Masatoshi

    2017-01-01

    Several laboratory markers used in lieu of liver biopsy are reportedly useful in the diagnosis of nonalcoholic steatohepatitis (NASH). In the present study, we investigated the diagnostic impact of various non-invasive markers for predicting NASH. A total of 229 nonalcoholic fatty liver disease (NAFLD) patients who underwent liver biopsy were enrolled for the study. The diagnostic ability of various markers to diagnose NASH from NAFLD was investigated. A total of 140 patients were histologically diagnosed with NASH. Of these, 104 had degree 0-2 fibrosis (F0-2), and 36 had degree 3-4 fibrosis (F3-4). Multiple logistic regression analysis identified hyaluronic acid (HA) (OR 1.014; 95% CI 1.002-1.026; p = 0.024), FIB-4 index (OR 2.097; 95% CI 1.177-3.735; p = 0.012), and cytokeratin-18 fragments (CK-18F) (OR 1.002; 95% CI 1.001-1.002; p < 0.001) as factors independently associated with the diagnosis of NASH. The areas under the receiver operating characteristic curves (AUROCs) of HA, FIB-4 index, and CK-18F for the diagnosis of NASH were 0.77, 0.76, and 0.72, respectively. In addition, FIB-4 index (OR 1.907; 95% CI 1.063-3.419; p = 0.03) and CK-18F (OR 1.002; 95% CI 1.001-1.002; p < 0.001) could differentiate between NASH and NAFL, even when NASH patients with advanced fibrosis (F3-4) were excluded. AUROCs of FIB-4 index and CK-18F for the diagnosis of NASH with mild fibrosis (F0-2) from NAFLD were 0.70 and 0.70, respectively. FIB-4 index and CK-18F have good diagnostic abilities not only for NASH overall, but also for NASH with mild fibrosis. © 2017 S. Karger AG, Basel.

  10. De Novo and Recurrence of Nonalcoholic Steatohepatitis After Liver Transplantation.

    PubMed

    Kappus, Matthew; Abdelmalek, Manal

    2017-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developing countries. Approximately 25% of patients with NAFLD develop nonalcoholic steatohepatitis (NASH). NASH-related cirrhosis is now a leading listing indication for liver transplantation in the United States. Although posttransplant survival for NASH-related cirrhosis is comparable with that of other liver diseases, many patients have features of metabolic syndrome, which can contribute to a recurrence of NAFLD or NASH. This article reviews the epidemiology, pathophysiology, and treatment of de novo and recurrence of NASH after liver transplantation. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Hyperthyroidism Improves the Pathological Condition of Nonalcoholic Steatohepatitis: A Case of Nonalcoholic Steatohepatitis with Graves' Disease.

    PubMed

    Miyake, Teruki; Matsuura, Bunzo; Furukawa, Shinya; Todo, Yasuhiko; Yamamoto, Shin; Yoshida, Osamu; Imai, Yusuke; Watanabe, Takao; Yamamoto, Yasunori; Hirooka, Masashi; Tokumoto, Yoshio; Kumagi, Teru; Abe, Masanori; Seike, Hirotaka; Miyauchi, Shozo; Hiasa, Yoichi

    2016-01-01

    3,5,3'-triiodo-L-thyronine regulates the glucose metabolism, lipid metabolism, and hepatic steatosis. Several groups have shown the relationships between hypothyroidism and nonalcoholic fatty liver and hypothyroidism and nonalcoholic steatohepatitis (NASH). However, the effect of hyperthyroidism on NASH has not yet been investigated. We herein report effects of thyroid hormone on the pathological condition of NASH in a patient with NASH complicated by Graves' disease. In our case, the liver enzyme level improved with the increasing thyroid hormone level; however, the liver enzyme level was aggravated with the improving thyroid hormone level. Therefore, hyperthyroidism may improve the pathological condition of NASH.

  12. Prevalence and outcome of non-alcoholic fatty liver disease in adolescents and young adults undergoing weight loss surgery.

    PubMed

    Corey, K E; Stanley, T L; Misdraji, J; Scirica, C; Pratt, J; Hoppin, A; Misra, M

    2014-10-01

    We evaluated the prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in 27 adolescents referred for weight loss surgery (WLS). On biopsy, 18 patients (66.7%) had NAFLD, and of those, 10 (37.0%) had NASH and 11 (40.7%) had fibrosis. Insulin, HbA1C and homeostatic model assessment of insulin resistance (HOMA-IR) were significantly higher in patients with NASH than those without NASH. Following WLS, 40% of patients with NASH had persistently elevated aminotransferase levels despite weight loss. We found that NASH is underdiagnosed in adolescents referred for WLS, and that hyperinsulinaemia, HOMA-IR and HbA1c can aid in identifying high-risk patients. © 2014 The Authors. Pediatric Obesity © 2014 International Association for the Study of Obesity.

  13. Dynamical and thermodynamical coupling between the North Atlantic subtropical high and the marine boundary layer clouds in boreal summer

    NASA Astrophysics Data System (ADS)

    Wei, Wei; Li, Wenhong; Deng, Yi; Yang, Song; Jiang, Jonathan H.; Huang, Lei; Liu, W. Timothy

    2018-04-01

    This study investigates dynamical and thermodynamical coupling between the North Atlantic subtropical high (NASH), marine boundary layer (MBL) clouds, and the local sea surface temperatures (SSTs) over the North Atlantic in boreal summer for 1984-2009 using NCEP/DOE Reanalysis 2 dataset, various cloud data, and the Hadley Centre sea surface temperature. On interannual timescales, the summer mean subtropical MBL clouds to the southeast of the NASH is actively coupled with the NASH and local SSTs: a stronger (weaker) NASH is often accompanied with an increase (a decrease) of MBL clouds and abnormally cooler (warmer) SSTs along the southeast flank of the NASH. To understand the physical processes between the NASH and the MBL clouds, the authors conduct a data diagnostic analysis and implement a numerical modeling investigation using an idealized anomalous atmospheric general circulation model (AGCM). Results suggest that significant northeasterly anomalies in the southeast flank of the NASH associated with an intensified NASH tend to induce stronger cold advection and coastal upwelling in the MBL cloud region, reducing the boundary surface temperature. Meanwhile, warm advection associated with the easterly anomalies from the African continent leads to warming over the MBL cloud region at 700 hPa. Such warming and the surface cooling increase the atmospheric static stability, favoring growth of the MBL clouds. The anomalous diabatic cooling associated with the growth of the MBL clouds dynamically excites an anomalous anticyclone to its north and contributes to strengthening of the NASH circulation in its southeast flank. The dynamical and thermodynamical couplings and their associated variations in the NASH, MBL clouds, and SSTs constitute an important aspect of the summer climate variability over the North Atlantic.

  14. Plasma phospholipids and fatty acid composition differ between liver biopsy-proven nonalcoholic fatty liver disease and healthy subjects

    PubMed Central

    Ma, D W L; Arendt, B M; Hillyer, L M; Fung, S K; McGilvray, I; Guindi, M; Allard, J P

    2016-01-01

    Background: There is growing evidence that nonalcoholic fatty liver disease (NAFLD) is associated with perturbations in liver lipid metabolism. Liver phospholipid and fatty acid composition have been shown to be altered in NAFLD. However, detailed profiles of circulating lipids in the pathogenesis of NAFLD are lacking. Objective: Therefore, the objective of the present study was to examine circulating lipids and potential mechanisms related to hepatic gene expression between liver biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH) and healthy subjects. Subjects: Plasma phospholipid and fatty acid composition were determined in 31 healthy living liver donors as healthy controls (HC), 26 patients with simple hepatic steatosis (SS) and 20 with progressive NASH. Hepatic gene expression was analyzed by Illumina microarray in a subset of 22 HC, 16 SS and 14 NASH. Results: Concentrations of phosphatidylethanolamine (PE) increased relative to disease progression, HCNASH (170<210<250 μg ml−1), and was significantly different (P<0.05) between HC and NASH. Circulating phosphatidylserine (PS) and phosphatidylinositol were higher in SS and NASH compared with HC (P<0.05), but there was no difference between SS and NASH. Fatty acid composition of phospholipids was also remodeled. In particular, docosahexaenoic and arachidonic acid were higher (P<0.05) in SS and NASH relative to HC in PS. Differentially expressed hepatic genes included ETNK1 and PLSCR1 that are involved in PE synthesis and PS transport, respectively. Conclusions: The present study demonstrates that there is a disruption in phospholipid metabolism that is present in SS, but more pronounced in NASH. Intervention studies targeted at lipid metabolism could benefit SS and NASH. PMID:27428872

  15. Noninvasive clinical model for the diagnosis of nonalcoholic steatohepatitis in overweight and morbidly obese patients undergoing bariatric surgery.

    PubMed

    Pirvulescu, I; Gheorghe, L; Csiki, I; Becheanu, G; Dumbravă, M; Fica, S; Martin, S; Sarbu, A; Gheorghe, C; Diculescu, M; Copăescu, C

    2012-01-01

    Liver biopsy, an invasive method, is the gold standard for differentiate nonalcoholic steatohepatitis (NASH) from other stages of fatty liver disease. A noninvasive test to diagnose NASH and disease severity before surgery and also for monitoring disease status after bariatric surgery (BS) will be an important medical challenge. To create a noninvasive biomarkers model for the diagnosis of NASH in overweight, obese and morbidly obese patients (MOP). Sixty patients (mean BMI= 47.81kg/m2) were admitted after exclusion of other causes of liver disease. Liver biopsies were obtained at the time of the bariatric surgery or by percutaneous liver biopsy and graded using Kleiner score. Continuous variables were compared using Wilcoxon rank sum test and for prediction of NASH we used logistic regression. Logistic regression analysis showed that BMI, ALT, AST, alkaline phosphatase (ALP), HOMA-R, hs-CRP, M30, M65, leptine and adiponectine levels remained independent predictors for NASH (p less than 0.02). Using AUC analysis, we established the following cutoff levels being indicative of NASH: BMI ė 47 kg/m2, ALT ė 32 IU/mL, AST ė 25 IU/mL, ALP ė 85 IU/mL, HOMA-IR ė 4, M65 ė 389 U/L. Adiponectine less than 13.5 mg/L. A NASH-score, calculated as the sum of these 7 parameters, at a cutoff level of 4 points, can accurately predict NASH (sensitivity of 90%, specificity of 93.94% and AUC of 0.9576). We propose a noninvasive model for NASH diagnosis in MOP that should be validated prospectively. Using this noninvasive score, NASH would be predicted without the risks of liver biopsy. Celsius.

  16. Acidophil Bodiesin Nonalcoholic Steatohepatitis

    PubMed Central

    Yeh, Matthew M.; Belt, Patricia; Brunt, Elizabeth M.; Kowdley, Kris V.; Wilson, Laura A.; Ferrell, Linda

    2016-01-01

    The significance of the quantity of acidophil bodies (AB)in nonalcoholic steatohepatitis (NASH) is not certain. We quantified AB in liver biopsies and examined the association with the diagnosis of NASH and other histologic features. We reviewed 157 liver biopsies from the NASH CRN Database collected in 2006. 127 biopsies were from adult patients. Diagnoses were 94 definite NASH, 40 borderline NASH, and 23 definitely not NASH. The total length and average width of the core biopsies were measured and the biopsy areas were calculated (mm2). Total AB were counted and mean AB count per mm2 was calculated (AB/mm2) to deriveacidophil body index (ABI). ABI was 0.04 (±0.08) in definite NASH and 0.02 (±0.05) in borderline/definitely not NASH groups combined (p=0.02) in all 157 biopsies; similar findings were present in the 127 adult only biopsies (0.04±0.05 and 0.02±0.05, respectively, p=0.05). In all 157 biopsies, increased ABI was associated with greater lobular inflammation (p=0.01) and many ballooned hepatocytes (p=0.048). There was a positive relationship between ABI and high nonalcoholic fatty liver disease (NAFLD) activity scores (NAS), but this association was not statistically significant. There was no association between ABI and steatosis or fibrosis stage in either the entire cohorts or in the subset of adult patients. In conclusion, the density of AB is associated with lobular inflammation, ballooned hepatocytes, and the diagnosis of NASH in adult and pediatric liver biopsies, suggesting the implication of the apoptotic pathway in NASH-associated liver cell injury. PMID:26980020

  17. National Audit of Seizure management in Hospitals (NASH): results of the national audit of adult epilepsy in the UK.

    PubMed

    Dixon, Peter A; Kirkham, Jamie J; Marson, Anthony G; Pearson, Mike G

    2015-03-31

    About 100,000 people present to hospitals each year in England with an epileptic seizure. How they are managed is unknown; thus, the National Audit of Seizure management in Hospitals (NASH) set out to assess prior care, management of the acute event and follow-up of these patients. This paper describes the data from the second audit conducted in 2013. 154 emergency departments (EDs) across the UK. Data from 4544 attendances (median age of 45 years, 57% men) showed that 61% had a prior diagnosis of epilepsy, 12% other neurological problems and 22% were first seizure cases. Each ED identified 30 consecutive adult cases presenting due to a seizure. Details were recorded of the patient's prior care, management at hospital and onward referral to neurological specialists onto an online database. Descriptive results are reported at national level. Of those with epilepsy, 498 (18%) were on no antiepileptic drug therapy and 1330 (48%) were on monotherapy. Assessments were often incomplete and witness histories were sought in only 759 (75%) of first seizure patients, 58% were seen by a senior doctor and 57% were admitted. For first seizure patients, advice on further seizure management was given to 264 (27%) and only 55% were referred to a neurologist or epilepsy specialist. For each variable, there was wide variability among sites that was not explicable. For the sites who partook in both audits, there was a trend towards better care in 2013, but this was small and dwarfed by the intersite variability. These results have parallels with the Sentinel Audit of Stroke performed a decade earlier. There is wide intersite variability in care covering the entire care pathway, and a need for better organised and accessible care for these patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  18. Liver injury and fibrosis induced by dietary challenge in the Ossabaw miniature Swine.

    PubMed

    Liang, Tiebing; Alloosh, Mouhamad; Bell, Lauren N; Fullenkamp, Allison; Saxena, Romil; Van Alstine, William; Bybee, Phelan; Werling, Klára; Sturek, Michael; Chalasani, Naga; Masuoka, Howard C

    2015-01-01

    Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet) develop metabolic syndrome and nonalcoholic steatohepatitis (NASH) characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model. Ossabaw swine were fed standard chow (control group; n = 6) or NASH diet (n = 6) for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24. The NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a) hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (>90% hepatocytes), (b) hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c) Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides. This report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a) hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b) hepatocyte ballooning generally precedes the development of fibrosis; (c) there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides.

  19. Promising therapies for treatment of nonalcoholic steatohepatitis

    PubMed Central

    Noureddin, Mazen; Zhang, Alice; Loomba, Rohit

    2018-01-01

    Introduction Non-alcoholic fatty liver disease (NAFLD) has become the most common etiology for abnormal aminotransferase levels and chronic liver disease. Its growing prevalence is largely linked to the presence of metabolic syndrome, particularly diabetes and insulin resistance. It is estimated that 60–80% of the type 2 diabetic population has NAFLD. NAFLD encompasses a range of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). A subset of patients with hepatic steatosis progress to NASH, while 15–20% of patients with NASH develop cirrhosis. This progression is thought to be multifactorial, and there are currently no FDA-approved medications for the treatment of NASH. Areas covered We review drugs currently in Phase II and III clinical trials for treatment of NAFLD and NASH, including their mechanisms of action, relationship to the pathophysiology of NASH, and rationale for their development. Expert opinion The treatment of NASH is complex and necessitates targeting a number of different pathways. Combination therapy, preferably tailored toward the disease stage and severity, will be needed to achieve maximum therapeutic effect. With multiple agents currently being developed, there may soon be an ability to effectively slow or even reverse the disease process in many NAFLD/NASH patients. PMID:27501374

  20. Docosahexaenoic acid blocks progression of western diet-induced nonalcoholic steatohepatitis in obese Ldlr-/- mice

    PubMed Central

    Lytle, Kelli A.; Wong, Carmen P.

    2017-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by hepatic steatosis, inflammation, oxidative stress and fibrosis. NASH is a risk factor for cirrhosis and hepatocellular carcinoma. NASH is predicted to be the leading cause of liver transplants by 2020. Despite this growing public health concern, there remain no Food and Drug Administration (FDA) approved NASH treatments. Using Ldlr -/- mice as a preclinical model of western diet (WD)-induced NASH, we previously established that dietary supplementation with docosahexaenoic acid (DHA, 22:6,ω3) attenuated WD-induced NASH in a prevention study. Herein, we evaluated the capacity of DHA supplementation of the WD and a low fat diet to fully reverse NASH in mice with pre-existing disease. Methods Ldlr -/- mice fed the WD for 22 wks developed metabolic syndrome (MetS) and a severe NASH phenotype, including obesity, dyslipidemia, hyperglycemia, hepatic steatosis, inflammation, fibrosis and low hepatic polyunsaturated fatty acid (PUFA) content. These mice were randomized to 5 groups: a baseline group (WDB, sacrificed at 22 wks) and 4 treatments: 1) WD + olive oil (WDO); 2) WD + DHA (WDD); 3) returned to chow + olive oil (WDChO); or 4) returned to chow + DHA (WDChD). The four treatment groups were maintained on their respective diets for 8 wks. An additional group was maintained on standard laboratory chow (Reference Diet, RD) for the 30-wk duration of the study. Results When compared to the WDB group, the WDO group displayed increased hepatic expression of genes linked to inflammation (Opn, Il1rn, Gdf15), hepatic fibrosis (collagen staining, Col1A1, Thbs2, Lox) reflecting disease progression. Mice in the WDD group, in contrast, had increased hepatic C20-22 ω3 PUFA and no evidence of NASH progression. MetS and NASH markers in the WDChO or WDChD groups were significantly attenuated

  1. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lake, April D.; Novak, Petr; Shipkova, Petia

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BAmore » profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile

  2. A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients.

    PubMed

    Campos, Guilherme M; Bambha, Kiran; Vittinghoff, Eric; Rabl, Charlotte; Posselt, Andrew M; Ciovica, Ruxandra; Tiwari, Umesh; Ferrel, Linda; Pabst, Mark; Bass, Nathan M; Merriman, Raphael B

    2008-06-01

    Nonalcoholic steatohepatitis (NASH) is common in morbidly obese persons. Liver biopsy is diagnostic but technically challenging in such individuals. This study was undertaken to develop a clinically useful scoring system to predict the probability of NASH in morbidly obese persons, thus assisting in the decision to perform liver biopsy. Consecutive subjects undergoing bariatric surgery without evidence of other liver disease underwent intraoperative liver biopsy. The outcome was pathologic diagnosis of NASH. Predictors evaluated were demographic, clinical, and laboratory variables. A clinical scoring system was constructed by rounding the estimated regression coefficients for the independent predictors in a multivariate logistic model for the diagnosis of NASH. Of 200 subjects studied, 64 (32%) had NASH. Median body mass index was 48 kg/m(2) (interquartile range, 43-55). Multivariate analysis identified six predictive factors for NASH: the diagnosis of hypertension (odds ratio [OR], 2.4; 95% confidence interval [CI], 1-5.6), type 2 diabetes (OR, 2.6; 95% CI, 1.1-6.3), sleep apnea (OR, 4.0; 95% CI, 1.3-12.2), AST > 27 IU/L (OR, 2.9; 95% CI, 1.2-7.0), alanine aminotransferase (ALT) > 27 IU/L (OR, 3.3; 95% CI, 1.4-8.0), and non-Black race (OR, 8.4; 95% CI, 1.9-37.1). A NASH Clinical Scoring System for Morbid Obesity was derived to predict the probability of NASH in four categories (low, intermediate, high, and very high). The proposed clinical scoring can predict NASH in morbidly obese persons with sufficient accuracy to be considered for clinical use, identifying a very high-risk group in whom liver biopsy would be very likely to detect NASH, as well as a low-risk group in whom biopsy can be safely delayed or avoided.

  3. Liver Injury and Fibrosis Induced by Dietary Challenge in the Ossabaw Miniature Swine

    PubMed Central

    Liang, Tiebing; Alloosh, Mouhamad; Bell, Lauren N.; Fullenkamp, Allison; Saxena, Romil; Van Alstine, William; Bybee, Phelan; Werling, Klára; Sturek, Michael; Chalasani, Naga; Masuoka, Howard C.

    2015-01-01

    Background Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet) develop metabolic syndrome and nonalcoholic steatohepatitis (NASH) characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model. Methods Ossabaw swine were fed standard chow (control group; n = 6) or NASH diet (n = 6) for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24. Results The NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a) hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (>90% hepatocytes), (b) hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c) Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides. Conclusions This report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a) hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b) hepatocyte ballooning generally precedes the development of fibrosis; (c) there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides. PMID:25978364

  4. Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E.

    PubMed

    Ni, Yinhua; Nagashimada, Mayumi; Zhuge, Fen; Zhan, Lili; Nagata, Naoto; Tsutsui, Akemi; Nakanuma, Yasuni; Kaneko, Shuichi; Ota, Tsuguhito

    2015-11-25

    Hepatic insulin resistance and nonalcoholic steatohepatitis (NASH) could be caused by excessive hepatic lipid accumulation and peroxidation. Vitamin E has become a standard treatment for NASH. However, astaxanthin, an antioxidant carotenoid, inhibits lipid peroxidation more potently than vitamin E. Here, we compared the effects of astaxanthin and vitamin E in NASH. We first demonstrated that astaxanthin ameliorated hepatic steatosis in both genetically (ob/ob) and high-fat-diet-induced obese mice. In a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat diet, astaxanthin alleviated excessive hepatic lipid accumulation and peroxidation, increased the proportion of M1-type macrophages/Kupffer cells, and activated stellate cells to improve hepatic inflammation and fibrosis. Moreover, astaxanthin caused an M2-dominant shift in macrophages/Kupffer cells and a subsequent reduction in CD4(+) and CD8(+) T cell recruitment in the liver, which contributed to improved insulin resistance and hepatic inflammation. Importantly, astaxanthin reversed insulin resistance, as well as hepatic inflammation and fibrosis, in pre-existing NASH. Overall, astaxanthin was more effective at both preventing and treating NASH compared with vitamin E in mice. Furthermore, astaxanthin improved hepatic steatosis and tended to ameliorate the progression of NASH in biopsy-proven human subjects. These results suggest that astaxanthin might be a novel and promising treatment for NASH.

  5. Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E

    PubMed Central

    Ni, Yinhua; Nagashimada, Mayumi; Zhuge, Fen; Zhan, Lili; Nagata, Naoto; Tsutsui, Akemi; Nakanuma, Yasuni; Kaneko, Shuichi; Ota, Tsuguhito

    2015-01-01

    Hepatic insulin resistance and nonalcoholic steatohepatitis (NASH) could be caused by excessive hepatic lipid accumulation and peroxidation. Vitamin E has become a standard treatment for NASH. However, astaxanthin, an antioxidant carotenoid, inhibits lipid peroxidation more potently than vitamin E. Here, we compared the effects of astaxanthin and vitamin E in NASH. We first demonstrated that astaxanthin ameliorated hepatic steatosis in both genetically (ob/ob) and high-fat-diet-induced obese mice. In a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat diet, astaxanthin alleviated excessive hepatic lipid accumulation and peroxidation, increased the proportion of M1-type macrophages/Kupffer cells, and activated stellate cells to improve hepatic inflammation and fibrosis. Moreover, astaxanthin caused an M2-dominant shift in macrophages/Kupffer cells and a subsequent reduction in CD4+ and CD8+ T cell recruitment in the liver, which contributed to improved insulin resistance and hepatic inflammation. Importantly, astaxanthin reversed insulin resistance, as well as hepatic inflammation and fibrosis, in pre-existing NASH. Overall, astaxanthin was more effective at both preventing and treating NASH compared with vitamin E in mice. Furthermore, astaxanthin improved hepatic steatosis and tended to ameliorate the progression of NASH in biopsy-proven human subjects. These results suggest that astaxanthin might be a novel and promising treatment for NASH. PMID:26603489

  6. Prevention of nonalcoholic steatohepatitis in rats by two manganese-salen complexes.

    PubMed

    Rezazadeh, Alireza; Yazdanparast, Razieh

    2014-01-01

    Nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis with inflammation. Investigations have suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. To provide further insights into beneficial effects of antioxidants in NASH prevention, we employed two manganese-superoxide dismutase/catalase mimetics, manganese N,N`-bis(salicyldene) ethylene diamine chloride (EUK-8) and manganese-3-methoxy N,N`-bis(salicyldene)ethylenediamine chloride (EUK-134), as two salen representatives and vitamin C as the standard antioxidant. Experimental NASH was induced in Male N-Mary rats by feeding a methionine/choline-deficient (MCD) diet to rats for 10 weeks. The rats (n = 5, 30 mg/kg/day) were randomly assigned to receive vitamin C, EUK-8, EUK-134 or vehicle orally. Administration of salens together with the MCD diet reduced the serum aminotransferases, glutathione transferase and alkaline phosphatase, cholesterol, and LDL contents. In addition, the EUK-8 and EUK-134 improved NASH pathological features in liver of MCD-fed rats. EUK-8 and EUK-134 supplementation reduces NASH-induced abnormalities, pointing out that antioxidant strategy could be beneficial for prevention of NASH.

  7. Nonalcoholic fatty liver disease and liver transplantation - Where do we stand?

    PubMed Central

    Mikolasevic, Ivana; Filipec-Kanizaj, Tajana; Mijic, Maja; Jakopcic, Ivan; Milic, Sandra; Hrstic, Irena; Sobocan, Nikola; Stimac, Davor; Burra, Patrizia

    2018-01-01

    Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) is a challenging and multisystem disease that has a high socioeconomic impact. NAFLD/NASH is a main cause of macrovesicular steatosis and has multiple impacts on liver transplantation (LT), on patients on the waiting list for transplant, on post-transplant setting as well as on organ donors. Current data indicate new trends in the area of chronic liver disease. Due to the increased incidence of metabolic syndrome (MetS) and its components, NASH cirrhosis and hepatocellular carcinoma caused by NASH will soon become a major indication for LT. Furthermore, due to an increasing incidence of MetS and, consequently, NAFLD, there will be more steatotic donor livers and less high quality organs available for LT, in addition to a lack of available liver allografts. Patients who have NASH and are candidates for LT have multiple comorbidities and are unique LT candidates. Finally, we discuss long-term grafts and patient survival after LT, the recurrence of NASH and NASH appearing de novo after transplantation. In addition, we suggest topics and areas that require more research for improving the health care of this increasing patient population. PMID:29662288

  8. 77 FR 43369 - Alumax Mill Products, Inc. Doing Business as Alcoa Mill Products Texarkana a Subsidiary of Alcoa...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-24

    .... Doing Business as Alcoa Mill Products Texarkana a Subsidiary of Alcoa, Inc. Nash, TX; Amended... Mill Products Texarkana, a subsidiary of Alcoa, Inc., Nash, Texas, was separated is Alumax Mill... Alcoa Mill Products Texarkana, a subsidiary of Alcoa, Inc., Nash, Texas, who became totally or partially...

  9. Vitamin B5 and N-acetylcysteine in nonalcoholic steatohepatitis: a pre-clinical study in a dietary mouse model

    PubMed Central

    Machado, Mariana Verdelho; Kruger, Leandi; Jewell, Mark L.; Michelotti, Gregory Alexander; de Almeida Pereira, Thiago; Xie, Guanhua; Moylan, Cynthia A.; Diehl, Anna Mae

    2015-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free Coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation. Objectives We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH. Methods CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD-diet fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH. Results Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity, and correlated with worse liver cell apoptosis, inflammation and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice. Conclusion In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH. PMID:26403427

  10. Advanced non-alcoholic steatohepatitis cirrhosis: A high-risk population for pre-liver transplant portal vein thrombosis.

    PubMed

    Stine, Jonathan G; Argo, Curtis K; Pelletier, Shawn J; Maluf, Daniel G; Caldwell, Stephen H; Northup, Patrick G

    2017-01-28

    To examine if liver transplant recipients with high-risk non-alcoholic steatohepatitis (NASH) are at increased risk for pre-transplant portal venous thrombosis. Data on all liver transplants in the United States from February 2002 through September 2014 were analyzed. Recipients were sorted into three distinct groups: High-risk (age > 60, body mass index > 30 kg/m 2 , hypertension and diabetes), low-risk and non-NASH cirrhosis. Multivariable logistic regression models were constructed. Thirty-five thousand and seventy-two candidates underwent liver transplantation and of those organ recipients, 465 were transplanted for high-risk and 2775 for low-risk NASH. Two thousand six hundred and twenty-six (7.5%) recipients had pre-transplant portal vein thrombosis; 66 (14.2%) of the high-risk NASH group had portal vein thrombosis vs 328 (11.8%) of the low-risk NASH group. In general, all NASH recipients were less likely to be male or African American and more likely to be obese. In adjusted multivariable regression analyses, high-risk recipients had the greatest risk of pre-transplant portal vein thrombosis with OR = 2.11 (95%CI: 1.60-2.76, P < 0.001) when referenced to the non-NASH group. Liver transplant candidates with high-risk NASH are at the greatest risk for portal vein thrombosis development prior to transplantation. These candidates may benefit from interventions to decrease their likelihood of clot formation and resultant downstream hepatic decompensating events. Prospective study is needed.

  11. Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease

    PubMed Central

    Machado, Mariana Verdelho; Michelotti, Gregory Alexander; Xie, Guanhua; de Almeida, Thiago Pereira; Boursier, Jerome; Bohnic, Brittany; Guy, Cynthia D.; Diehl, Anna Mae

    2015-01-01

    Background and aims Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet. Methods Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared. Results The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation. Conclusion Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH. PMID:26017539

  12. Game Design and Analysis for Price-Based Demand Response: An Aggregate Game Approach.

    PubMed

    Ye, Maojiao; Hu, Guoqiang

    2016-02-18

    In this paper, an aggregate game is adopted for the modeling and analysis of energy consumption control in smart grid. Since the electricity users' cost functions depend on the aggregate energy consumption, which is unknown to the end users, an average consensus protocol is employed to estimate it. By neighboring communication among the users about their estimations on the aggregate energy consumption, Nash seeking strategies are developed. Convergence properties are explored for the proposed Nash seeking strategies. For energy consumption game that may have multiple isolated Nash equilibria, a local convergence result is derived. The convergence is established by utilizing singular perturbation analysis and Lyapunov stability analysis. Energy consumption control for a network of heating, ventilation, and air conditioning systems is investigated. Based on the uniqueness of the Nash equilibrium, it is shown that the players' actions converge to a neighborhood of the unique Nash equilibrium nonlocally. More specially, if the unique Nash equilibrium is an inner Nash equilibrium, an exponential convergence result is obtained. Energy consumption game with stubborn players is studied. In this case, the actions of the rational players can be driven to a neighborhood of their best response strategies by using the proposed method. Numerical examples are presented to verify the effectiveness of the proposed methods.

  13. Prevention of Nonalcoholic Steatohepatitis in Rats by Two Manganese-Salen Complexes

    PubMed Central

    Rezazadeh, Alireza; Yazdanparast, Razieh

    2014-01-01

    Background: Nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis with inflammation. Investigations have suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. To provide further insights into beneficial effects of antioxidants in NASH prevention, we employed two manganese-superoxide dismutase/catalase mimetics, manganese N,N`-bis(salicyldene) ethylene diamine chloride (EUK-8) and manganese-3-methoxy N,N`-bis(salicyldene)ethylenediamine chloride (EUK-134), as two salen representatives and vitamin C as the standard antioxidant. Methods: Experimental NASH was induced in Male N-Mary rats by feeding a methionine/choline-deficient (MCD) diet to rats for 10 weeks. The rats (n = 5, 30 mg/kg/day) were randomly assigned to receive vitamin C, EUK-8, EUK-134 or vehicle orally. Results: Administration of salens together with the MCD diet reduced the serum aminotransferases, glutathione transferase and alkaline phosphatase, cholesterol, and LDL contents. In addition, the EUK-8 and EUK-134 improved NASH pathological features in liver of MCD-fed rats. Conclusion: EUK-8 and EUK-134 supplementation reduces NASH-induced abnormalities, pointing out that antioxidant strategy could be beneficial for prevention of NASH. PMID:24375162

  14. TNF-α messenger ribonucleic acid (mRNA) in patients with nonalcoholic steatohepatitis.

    PubMed

    Alaaeddine, Nada; Sidaoui, Joseph; Hilal, George; Serhal, Reem; Abedelrahman, Abir; Khoury, Salem

    2012-01-01

    tumor necrosis factor (TNF)-α plays a significant role in the pathogenesis of nonalcoholic steatohepatitis (NASH). A few studies have confirmed high TNF-α plasma protein levels in patients with NASH compared to healthy volunteers. We herein aimed to revisit these findings using other molecular techniques. a cross-sectional evaluation of patients newly diagnosed with NASH. A quantitative assay for the measurement of TNF-α messenger ribonucleic acid (mRNA) was performed for NASH patients and controls using real-time reverse transcription polymerase chain reaction (RT-PCR). in 39 patients with NASH (mean age 38.6 ± 9.4 years, range 28-60 years; 79% males), the mean TNF-α mRNA level was significantly higher than that found for controls (137.6 ± 102.3 ng/mL versus 83.5 ± 43.8 ng/mL, respectively; P = 0.012). A TNF-α mRNA cut-off of 100 ng/mL predicted NASH most optimally (AUC 0.685 ± 0.066, P = 0.01; with 66.7% sensitivity and 74.1% specificity). Serum TNF-α and soluble TNF-α receptor II (sTNFRII) levels were significantly higher in patients compared to controls using ELISA. high TNF-α mRNA levels, determined by RT-PCR, characterize patients with NASH.

  15. Phosphoproteomic biomarkers predicting histologic nonalcoholic steatohepatitis and fibrosis.

    PubMed

    Younossi, Zobair M; Baranova, Ancha; Stepanova, Maria; Page, Sandra; Calvert, Valerie S; Afendy, Arian; Goodman, Zachary; Chandhoke, Vikas; Liotta, Lance; Petricoin, Emanuel

    2010-06-04

    The progression of nonalcoholic fatty liver disease (NAFLD) has been linked to deregulated exchange of the endocrine signaling between adipose and liver tissue. Proteomic assays for the phosphorylation events that characterize the activated or deactivated state of the kinase-driven signaling cascades in visceral adipose tissue (VAT) could shed light on the pathogenesis of nonalcoholic steatohepatitis (NASH) and related fibrosis. Reverse-phase protein microarrays (RPMA) were used to develop biomarkers for NASH and fibrosis using VAT collected from 167 NAFLD patients (training cohort, N = 117; testing cohort, N = 50). Three types of models were developed for NASH and advanced fibrosis: clinical models, proteomics models, and combination models. NASH was predicted by a model that included measurements of two components of the insulin signaling pathway: AKT kinase and insulin receptor substrate 1 (IRS1). The models for fibrosis were less reliable when predictions were based on phosphoproteomic, clinical, or the combination data. The best performing model relied on levels of the phosphorylation of GSK3 as well as on two subunits of cyclic AMP regulated protein kinase A (PKA). Phosphoproteomics technology could potentially be used to provide pathogenic information about NASH and NASH-related fibrosis. This information can lead to a clinically relevant diagnostic/prognostic biomarker for NASH.

  16. Anti-oxidative and anti-inflammatory effects of spirulina on rat model of non-alcoholic steatohepatitis

    PubMed Central

    Pak, Wing; Takayama, Fusako; Mine, Manaka; Nakamoto, Kazuo; Kodo, Yasumasa; Mankura, Mitsumasa; Egashira, Toru; Kawasaki, Hiromu; Mori, Akitane

    2012-01-01

    The pathogenesis of nonalcoholic steatohepatitis (NASH) remains unclear, but accumulating data suggest oxidative stress and the relationship between inflammation and immunity plays a crucial role. The aim of this study is to investigate the spirulina, which is a blue-green algae rich in proteins and other nutritional elements, and its component-phycocyanin effect on a rat model of NASH. NASH model rats were established by feeding male Wistar rats with choline-deficient high-fat diet (CDHF) and intermittent hypoxemia by sodium nitrite challenge after 5 weeks of CDHF. After experimental period of 10 weeks, blood and liver were collected to determine oxidative stress injuries and efficacies of spirulina or phycocyanin on NASH model rats. In the NASH model rats, increase in plasma liver enzymes and liver fibrosis, increases in productions of reactive oxygen species from liver mitochondria and from leukocytes, the activation of nuclear factor-kappa B, and the change in the lymphocyte surface antigen ratio (CD4+/CD8+) were observed. The spirulina and phycocyanin administration significantly abated these changes. The spirulina or phycocyanin administration to model rats of NASH might lessen the inflammatory response through anti-oxidative and anti-inflammatory mechanisms, breaking the crosstalk between oxidative stress and inflammation, and effectively inhibit NASH progression. PMID:23170052

  17. Taking Student Success to Scale

    ERIC Educational Resources Information Center

    Martin, Rebecca R.

    2017-01-01

    In 2014 the National Association of System Heads (NASH) launched the landmark initiative "NASH TS[superscript 3]: Taking Student Success to Scale." Collectively, TS[superscript 3] is made up of 23 systems and over 300 institutions that span 18 states. (NASH: Taking Student Success to Scale 2016) These systems have a combined…

  18. M1 polarization bias and subsequent nonalcoholic steatohepatitis progression is attenuated by nitric oxide donor DETA NONOate via inhibition of CYP2E1-induced oxidative stress in obese mice.

    PubMed

    Seth, Ratanesh Kumar; Das, Suvarthi; Pourhoseini, Sahar; Dattaroy, Diptadip; Igwe, Stephen; Ray, Julie Basu; Fan, Daping; Michelotti, Gregory A; Diehl, Anna Mae; Chatterjee, Saurabh

    2015-01-01

    Activation of M1 macrophages in nonalcoholic steatohepatitis (NASH) is produced by several external or endogenous factors: inflammatory stimuli, oxidative stress, and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH, and that nitric oxide (NO) donor administration inhibits CYP2E1-mediated inflammation with concomitant attenuation of M1 polarization. Because CYP2E1 takes center stage in these studies, we used a toxin model of NASH that uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently, we used a methionine and choline-deficient diet-induced rodent NASH model where the role of CYP2E1 in disease progression has been shown. Our results show that CYP2E1 causes M1 polarization bias, which includes a significant increase in interleukin-1β (IL-1β) and IL-12 in both models of NASH, whereas CYP2E1-null mice or diallyl sulfide administration prevented it. Administration of gadolinium chloride (GdCl3), a macrophage toxin, attenuated both the initial M1 response and the subsequent M2 response, showing that the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, the NO donor administration in vivo that mechanistically inhibited CYP2E1 catalyzed the oxidative stress during the entire study in NASH-abrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization, and that inhibition of CYP2E1 catalyzed oxidative stress by an NO donor (DETA NONOate [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate]) can be a promising therapeutic strategy in NASH. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  19. M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

    PubMed Central

    Seth, Ratanesh Kumar; Das, Suvarthi; Pourhoseini, Sahar; Dattaroy, Diptadip; Igwe, Stephen; Ray, Julie Basu; Fan, Daping; Michelotti, Gregory A.; Diehl, Anna Mae

    2015-01-01

    Activation of M1 macrophages in nonalcoholic steatohepatitis (NASH) is produced by several external or endogenous factors: inflammatory stimuli, oxidative stress, and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH, and that nitric oxide (NO) donor administration inhibits CYP2E1-mediated inflammation with concomitant attenuation of M1 polarization. Because CYP2E1 takes center stage in these studies, we used a toxin model of NASH that uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently, we used a methionine and choline–deficient diet-induced rodent NASH model where the role of CYP2E1 in disease progression has been shown. Our results show that CYP2E1 causes M1 polarization bias, which includes a significant increase in interleukin-1β (IL-1β) and IL-12 in both models of NASH, whereas CYP2E1-null mice or diallyl sulfide administration prevented it. Administration of gadolinium chloride (GdCl3), a macrophage toxin, attenuated both the initial M1 response and the subsequent M2 response, showing that the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, the NO donor administration in vivo that mechanistically inhibited CYP2E1 catalyzed the oxidative stress during the entire study in NASH-abrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization, and that inhibition of CYP2E1 catalyzed oxidative stress by an NO donor (DETA NONOate [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate]) can be a promising therapeutic strategy in NASH. PMID:25347994

  20. Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis

    PubMed Central

    Das, Suvarthi; Seth, Ratanesh Kumar; Kumar, Ashutosh; Kadiiska, Maria B.; Michelotti, Gregory; Diehl, Anna Mae

    2013-01-01

    Recent studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanisms that link these important events in NASH remain unclear. In this study, we investigated the mechanistic role of purinergic receptor X7 (P2X7) in modulating autophagy and resultant inflammation in NASH in response to metabolic oxidative stress. The study uses two rodent models of NASH. In one of them, a CYP2E1 substrate bromodichloromethane is used to induce metabolic oxidative stress and NASH. Methyl choline-deficient diet feeding is used for the other NASH model. CYP2E1 and P2X7 receptor gene-deleted mice are used to establish their roles in regulating metabolic oxidative stress and autophagy. Autophagy gene expression, protein levels, confocal microscopy based-immunolocalization of lysosome-associated membrane protein (LAMP)2A and histopathological analysis were performed. CYP2E1-dependent metabolic oxidative stress induced increases in P2X7 receptor expression and chaperone-mediated autophagy markers LAMP2A and heat shock cognate 70 but caused depletion of light chain 3 isoform B (LC3B) protein levels. P2X7 receptor gene deletion significantly decreased LAMP2A and inflammatory indicators while significantly increasing LC3B protein levels compared with wild-type mice treated with bromodichloromethane. P2X7 receptor-deleted mice were also protected from NASH pathology as evidenced by decreased inflammation and fibrosis. Our studies establish that P2X7 receptor is a key regulator of autophagy induced by metabolic oxidative stress in NASH, thereby modulating hepatic inflammation. Furthermore, our findings presented here form a basis for P2X7 receptor as a potential therapeutic target in the treatment for NASH. PMID:24157968

  1. Usefulness of Cytokeratin-18M65 in Diagnosing Non-Alcoholic Steatohepatitis in Japanese Population.

    PubMed

    Hasegawa, Yutaka; Kim, Soo Ryang; Hatae, Takashi; Ohta, Mitsuhiro; Fujinami, Aya; Sugimoto, Kayo; Kim, Ke Ih; Imoto, Susumu; Tohyama, Madoka; Kim, Soo Ki; Ikura, Yoshihiro; Kudo, Masatoshi

    2015-10-01

    The aim of this study was to evaluate cytokeratin-18M65 (CK-18M65) for distinguishing between simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) against healthy individuals (HIs) in Japanese population. The serum from 24 HIs, 21 patients with SS and 20 patients with NASH were examined. Serum CK-18M65 was measured by enzyme-linked immunosorbent assay. Aspartate aminotransferase was significantly different between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001), as was alanine aminotransferase between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001). Serum CK-18M65 increased in a stepwise fashion in HIs and also in SS and NASH patients. Multivariate logistic regression analysis revealed that NASH could be diagnosed with the use of CK-18M65 alone (p = 0.0285, OR 1.0038, 95% CI 1.0004-1.0073). At the optimal cut-off level of 548 U/l, CK-18M65 had an AUC value of 0.7369, 60.00% sensitivity and 85.70% specificity. In patients with NASH, no significant difference was observed between low fibrosis (Stage 0-1, 794.30 ± 454.41, n = 10) and high fibrosis (Stage 2-3, 809.70 ± 641.43, n = 10; p = 0.5967) and between slight steatosis (<33%, 512.89 ± 229.65, n = 9) and moderate steatosis (≥33%, 655.13 ± 480.78, n = 32) in patients with non-alcoholic fatty liver disease (NAFLD; p = 0.7647) with the use of CK-18M65. Serum CK-18M65 distinguished NASH from SS, but could not assess the severity of steatosis in NAFLD patients or the grade of fibrosis in NASH patients in Japanese population. © 2015 S. Karger AG, Basel.

  2. Neonatal monosodium glutamate treatment causes obesity, diabetes, and macrovesicular steatohepatitis with liver nodules in DIAR mice.

    PubMed

    Tsuneyama, Koichi; Nishida, Takeshi; Baba, Hayato; Taira, Shu; Fujimoto, Makoto; Nomoto, Kazuhiro; Hayashi, Shinichi; Miwa, Shigeharu; Nakajima, Takahiko; Sutoh, Mitsuko; Oda, Emu; Hokao, Ryoji; Imura, Johji

    2014-09-01

    Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome (MS). Monosodium glutamate (MSG)-treated ICR mice is a useful model of MS and NASH, but it shows the different patterns of steatosis from human NASH. Because inbred aged DIAR (ddY, Institute for Animal Reproduction) mice spontaneously show the similar pattern of steatosis as NASH, we analyzed their liver pathology after administering MSG. MSG-treated DIAR mice (DIAR-MSG) and untreated DIAR mice (DIAR-controls) were sacrificed and assessed histopathologically at 29, 32, 40, 48, and 54 weeks of age. The NASH activity score, body mass index, blood glucose level, and oral glucose tolerance test were also assessed. The body mass index and blood glucose levels of DIAR-MSG were significantly higher than controls. The oral glucose tolerance test revealed a type 2 diabetes pattern in DIAR-MSG. The livers of DIAR-MSG mice showed macrovesicular steatosis, lobular inflammation with neutrophils, and ballooning degeneration after 29 weeks. At 54 weeks, mild fibrosis was observed in 5/6 DIAR-MSG and 2/5 DIAR-control mice. In imaging mass spectrometry analysis, cholesterol as well as triglyceride accumulated in the liver of DIAR-MSG mice. Atypical liver nodules were also observed after 32 weeks in DIAR-MSG, some with cellular and structural atypia mimicking human hepatocellular carcinoma. The NASH activity score of DIAR-MSG after 29 weeks was higher than that of control mice, suggesting the development of NASH. DIAR-MSG had NASH-like liver pathology and liver nodules typically associated with MS symptoms. DIAR-MSG provides a valuable animal model to analyze NASH pathogenesis and carcinogenesis. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  3. Impact of Renal Impairment on Cardiovascular Disease Mortality After Liver Transplantation for Nonalcoholic Steatohepatitis Cirrhosis

    PubMed Central

    VanWagner, Lisa B.; Lapin, Brittany; Skaro, Anton I.; Lloyd-Jones, Donald M.; Rinella, Mary E.

    2016-01-01

    BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is an independent risk factor for cardiovascular disease (CVD) morbidity after liver transplantation, but its impact on CVD mortality is unknown. We sought to assess the impact of NASH on CVD mortality after liver transplantation and to predict which NASH recipients are at highest risk of a CVD-related death following a liver transplant. METHODS Using the Organ Procurement and Transplantation Network database we examined associations between NASH and post liver transplant CVD mortality, defined as primary cause of death from thromboembolism, arrhythmia, heart failure, myocardial infarction, or stroke. A physician panel reviewed cause of death. RESULTS Of 48,360 liver transplants (2/2002–12/2011), 5,057 (10.5%) were performed for NASH cirrhosis. NASH recipients were more likely to be older, female, obese, diabetic, and have history of renal failure or prior CVD versus non-NASH (p<0.001 for all). Although there was no difference in overall all-cause mortality (log-rank p=0.96), both early (30-day) and long-term CVD-specific mortality was increased among NASH recipients (Odds ratio=1.30, 95% Confidence interval (CI): 1.02–1.66; Hazard ratio=1.42, 95% CI: 1.07–1.41, respectively). These associations were no longer significant after adjustment for pre-transplant diabetes, renal impairment or CVD. A risk score comprising age ≥ 55, male sex, diabetes and renal impairment was developed for prediction of post liver transplant CVD mortality (c-statistic 0.60). CONCLUSION NASH recipients have an increased risk of CVD mortality after liver transplantation explained by a high prevalence of co-morbid cardiometabolic risk factors that in aggregate identify those at highest risk of post-transplant CVD mortality. PMID:25977117

  4. Systems Level Metabolic Phenotype of Methotrexate Administration in the Context of Non-alcoholic Steatohepatitis in the Rat

    PubMed Central

    Kyriakides, Michael; Hardwick, Rhiannon N.; Jin, Zhaosheng; Goedken, Michael J.; Holmes, Elaine; Cherrington, Nathan J.; Coen, Muireann

    2014-01-01

    Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs. PMID:25145655

  5. Obstructive Sleep Apnea Is Associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology.

    PubMed

    Corey, Kathleen E; Misdraji, Joseph; Gelrud, Lou; King, Lindsay Y; Zheng, Hui; Malhotra, Atul; Chung, Raymond T

    2015-08-01

    Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are growing in prevalence in the USA. Existing data on the relationship between OSA and NAFLD are conflicting and limited by the use of various histologic definitions of nonalcoholic steatohepatitis (NASH). Using a robust definition of NASH in a large, well-characterized cohort, we sought to evaluate whether OSA was associated with NASH and advanced fibrosis. Two hundred and thirteen subjects undergoing weight loss surgery were queried for OSA and then underwent liver biopsy. NASH was defined, as recommended by the American Association for the Study of Liver Disease, by the presence of all of the following: >5 % macrovesicular steatosis, lobular inflammation, and hepatocyte ballooning. NAFLD activity score (NAS) was also determined for each subject. Subjects with OSA had significantly higher alanine and aspartate aminotransferase levels than subjects without OSA (ALT 54.1 vs. 37.7 U/L, P = 0.0007; AST 31.7 vs. 20.5 U/L, P = 0.0007). OSA was associated with the presence of NASH, and this remained significant after adjusting for age, gender, race, and diabetes mellitus (P = 0.03 OR 2.01; 95 %, 1.05-3.87). Steatosis grade, lobular inflammation grade, NAS score, and fibrosis stage were all significantly associated with the presence of OSA and remained so after adjustment. OSA is associated with elevated aminotransferase levels, the presence of NASH, and advanced NASH histology. Further studies are needed to evaluate the impact of OSA treatment on NASH.

  6. Obstructive Sleep Apnea is associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology

    PubMed Central

    Corey, Kathleen E; Misdraji, Joseph; Gelrud, Lou; King, Lindsay Y.; Zheng, Hui; Malhotra, Atul; Chung, Raymond T

    2015-01-01

    Background and Aims Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are growing in prevalence in the United States. Existing data on the relationship between OSA and NAFLD is conflicting and limited by the use of various histologic definitions of nonalcoholic steatohepatitis (NASH). Using a robust definition of NASH in a large, well-characterized cohort we sought to evaluate whether OSA was associated with NASH and advanced fibrosis. Methods Two hundred thirteen subjects undergoing weight loss surgery were queried for OSA and then underwent liver biopsy. NASH was defined, as recommended by the American Association for the Study of Liver Disease, by the presence of all of the following: >5% macrovesicular steatosis, lobular inflammation and hepatocyte ballooning. NAFLD activity score (NAS) was also determined for each subject. Results Subjects with OSA had significantly higher alanine and aspartate aminotransferase levels than subjects without OSA (ALT 54.1 U/L vs. 37.7 U/L, P=0.0007; AST 31.7 U/L vs. 20.5 U/L, P=0.0007). OSA was associated with the presence of NASH and this remained significant after adjusting for age, gender, race, and diabetes mellitus (P =0.03 OR, 2.01; 95%, 1.05-3.87). Steatosis grade, lobular inflammation grade, NAS score and fibrosis stage were all significantly associated with the presence of OSA and remained so after adjustment. Conclusions OSA is associated with elevated aminotransferase levels, the presence of NASH and advanced NASH histology. Further studies are needed to evaluate the impact of OSA treatment on NASH. PMID:25840922

  7. Influence of gut microbiota on the development and progression of nonalcoholic steatohepatitis.

    PubMed

    de Faria Ghetti, Fabiana; Oliveira, Daiane Gonçalves; de Oliveira, Juliano Machado; de Castro Ferreira, Lincoln Eduardo Villela Vieira; Cesar, Dionéia Evangelista; Moreira, Ana Paula Boroni

    2018-04-01

    Nonalcoholic steatohepatitis (NASH) is characterized by the presence of steatosis, inflammation, and ballooning degeneration of hepatocytes, with or without fibrosis. The prevalence of NASH has increased with the obesity epidemic, but its etiology is multifactorial. The current studies suggest the role of gut microbiota in the development and progression of NASH. The aim is to review the studies that investigate the relationship between gut microbiota and NASH. These review also discusses the pathophysiological mechanisms and the influence of diet on the gut-liver axis. The available literature has proposed mechanisms for an association between gut microbiota and NASH, such as: modification energy homeostasis, lipopolysaccharides (LPS)-endotoxemia, increased endogenous production of ethanol, and alteration in the metabolism of bile acid and choline. There is evidence to suggest that NASH patients have a higher prevalence of bacterial overgrowth in the small intestine and changes in the composition of the gut microbiota. However, there is still a controversy regarding the microbiome profile in this population. The abundance of Bacteroidetes phylum may be increased, decreased, or unaltered in NASH patients. There is an increase in the Escherichia and Bacteroides genus. There is depletion of certain taxa, such as Prevotella and Faecalibacterium. Although few studies have evaluated the composition of the gut microbiota in patients with NASH, it is observed that these individuals have a distinct gut microbiota, compared to the control groups, which explains, at least in part, the genesis and progression of the disease through multiple mechanisms. Modulation of the gut microbiota through diet control offers new challenges for future studies.

  8. Rising Rate of Liver Transplantation in the Baby Boomer Generation with Non-alcoholic Steatohepatitis in the United States.

    PubMed

    Siddique, Osama; Joseph-Talreja, Mairin; Yoo, Eric R; Perumpail, Ryan B; Cholankeril, George; Harrison, Stephen A; Younossi, Zobair M; Wong, Robert J; Ahmed, Aijaz

    2017-09-28

    Background and Aims: Nonalcoholic steatohepatitis (NASH) is the most rapidly growing indication for liver transplantation (LT) in the United States and is on a trajectory to become the leading indication for LT in the next decade. We aimed to study the trends in NASH-related LT among persons born between 1945 and 1965, the baby boomer (BB) generation. Methods: We performed a retrospective cohort analysis using population-based data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network registry from 2004-2015 to evaluate the birth cohort-specific trends in liver transplant waitlist registrations and liver transplant surgeries in patients with NASH. We stratified our study population into three birth cohorts: 1) birth before 1945, 2) birth between 1945 and 1965, and 3) birth after 1965. Results: The overall rates of NASH-related waitlist registrations and liver transplant surgeries steadily increased from 2004 to 2015 and were reflective of a sharp rise noted in the NASH BB sub-group. From 2004 to 2015, the proportion of BB patients with NASH added to LT waitlist demonstrated an incremental growth, 60.6% in 2004 versus 83.2% in 2015 ( p < 0.01). Among the liver transplant recipients with NASH, the proportion represented by the BB cohort increased from 56.3% in 2004 to 80.0% in 2015 ( p < 0.01). Conclusions: We report rising rates of waitlist registration and LT for the indication of NASH. More importantly, the BB sub-cohort was mainly responsible for these alarming trends.

  9. Rising Rate of Liver Transplantation in the Baby Boomer Generation with Non-alcoholic Steatohepatitis in the United States

    PubMed Central

    Siddique, Osama; Joseph-Talreja, Mairin; Yoo, Eric R.; Perumpail, Ryan B.; Cholankeril, George; Harrison, Stephen A.; Younossi, Zobair M.; Wong, Robert J.; Ahmed, Aijaz

    2017-01-01

    Abstract Background and Aims: Nonalcoholic steatohepatitis (NASH) is the most rapidly growing indication for liver transplantation (LT) in the United States and is on a trajectory to become the leading indication for LT in the next decade. We aimed to study the trends in NASH-related LT among persons born between 1945 and 1965, the baby boomer (BB) generation. Methods: We performed a retrospective cohort analysis using population-based data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network registry from 2004–2015 to evaluate the birth cohort-specific trends in liver transplant waitlist registrations and liver transplant surgeries in patients with NASH. We stratified our study population into three birth cohorts: 1) birth before 1945, 2) birth between 1945 and 1965, and 3) birth after 1965. Results: The overall rates of NASH-related waitlist registrations and liver transplant surgeries steadily increased from 2004 to 2015 and were reflective of a sharp rise noted in the NASH BB sub-group. From 2004 to 2015, the proportion of BB patients with NASH added to LT waitlist demonstrated an incremental growth, 60.6% in 2004 versus 83.2% in 2015 (p < 0.01). Among the liver transplant recipients with NASH, the proportion represented by the BB cohort increased from 56.3% in 2004 to 80.0% in 2015 (p < 0.01). Conclusions: We report rising rates of waitlist registration and LT for the indication of NASH. More importantly, the BB sub-cohort was mainly responsible for these alarming trends. PMID:28936399

  10. Deficiency of iNOS-derived NO accelerates lipid accumulation-independent liver fibrosis in non-alcoholic steatohepatitis mouse model.

    PubMed

    Nozaki, Yuichi; Fujita, Koji; Wada, Koichiro; Yoneda, Masato; Kessoku, Takaomi; Shinohara, Yoshiyasu; Imajo, Kento; Ogawa, Yuji; Nakamuta, Makoto; Saito, Satoru; Masaki, Naohiko; Nagashima, Yoji; Terauchi, Yasuo; Nakajima, Atsushi

    2015-04-01

    Although many of the factors and molecules closely associated with non-alcoholic steatohepatitis (NASH) have been reported, the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) on the progression of NASH remains unclear. We therefore investigated the role of iNOS-derived NO in NASH pathogenesis with a long-term follow-up study using systemic iNOS-knockout mice under high-fat diet (HFD) conditions. iNOS-knockout and wild-type mice were fed a basal or HFD for 10 or 48 weeks. Lipid accumulation, fibrosis, and inflammation were evaluated, and various factors and molecules closely associated with NASH were analyzed. Marked fibrosis and inflammation (indicators of NASH) were observed in the livers of iNOS-knockout mice compared to wild-type mice after 48 weeks of a HFD; however, lipid accumulation in iNOS-knockout mice livers was less than in the wild-type. Increased expressions of various cytokines that are transcriptionally controlled by NF-kB in iNOS-deficient mice livers were observed during HFD conditions. iNOS-derived NO may play a protective role against the progression to NASH during an HFD by preventing fibrosis and inflammation, which are mediated by NF-kB activation in Kupffer cells. A lack of iNOS-derived NO accelerates progression to NASH without excessive lipid accumulation.

  11. Teucrium polium reversed the MCD diet-induced liver injury in rats.

    PubMed

    Amini, Rahim; Yazdanparast, Razieh; Aghazadeh, Safiyeh; Ghaffari, Seyed H

    2011-09-01

    In the present study, we evaluated the ability of Teucrium polium ethyl acetate fraction, with high antioxidant activity, in the treatment of nonalcoholic steatohepatitis (NASH) in rats and its possible effect on factors involved in pathogenesis of the disease. To induce NASH, a methionine and choline deficient (MCD) diet was given to N-Mary rats for 8 weeks. After NASH development, MCD-fed rats were divided into 2 groups: NASH group that received MCD diet and NASH + T group which was fed MCD diet plus ethyl acetate fraction of T. polium orally for 3 weeks. Histopathological evaluations revealed that treatment with the extract has abated the severity of NASH among the MCD-fed rats. In addition, the fraction reduced the elevated levels of hepatic tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) gene expression and also the elevated level of malondialdehyde (MDA). In addition, the extract increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and enhanced the level of hepatic glutathione (GSH). Moreover, the fraction treatments lowered caspase-3 level and the phosphorylated form of C-Jun N-terminal kinase (JNK) and augmented the phosphorylated level of extracellular regulated kinase1/2 (ERK1/2). These results indicate that the ethyl acetate fraction of T. poium effectively reversed NASH, mainly due to its strong antioxidant and anti-inflammatory properties.

  12. Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple Steatosis: A Systematic Review and Meta-analysis.

    PubMed

    Verhaegh, Pauline; Bavalia, Roisin; Winkens, Bjorn; Masclee, Ad; Jonkers, Daisy; Koek, Ger

    2018-06-01

    Nonalcoholic fatty liver disease is a rapidly increasing health problem. Liver biopsy analysis is the most sensitive test to differentiate between nonalcoholic steatohepatitis (NASH) and simple steatosis (SS), but noninvasive methods are needed. We performed a systematic review and meta-analysis of noninvasive tests for differentiating NASH from SS, focusing on blood markers. We performed a systematic search of the PubMed, Medline and Embase (1990-2016) databases using defined keywords, limited to full-text papers in English and human adults, and identified 2608 articles. Two independent reviewers screened the articles and identified 122 eligible articles that used liver biopsy as reference standard. If at least 2 studies were available, pooled sensitivity (sens p ) and specificity (spec p ) values were determined using the Meta-Analysis Package for R (metafor). In the 122 studies analyzed, 219 different blood markers (107 single markers and 112 scoring systems) were identified to differentiate NASH from simple steatosis, and 22 other diagnostic tests were studied. Markers identified related to several pathophysiological mechanisms. The markers analyzed in the largest proportions of studies were alanine aminotransferase (sens p , 63.5% and spec p , 74.4%) within routine biochemical tests, adiponectin (sensp, 72.0% and spec p , 75.7%) within inflammatory markers, CK18-M30 (sens p , 68.4% and spec p , 74.2%) within markers of cell death or proliferation and homeostatic model assessment of insulin resistance (sens p , 69.0% and spec p , 72.7%) within the metabolic markers. Two scoring systems could also be pooled: the NASH test (differentiated NASH from borderline NASH plus simple steatosis with 22.9% sens p and 95.3% spec p ) and the GlycoNASH test (67.1% sens p and 63.8% spec p ). In the meta-analysis, we found no test to differentiate NASH from SS with a high level of pooled sensitivity and specificity (≥80%). However, some blood markers, when included in scoring

  13. Docosahexaenoic Acid Attenuates Hepatic Inflammation, Oxidative Stress, and Fibrosis without Decreasing Hepatosteatosis in a Ldlr−/− Mouse Model of Western Diet-Induced Nonalcoholic Steatohepatitis123

    PubMed Central

    Depner, Christopher M.; Philbrick, Kenneth A.; Jump, Donald B.

    2013-01-01

    The incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with the incidence of obesity. While both NAFLD and NASH are characterized by hepatosteatosis, NASH is characterized by hepatic damage, inflammation, oxidative stress, and fibrosis. We previously reported that feeding Ldlr−/− mice a high-fat, high-cholesterol diet containing menhaden oil attenuated several markers of NASH, including hepatosteatosis, inflammation, and fibrosis. Herein, we test the hypothesis that DHA [22:6 (n-3)] is more effective than EPA [20:5 (n-3)] at preventing Western diet (WD)-induced NASH in Ldlr−/− mice. Mice were fed the WD supplemented with either olive oil (OO), EPA, DHA, or EPA + DHA for 16 wk. WD + OO feeding induced a severe NASH phenotype, characterized by robust hepatosteatosis, inflammation, oxidative stress, and fibrosis. Whereas none of the C20–22 (n-3) fatty acid treatments prevented WD-induced hepatosteatosis, all 3 (n-3) PUFA-containing diets significantly attenuated WD-induced inflammation, fibrosis, and hepatic damage. The capacity of dietary DHA to suppress hepatic markers of inflammation (Clec4F, F4/80, Trl4, Trl9, CD14, Myd88), fibrosis (Procol1α1, Tgfβ1), and oxidative stress (NADPH oxidase subunits Nox2, p22phox, p40phox, p47phox, p67phox) was significantly greater than dietary EPA. The effects of DHA on these markers paralleled DHA-mediated suppression of hepatic Fads1 mRNA abundance and hepatic arachidonic acid content. Because DHA suppression of NASH markers does not require a reduction in hepatosteatosis, dietary DHA may be useful in combating NASH in obese humans. PMID:23303872

  14. Impact of dietary fat on the development of non-alcoholic fatty liver disease in Ldlr−/− mice

    PubMed Central

    Jump, Donald B.; Depner, Christopher M.; Tripathy, Sasmita; Lytle, Kelli A.

    2015-01-01

    The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity and is now the most common chronic liver disease in developed countries. NAFLD is defined as excessive accumulation of lipid in the liver, i.e. hepatosteatosis. The severity of NAFLD ranges from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH). Simple steatosis is relatively benign until it progresses to NASH, which is characterised by hepatic injury, inflammation, oxidative stress and fibrosis. Hepatic fibrosis is a risk factor for cirrhosis and primary hepatocellular carcinoma. Our studies have focused on the impact of diet on the onset and progression of NASH. We developed a mouse model of NASH by feeding Ldlr−/− mice a western diet (WD), a diet moderately high in saturated and trans-fat, sucrose and cholesterol. The WD induced a NASH phenotype in Ldlr−/− mice that recapitulates many of the clinical features of human NASH. We also assessed the capacity of the dietary n-3 PUFA, i.e. EPA (20 : 5,n-3) and DHA (22 : 6,n-3), to prevent WD-induced NASH in Ldlr−/− mice. Histologic, transcriptomic, lipidomic and metabolomic analyses established that DHA was equal or superior to EPA at attenuating WD-induced dyslipidemia and hepatic injury, inflammation, oxidative stress and fibrosis. Dietary n-3 PUFA, however, had no significant effect on WD-induced changes in body weight, body fat or blood glucose. These studies provide a molecular and metabolic basis for understanding the strengths and weaknesses of using dietary n-3 PUFA to prevent NASH in human subjects. PMID:26282529

  15. Liver fibrosis markers of nonalcoholic steatohepatitis

    PubMed Central

    Enomoto, Hirayuki; Bando, Yukihiro; Nakamura, Hideji; Nishiguchi, Shuhei; Koga, Masafumi

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH. PMID:26139988

  16. Liver fibrosis markers of nonalcoholic steatohepatitis.

    PubMed

    Enomoto, Hirayuki; Bando, Yukihiro; Nakamura, Hideji; Nishiguchi, Shuhei; Koga, Masafumi

    2015-06-28

    Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.

  17. Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

    PubMed Central

    Magee, Nancy; Zou, An

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning), inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER) stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future. PMID:27822476

  18. Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients.

    PubMed

    Noureddin, Mazen; Yates, Katherine P; Vaughn, Ivana A; Neuschwander-Tetri, Brent A; Sanyal, Arun J; McCullough, Arthur; Merriman, Raphael; Hameed, Bilal; Doo, Edward; Kleiner, David E; Behling, Cynthia; Loomba, Rohit

    2013-11-01

    The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥65 years) and 735 nonelderly (18-64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P = 0.02), and advanced fibrosis (25% versus 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P ≤ 0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR] = 1.12, P = 0.007) and lower platelets (OR = 0.98, P = 0.02); and independent determinants of advanced fibrosis included higher AST (OR = 1.08, P = 0.007), lower alanine aminotransferase value (OR = 0.91, P = 0.002), and an increased odds of having low high-density lipoprotein (OR = 8.35, P = 0.02). Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis.

  19. Interactions of a PPARGC1A Variant and a PNPLA3 Variant Affect Nonalcoholic Steatohepatitis in Severely Obese Taiwanese Patients.

    PubMed

    Tai, Chi-Ming; Huang, Chih-Kun; Tu, Hung-Pin; Hwang, Jau-Chung; Yeh, Ming-Lun; Huang, Chung-Feng; Huang, Jee-Fu; Dai, Chia-Yen; Chuang, Wan-Long; Yu, Ming-Lung

    2016-03-01

    The patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant is associated with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, the role of genetic variations of the peroxisome proliferator-activated receptor gamma coactivator-1-alpha gene (PPARGC1A) and glucokinase regulatory (GCKR) gene on NASH in obese patients remains unclear. We studied the effects and interaction of these genetic polymorphisms on NASH in severely obese Taiwanese patients.The genotypes of PPARGC1A rs8192678, PNPLA3 rs738409, and GCKR rs780094 were determined in 177 severely obese patients who underwent bariatric surgery. NASH was evaluated by liver histopathology.Of 177 patients, 29 (16.4%), 57 (33.2%), and 91 (51.4%) were in the non-NAFLD, steatosis, and NASH groups, respectively. We found that the PPARGC1A and PNPLA3 variants, but not the GCKR variant, were associated with NASH. The PPARGC1A rs8192678 GA/AA genotype was associated with higher steatosis grade and presence of ballooning degeneration. The PNPLA3 rs738409 GG genotype was associated with higher severity in all histologic features except for fibrosis. In multivariate analysis, both the PPARGC1A rs8192678 GA/AA genotype (odds ratio [OR] 2.32; 95% confidence interval [CI] 1.08-4.98; P = 0.031) and the PNPLA3 rs738409 GG genotype (OR 4.05; 95% CI 1.24-13.23; P = 0.021), and also body mass index were independent risk factors for NASH. Further, there was an additive effect of the PPARGC1A rs8192678 GA/AA genotype and the PNPLA3 rs738409 GG genotype on the presence of NASH (OR 6.83; 95% CI 1.61-29.01; P = 0.009).The PPARGC1A rs8192678 GA/AA genotype and the PNPLA3 rs738409 GG genotype had an additive effect on NASH in severely obese Taiwanese patients.

  20. Urinary metabolomics analysis identifies key biomarkers of different stages of nonalcoholic fatty liver disease

    PubMed Central

    Dong, Shu; Zhan, Zong-Ying; Cao, Hong-Yan; Wu, Chao; Bian, Yan-Qin; Li, Jian-Yuan; Cheng, Gen-Hong; Liu, Ping; Sun, Ming-Yu

    2017-01-01

    AIM To identify a panel of biomarkers that can distinguish between non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and explore molecular mechanism involved in the process of developing NASH from NAFLD. METHODS Biomarkers may differ during stages of NAFLD. Urine and blood were obtained from non-diabetic subjects with NAFLD and steatosis, with normal liver function (n = 33), from patients with NASH, with abnormal liver function (n = 45), and from healthy age and sex-matched controls (n = 30). Samples were subjected to metabolomic analysis to identify potential non-invasive biomarkers. Differences in urinary metabolic profiles were analyzed using liquid chromatography tandem mass spectrometry with principal component analysis and partial least squares-discriminate analysis. RESULTS Compared with NAFLD patients, patients with NASH had abnormal liver function and high serum lipid concentrations. Urinary metabonomics found differences in 31 metabolites between these two groups, including differences in nucleic acids and amino acids. Pathway analysis based on overlapping metabolites showed that pathways of energy and amino acid metabolism, as well as the pentose phosphate pathway, were closely associated with pathological processes in NAFLD and NASH. CONCLUSION These findings suggested that a panel of biomarkers could distinguish between NAFLD and NASH, and could help to determine the molecular mechanism involved in the process of developing NASH from NAFLD. Urinary biomarkers may be diagnostic in these patients and could be used to assess responses to therapeutic interventions. PMID:28487615

  1. Rising Rates of Hepatocellular Carcinoma Leading to Liver Transplantation in Baby Boomer Generation with Chronic Hepatitis C, Alcohol Liver Disease, and Nonalcoholic Steatohepatitis-Related Liver Disease

    PubMed Central

    Cholankeril, George; Perumpail, Ryan B.; Liu, Andy; Sandhu, Jeevin S.; Nair, Satheesh; Hu, Menghan; Ahmed, Aijaz

    2017-01-01

    We aim to study the impact of the baby boomer (BB) generation, a birth-specific cohort (born 1945–1965) on hepatocellular carcinoma (HCC)-related liver transplantation (LT) in patients with chronic hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH). We performed a retrospective analysis using the United Network for Organ Sharing (UNOS)/Organ Procurement Transplant Network (OPTN) database from 2003 to 2014 to compare HCC-related liver transplant surgery trends between two cohorts—the BB and non-BB—with a secondary diagnosis of HCV, ALD, or NASH. From 2003–2014, there were a total of 8313 liver transplant recipients for the indication of HCC secondary to HCV, ALD, or NASH. Of the total, 6658 (80.1%) HCC-related liver transplant recipients were BB. The number of liver transplant surgeries for the indication of HCC increased significantly in NASH (+1327%), HCV (+382%), and ALD (+286%) during the study period. The proportion of BB who underwent LT for HCC was the highest in HCV (84.7%), followed by NASH (70.3%) and ALD (64.7%). The recommendations for birth-cohort specific HCV screening stemmed from a greater understanding of the high prevalence of chronic HCV and HCV-related HCC within BB. The rising number of HCC-related LT among BB with ALD and NASH suggests the need for increased awareness and improved preventative screening/surveillance measures within NASH and ALD cohorts as well. PMID:28954412

  2. Rising Rates of Hepatocellular Carcinoma Leading to Liver Transplantation in Baby Boomer Generation with Chronic Hepatitis C, Alcohol Liver Disease, and Nonalcoholic Steatohepatitis-Related Liver Disease.

    PubMed

    Cholankeril, George; Yoo, Eric R; Perumpail, Ryan B; Liu, Andy; Sandhu, Jeevin S; Nair, Satheesh; Hu, Menghan; Ahmed, Aijaz

    2017-09-26

    We aim to study the impact of the baby boomer (BB) generation, a birth-specific cohort (born 1945-1965) on hepatocellular carcinoma (HCC)-related liver transplantation (LT) in patients with chronic hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH). We performed a retrospective analysis using the United Network for Organ Sharing (UNOS)/Organ Procurement Transplant Network (OPTN) database from 2003 to 2014 to compare HCC-related liver transplant surgery trends between two cohorts-the BB and non-BB-with a secondary diagnosis of HCV, ALD, or NASH. From 2003-2014, there were a total of 8313 liver transplant recipients for the indication of HCC secondary to HCV, ALD, or NASH. Of the total, 6658 (80.1%) HCC-related liver transplant recipients were BB. The number of liver transplant surgeries for the indication of HCC increased significantly in NASH (+1327%), HCV (+382%), and ALD (+286%) during the study period. The proportion of BB who underwent LT for HCC was the highest in HCV (84.7%), followed by NASH (70.3%) and ALD (64.7%). The recommendations for birth-cohort specific HCV screening stemmed from a greater understanding of the high prevalence of chronic HCV and HCV-related HCC within BB. The rising number of HCC-related LT among BB with ALD and NASH suggests the need for increased awareness and improved preventative screening/surveillance measures within NASH and ALD cohorts as well.

  3. Bofutsushosan, a Japanese herbal (Kampo) medicine, attenuates progression of nonalcoholic steatohepatitis in mice.

    PubMed

    Ono, Masafumi; Ogasawara, Mitsunari; Hirose, Akira; Mogami, Sachiko; Ootake, Nobuhiro; Aritake, Kosuke; Higuchi, Takuma; Okamoto, Nobuto; Sakamoto, Shuji; Yamamoto, Masahiro; Urade, Yoshihiro; Saibara, Toshiji; Oben, Jude A

    2014-06-01

    Obesity-induced liver disease (nonalcoholic fatty liver disease, NAFLD) is now the commonest cause of chronic liver disease in affluent nations. There are presently no proven treatments for NAFLD or its more severe stage, nonalcoholic steatohepatitis (NASH). Bofutsushosan (BTS), a Japanese herbal (Kampo) medicine, long used as an anti-obesity medicine in Japan and other Asian countries, has been shown to reduce body weight and improve insulin resistance (IR) and hepatic steatosis. The precise mechanism of action of BTS, however, remains unclear. To evaluate the ability of BTS to prevent the development of NASH, and determine the mediators and pathways involved. C57BL/6 mice were injected intra-peritoneally with gold-thioglucose and fed a high-fat diet (HF) or HF diet admixed with either 2 or 5 % BTS for 12 weeks. The effectiveness of BTS in attenuating features of NASH and the mechanisms through which BTS attenuated NASH were then assayed through an assessment of the anthropometric, radiological, biochemical and histological parameters. BTS attenuated the progression of NASH through induction of adiponectin and its receptors along with an induction of PPAR-α and PPAR-γ, decreased expression of SREBP-1c, increased hepatic fatty acid oxidation and increased hepatic export of triglycerides. BTS moreover, reduced IR through phosphorylation of the protein kinase, Akt. BTS through induction of adiponectin signaling and Akt attenuated development of NASH. Identification of the active entity in BTS should allow development of novel treatments for NASH.

  4. The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model.

    PubMed

    Nakatsu, Yusuke; Seno, Yasuyuki; Kushiyama, Akifumi; Sakoda, Hideyuki; Fujishiro, Midori; Katasako, Aya; Mori, Keiichi; Matsunaga, Yasuka; Fukushima, Toshiaki; Kanaoka, Ryuhei; Yamamotoya, Takeshi; Kamata, Hideaki; Asano, Tomoichiro

    2015-07-01

    Xanthine oxidase (XO) is an enzyme involved in the production of uric acid (UA) from purine nucleotides. Numerous recent studies have revealed the likelihood of metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) to be related to hyperuricemia. However, it remains unclear whether elevated serum UA during the development of NAFLD or NASH is a cause or a consequence of these diseases. In this study, the XO inhibitor febuxostat was administered to two types of NASH model mice. Febuxostat exerted a strong protective effect against NASH development induced by a high-fat diet containing trans fatty acid (HFDT). In contrast, methionine choline-deficient-diet-induced NASH development not accompanied by hyperuricemia showed no UA normalization, suggesting that the ameliorating effect of febuxostat occurs via the normalization of hyperuricemia itself and/or accompanying molecular mechanism(s) such as oxidative stress. In the HFDT-fed mice, hyperuricemia, elevated alanine aminotransferase, and increased Tunnel-positive cells in the liver were normalized by febuxostat administration. In addition, upregulation of fatty acid oxidation-related genes, fibrotic change, and increases in collagen deposition, inflammatory cytokine expressions, and lipid peroxidation in the HFDT-fed mice were also normalized by febuxostat administration. Taken together, these observations indicate that administration of febuxostat has a protective effect against HFDT-induced NASH development, suggesting the importance of XO in its pathogenesis. Thus XO inhibitors are potentially potent therapies for patients with NASH, particularly that associated with hyperuricemia. Copyright © 2015 the American Physiological Society.

  5. B cell-activating factor is associated with the histological severity of nonalcoholic fatty liver disease.

    PubMed

    Miyake, Teruki; Abe, Masanori; Tokumoto, Yoshio; Hirooka, Masashi; Furukawa, Shinya; Kumagi, Teru; Hamada, Maho; Kawasaki, Keitarou; Tada, Fujimasa; Ueda, Teruhisa; Hiasa, Yoichi; Matsuura, Bunzo; Onji, Morikazu

    2013-06-01

    B cell-activating factor (BAFF) is expressed in adipocytes and affects lipogenesis and insulin sensitivity. In addition, the BAFF receptor is expressed in visceral adipose tissue and liver. The aim of this study was to analyze serum BAFF levels in patients with nonalcoholic steatohepatitis (NASH) and simple steatosis (SS) and to compare their respective clinical and histological findings. A total of 96 patients with nonalcoholic fatty liver disease (20 with SS and 76 with NASH) were enrolled and their serum BAFF levels were analyzed. Comprehensive blood chemistry analysis and histological examination of liver samples were also conducted. Serum BAFF levels were higher in patients with NASH than in those with SS (p = 0.016). NASH patients with ballooning hepatocytes and advanced fibrosis had higher levels of BAFF in sera (p = 0.016 and p = 0.006, respectively). In addition, the prevalence of NASH increased significantly as the serum BAFF level increased (p = 0.004). Higher serum BAFF levels were found to be an independent risk factor for development of NASH (OR 1.003, 95% CI 1.0003-1.006; p = 0.047). Nonalcoholic steatohepatitis patients had higher levels of serum BAFF than patients with SS, and higher levels were associated with the presence of hepatocyte ballooning and advanced fibrosis. The serum BAFF level may be a useful tool for distinguishing NASH from SS.

  6. Connor P. Nash | NREL

    Science.gov Websites

    catalysts Electrochemical reactor design and operation for transformation of biomass-derived intermediates Education B.S., Chemical and Biological Engineering, Colorado State University, 2010-2014 Professional

  7. Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease: An update

    PubMed Central

    Athyros, Vasilios G; Tziomalos, Konstantinos; Katsiki, Niki; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is considered to be an independent cardiovascular disease (CVD) risk factor. However, simple steatosis has a benign clinical course without excess mortality. In contrast, the advanced form of NAFLD, non-alcoholic steatohepatitis (NASH) with liver fibrosis increases mortality by approximately 70%, due to an increase in CVD mortality by approximately 300%. Chronic kidney disease (CKD) may be caused by NAFLD/NASH and it substantially increases CVD risk, especially in the presence of type 2 diabetes mellitus. Moreover, CKD may trigger NAFLD/NASH deterioration in a vicious cycle. NAFLD/NASH is also related to increased arterial stiffness (AS), an independent CVD risk factor that further raises CVD risk. Diagnosis of advanced liver fibrosis (mainly by simple non-invasive tests), CKD, and increased AS should be made early in the course of NAFLD and treated appropriately. Lifestyle measures and statin treatment may help resolve NAFLD/NASH and beneficially affect the CVD risk factors mentioned above. PMID:26078558

  8. Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice.

    PubMed

    Jang, Jung Eun; Park, Han-Sol; Yoo, Hyun Ju; Baek, In-Jeoung; Yoon, Ji Eun; Ko, Myoung Seok; Kim, Ah-Ram; Kim, Hyoun Sik; Park, Hye-Sun; Lee, Seung Eun; Kim, Seung-Whan; Kim, Su Jung; Leem, Jaechan; Kang, Yu Mi; Jung, Min Kyo; Pack, Chan-Gi; Kim, Chong Jai; Sung, Chang Ohk; Lee, In-Kyu; Park, Joong-Yeol; Fernández-Checa, José C; Koh, Eun Hee; Lee, Ki-Up

    2017-08-01

    Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing sterol regulatory element-binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator-activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat +/- mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that

  9. Nonalcoholic fatty liver disease: Update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine

    PubMed Central

    Mato, José M; Lu, Shelly C

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide affecting over one-third of the population in the U.S. It has been associated with obesity, type 2 diabetes, hyperlipidemia, and insulin resistance and is initiated by the accumulation of triglycerides in hepatocytes. Isolated hepatic steatosis (IHS) remains a benign process, while a subset develops superimposed inflammatory activity and progression to nonalcoholic steatohepatitis (NASH) with or without fibrosis. However, the molecular mechanisms underlying NAFLD progression are not completely understood. Liver biopsy is still required to differentiate IHS from NASH as easily accessible noninvasive biomarkers are lacking. In terms of treatments for NASH, pioglitazone, vitamin E, and obeticholic acid have shown some benefit. All of these agents have potential complications associated with long-term use. Nowadays, a complex hypothesis suggests that multiple parallel hits are involved in NASH development. However, the ‘key switch’ between IHS and NASH remains to be discovered. We have recently shown that knocking out enzymes involved in S-adenosylmethionine (SAMe) metabolism, the main biological methyl donor in humans that is abundant in the liver, will lead to NASH development in mice. This could be due to the fact that a normal SAMe level is required to establish the proper ratio of phosphatidylethanolamine to phosphatidylcholine that has been found to be important in NAFLD progression. New data from humans have also suggested that these enzymes play a role in the pathogenesis of NAFLD and that some of SAMe cycle metabolites may serve as noninvasive biomarkers of NASH. In this review, we discuss the evidence of the role of SAMe in animal models and humans with NAFLD and how studying this area may lead to the discovery of new noninvasive biomarkers and possibly personalized treatment for NASH. PMID:25873078

  10. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de; Borkham-Kamphorst, Erawan, E-mail: ekamphorst@ukaachen.de; Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de

    Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. Themore » aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH.« less

  11. Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH[S

    PubMed Central

    Ioannou, George N.; Subramanian, Savitha; Chait, Alan; Haigh, W. Geoffrey; Yeh, Matthew M.; Farrell, Geoffrey C.; Lee, Sum P.; Savard, Christopher

    2017-01-01

    We recently reported that cholesterol crystals form in hepatocyte lipid droplets (LDs) in human and experimental nonalcoholic steatohepatitis. Herein, we assigned WT C57BL/6J mice to a high-fat (15%) diet for 6 months, supplemented with 0%, 0.25%, 0.5%, 0.75%, or 1% dietary cholesterol. Increasing dietary cholesterol led to cholesterol loading of the liver, but not of adipose tissue, resulting in fibrosing steatohepatitis at a dietary cholesterol concentration of ≥0.5%, whereas mice on lower-cholesterol diets developed only simple steatosis. Hepatic cholesterol crystals and crown-like structures also developed at a dietary cholesterol concentration ≥0.5%. Crown-like structures consisted of activated Kupffer cells (KCs) staining positive for NLRP3 and activated caspase 1, which surrounded and processed cholesterol crystal-containing remnant LDs of dead hepatocytes. The KCs processed LDs at the center of crown-like structures in the extracellular space by lysosomal enzymes, ultimately transforming into lipid-laden foam cells. When HepG2 cells were exposed to LDL cholesterol, they developed cholesterol crystals in LD membranes, which caused activation of THP1 cells (macrophages) grown in coculture; upregulation of TNF-alpha, NLRP3, and interleukin 1beta (IL1β) mRNA; and secretion of IL-1beta. In conclusion, cholesterol crystals form on the LD membrane of hepatocytes and cause activation and cholesterol loading of KCs that surround and process these LDs by lysosomal enzymes. PMID:28404639

  12. Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice.

    PubMed

    Okubo, Hirofumi; Kushiyama, Akifumi; Sakoda, Hideyuki; Nakatsu, Yusuke; Iizuka, Masaki; Taki, Naoyuki; Fujishiro, Midori; Fukushima, Toshiaki; Kamata, Hideaki; Nagamachi, Akiko; Inaba, Toshiya; Nishimura, Fusanori; Katagiri, Hideki; Asahara, Takashi; Yoshida, Yasuto; Chonan, Osamu; Encinas, Jeffery; Asano, Tomoichiro

    2016-01-28

    Resistin-like molecule β (RELMβ) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELMβ to non-alcoholic steatohepatitis (NASH) development. First, RELMβ knock-out (KO) mice were shown to be resistant to methionine-choline deficient (MCD) diet-induced NASH development. Since it was newly revealed that Kupffer cells in the liver express RELMβ and that RELMβ expression levels in the colon and the numbers of RELMβ-positive Kupffer cells were both increased in this model, we carried out further experiments using radiation chimeras between wild-type and RELMβ-KO mice to distinguish between the contributions of RELMβ in these two organs. These experiments revealed the requirement of RELMβ in both organs for full manifestation of NASH, while deletion of each one alone attenuated the development of NASH with reduced serum lipopolysaccharide (LPS) levels. The higher proportion of lactic acid bacteria in the gut microbiota of RELMβ-KO than in that of wild-type mice may be one of the mechanisms underlying the lower serum LPS level the former. These data suggest the contribution of increases in RELMβ in the gut and Kupffer cells to NASH development, raising the possibility of RELMβ being a novel therapeutic target for NASH.

  13. Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice

    PubMed Central

    Okubo, Hirofumi; Kushiyama, Akifumi; Sakoda, Hideyuki; Nakatsu, Yusuke; Iizuka, Masaki; Taki, Naoyuki; Fujishiro, Midori; Fukushima, Toshiaki; Kamata, Hideaki; Nagamachi, Akiko; Inaba, Toshiya; Nishimura, Fusanori; Katagiri, Hideki; Asahara, Takashi; Yoshida, Yasuto; Chonan, Osamu; Encinas, Jeffery; Asano, Tomoichiro

    2016-01-01

    Resistin-like molecule β (RELMβ) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELMβ to non-alcoholic steatohepatitis (NASH) development. First, RELMβ knock-out (KO) mice were shown to be resistant to methionine-choline deficient (MCD) diet-induced NASH development. Since it was newly revealed that Kupffer cells in the liver express RELMβ and that RELMβ expression levels in the colon and the numbers of RELMβ-positive Kupffer cells were both increased in this model, we carried out further experiments using radiation chimeras between wild-type and RELMβ-KO mice to distinguish between the contributions of RELMβ in these two organs. These experiments revealed the requirement of RELMβ in both organs for full manifestation of NASH, while deletion of each one alone attenuated the development of NASH with reduced serum lipopolysaccharide (LPS) levels. The higher proportion of lactic acid bacteria in the gut microbiota of RELMβ-KO than in that of wild-type mice may be one of the mechanisms underlying the lower serum LPS level the former. These data suggest the contribution of increases in RELMβ in the gut and Kupffer cells to NASH development, raising the possibility of RELMβ being a novel therapeutic target for NASH. PMID:26818807

  14. Symmetric Decomposition of Asymmetric Games.

    PubMed

    Tuyls, Karl; Pérolat, Julien; Lanctot, Marc; Ostrovski, Georg; Savani, Rahul; Leibo, Joel Z; Ord, Toby; Graepel, Thore; Legg, Shane

    2018-01-17

    We introduce new theoretical insights into two-population asymmetric games allowing for an elegant symmetric decomposition into two single population symmetric games. Specifically, we show how an asymmetric bimatrix game (A,B) can be decomposed into its symmetric counterparts by envisioning and investigating the payoff tables (A and B) that constitute the asymmetric game, as two independent, single population, symmetric games. We reveal several surprising formal relationships between an asymmetric two-population game and its symmetric single population counterparts, which facilitate a convenient analysis of the original asymmetric game due to the dimensionality reduction of the decomposition. The main finding reveals that if (x,y) is a Nash equilibrium of an asymmetric game (A,B), this implies that y is a Nash equilibrium of the symmetric counterpart game determined by payoff table A, and x is a Nash equilibrium of the symmetric counterpart game determined by payoff table B. Also the reverse holds and combinations of Nash equilibria of the counterpart games form Nash equilibria of the asymmetric game. We illustrate how these formal relationships aid in identifying and analysing the Nash structure of asymmetric games, by examining the evolutionary dynamics of the simpler counterpart games in several canonical examples.

  15. Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis.

    PubMed

    de Almeida, I Tavares; Cortez-Pinto, H; Fidalgo, G; Rodrigues, D; Camilo, M E

    2002-06-01

    Non-alcoholic steatohepatitis (NASH), the association of steatosis with an inflammatory response, is a novel liver disease of unknown pathogenesis and prognosis. Triacylglycerols and their precursors, the fatty acids, are the likely candidates to accumulate in the hepatocyte. Disturbed fatty acid metabolism can be involved in the pathogenesis of NASH but there is no information concerning its plasma fatty acid profile. The aim of this study was to evaluate plasma total (esterified plus free) and free fatty acids concentrations to assess the association of NASH with plasma fatty acid accumulation. Overnight fasting blood samples from 22 biopsy-proven NASH patients and of 6 matched age healthy controls were studied. NASH patients had significantly higher concentration of total and free fatty acids than controls (P<0.05), higher total saturated and monounsaturated levels in both studied lipid fractions (P<0.05), mainly due to the increase of hexadecanoic, hexadecenoic and octadecenoic acids. Absolute polyunsaturated fatty acids (PUFA) concentrations were similar in both groups. The C20:4/C18:2 and the C18:1/C18:0 ratios as well as the peroxidability index were not significantly different. In overweight/obese patients NASH is associated with deranged fatty acid metabolism which may be involved in its pathogenesis and/or progression.

  16. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.

    PubMed

    Wong, Robert J; Aguilar, Maria; Cheung, Ramsey; Perumpail, Ryan B; Harrison, Stephen A; Younossi, Zobair M; Ahmed, Aijaz

    2015-03-01

    Nonalcoholic steatohepatitis (NASH) has been predicted to become the leading indication for liver transplantation (LT) in the United States. However, few studies have evaluated changes in the etiology of liver diseases among patients awaiting LT, and none have focused on the effects of NASH on liver transplant waitlists in the United States. We collected data from the United Network for Organ Sharing and Organ Procurement and Transplantation Network registry from 2004 through 2013, on liver transplant waitlist registrants with hepatitis C virus (HCV) infection, NASH, alcoholic liver disease (ALD), or a combination of HCV infection and ALD. We compared differences in survival within 90 days of registration (90-day survival) and probability of LT among patients with different diseases using Kaplan-Meier and multivariate logistic regression models. Between 2004 and 2013, new waitlist registrants with NASH increased by 170% (from 804 to 2174), with ALD increased by 45% (from 1400 to 2024), and with HCV increased by 14% (from 2887 to 3291); registrants with HCV and ALD decreased by 9% (from 880 to 803). In 2013, NASH became the second-leading disease among liver transplant waitlist registrants, after HCV. Patients with ALD had a significantly higher mean Model for End-Stage Liver Disease score at time of waitlist registration than other registrants. However, after multivariate adjustment, patients with ALD were less likely to die within 90 days when compared with patients with NASH (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.67-0.89; P < .001); patients with HCV infection or HCV and ALD had similar odds for 90-day survival compared with NASH patients. Compared with patients with NASH, patients with HCV (OR = 1.45; 95% CI: 1.35-1.55; P < .001), ALD (OR = 1.15; 95% CI: 1.06-1.24; P < .001), or HCV and ALD (OR = 1.29; 95% CI: 1.18-1.42; P < .001) had higher odds for 90-day survival. Based on data from US adult LT databases, since 2004 the number of

  17. The severity of NAFLD is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota

    PubMed Central

    Boursier, Jérôme; Mueller, Olaf; Barret, Matthieu; Machado, Mariana; Fizanne, Lionel; Araujo-Perez, Felix; Guy, Cynthia D.; Seed, Patrick C.; Rawls, John F.; David, Lawrence A.; Hunault, Gilles; Oberti, Frédéric; Calès, Paul; Diehl, Anna Mae

    2016-01-01

    Background & aims Several animal studies have emphasized the role of gut microbiota in non-alcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remains scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, i.e. non-alcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Methods 57 patients with biopsy-proven NAFLD were enrolled. The taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Results 30 patients had F0/1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F≥2 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F≥2 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F≥2 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F≥2 fibrosis. Stratification according to the abundance of these 2 bacteria generated 3 patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, KEGG pathways significantly related to NASH and fibrosis F≥2 were mostly related to carbohydrate, lipid, and amino acid metabolism. Conclusion NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre/probiotics therapies. PMID:26600078

  18. Non-alcoholic fatty liver and the gut microbiota.

    PubMed

    Bashiardes, Stavros; Shapiro, Hagit; Rozin, Shachar; Shibolet, Oren; Elinav, Eran

    2016-09-01

    Non-alcoholic fatty liver (NAFLD) is a common, multi-factorial, and poorly understood liver disease whose incidence is globally rising. NAFLD is generally asymptomatic and associated with other manifestations of the metabolic syndrome. Yet, up to 25% of NAFLD patients develop a progressive inflammatory liver disease termed non-alcoholic steatohepatitis (NASH) that may progress towards cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. In recent years, several lines of evidence suggest that the gut microbiome represents a significant environmental factor contributing to NAFLD development and its progression into NASH. Suggested microbiome-associated mechanisms contributing to NAFLD and NASH include dysbiosis-induced deregulation of the gut endothelial barrier function, which facilitates systemic bacterial translocation, and intestinal and hepatic inflammation. Furthermore, increased microbiome-modulated metabolites such as lipopolysaccharides, short chain fatty acids (SCFAs), bile acids, and ethanol, may affect liver pathology through multiple direct and indirect mechanisms. Herein, we discuss the associations, mechanisms, and clinical implications of the microbiome's contribution to NAFLD and NASH. Understanding these contributions to the development of fatty liver pathogenesis and its clinical course may serve as a basis for development of therapeutic microbiome-targeting approaches for treatment and prevention of NAFLD and NASH. Intestinal host-microbiome interactions play diverse roles in the pathogenesis and progression of NAFLD and NASH. Elucidation of the mechanisms driving these microbial effects on the pathogenesis of NAFLD and NASH may enable to identify new diagnostic and therapeutic targets of these common metabolic liver diseases. This article is part of a special issue on microbiota.

  19. Pathology and biopsy assessment of non-alcoholic fatty liver disease.

    PubMed

    Straub, Beate Katharina; Schirmacher, Peter

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases in Western industrialized countries with dramatically rising incidence. The diagnosis of NAFLD requires the existence of steatosis in the absence of significant alcohol consumption. In cases of relevant inflammation pathogenetically linked to steatosis, it is termed non-alcoholic steatohepatitis (NASH). While pure steatosis represents a relatively harmless and rapidly reversible condition without a significant tendency to progression, NASH carries a significant morbidity and progression risk. Noninvasive methods neither reliably establish the diagnosis nor define the extent of disease in NASH, making histopathology the diagnostic gold standard. Since current therapeutic options in NASH are limited, indication for biopsy is made in the clinical context, predominantly in unclear clinical constellations, prior to invasive measures, for follow-up purposes and in the context of clinical studies. Histological hallmarks of NASH are steatosis, hepatocellular ballooning (with and without Mallory-Denk bodies), necroinflammation, and progressing disease a characteristic with perisinusoidal fibrosis. For semiquantitative assessment of necroinflammation (grading) and fibrosis (staging), a score has recently been implemented. Although histology does not reliably distinguish alcoholic steatohepatitis/alcoholic fatty liver disease from NASH/NAFLD, it may give valuable hints. NASH has a tendency for more steatosis, the so-called glycogenated nuclei, and less necroinflammatory activity. Future development of biopsy diagnosis will be coupled to the development of differential systemic therapeutic approaches. Especially in the context of clinical studies, detailed histological evaluation should be considered for the detection of predictive parameters. Copyright 2010 S. Karger AG, Basel.

  20. Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis

    PubMed Central

    Farhadi, Ashkan; Gundlapalli, Sushama; Shaikh, Maliha; Frantzides, Constantine; Harrell, Laura; Kwasny, Mary M.; Keshavarzian, Ali

    2014-01-01

    Introduction One of the proposed second hit mechanisms in the pathophysiology of non-alcoholic steatohepatitis (NASH) is hepatic oxidative stress triggered by elevated levels of endotoxin. We investigated one possible mechanism for the endotoxaemia – disruption of intestinal barrier integrity. Methods We enrolled 16 subjects with fatty liver (10 NASH; 6 steatosis) and 12 healthy subjects. Steatosis and NASH were diagnosed by liver biopsy using the Brunt criteria. Gastrointestinal permeability was measured using urinary excretion of 5-h lactulose/mannitol (L/M) ratio and 24-h sucralose. Permeability testing was repeated after aspirin challenge. Results Groups had similar baseline urinary 0–5 h L/M ratio (small bowel permeability) and 0–24 h sucralose (whole-gut permeability). Aspirin increased 0–5 h urinary L/M in most subjects. In contrast, aspirin significantly increased whole-gut permeability only in NASH subjects. In fact, the major increase in the urinary sucralose occurred in the 6–24 h samples, which points towards the colon as the major site responsible for aspirin-induced leakiness in NASH patients. Serum endotoxin levels were significantly higher in NASH subjects. Discussion Our findings suggest that aspirin acts on the colon to unmask a susceptibility to gut leakiness in patients with NASH. This effect may be the underlying mechanism for increased serum endotoxin, which is the second hit (after altered lipid metabolism) that is required to initiate a necroinflammatory cascade in hepatocytes which are already primed with obesity-induced abnormal lipid homoeostasis. PMID:18397235

  1. Redox nanoparticles as a novel treatment approach for inflammation and fibrosis associated with nonalcoholic steatohepatitis

    PubMed Central

    Eguchi, Akiko; Yoshitomi, Toru; Lazic, Milos; Johnson, Casey D; Vong, Long Binh; Wree, Alexander; Povero, Davide; Papouchado, Bettina G; Nagasaki, Yukio; Feldstein, Ariel E

    2015-01-01

    Aim: Oxidative stress (OS) is largely thought to be a central mechanism responsible for liver damage, inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Our aim was to investigate whether suppression of OS in the liver via redox nanoparticles (RNPs) reduces liver damage in a mouse model of NASH. Materials & methods: RNPs were prepared by self-assembly of redox polymers possessing antioxidant nitroxide radicals and were orally administered by daily gavage for 4 weeks. Results: The redox polymer was delivered to the liver after disintegration of nanoparticle in the stomach. RNP treatment in NASH mice via gavage led to a reduction of liver OS, improvement of fibrosis, and significant reduction of inflammation. Conclusion: These findings uncover RNP as a novel potential NASH therapy. PMID:26020857

  2. Prediction of Nonalcoholic Fatty Liver Disease Via a Novel Panel of Serum Adipokines

    PubMed Central

    Jamali, Raika; Arj, Abbas; Razavizade, Mohsen; Aarabi, Mohammad Hossein

    2016-01-01

    Abstract Considering limitations of liver biopsy for diagnosis of nonalcoholic liver disease (NAFLD), biomarkers’ panels were proposed. The aims of this study were to establish models based on serum adipokines for discriminating NAFLD from healthy individuals and nonalcoholic steatohepatitis (NASH) from simple steatosis. This case-control study was conducted in patients with persistent elevated serum aminotransferase levels and fatty liver on ultrasound. Individuals with evidence of alcohol consumption, hepatotoxic medication, viral hepatitis, and known liver disease were excluded. Liver biopsy was performed in the remaining patients to distinguish NAFLD/NASH. Histologic findings were interpreted using “nonalcoholic fatty liver activity score.” Control group consisted of healthy volunteers with normal physical examination, liver function tests, and liver ultrasound. Binary logistic regression analysis was applied to ascertain the effects of independent variables on the likelihood that participants have NAFLD/NASH. Decreased serum adiponectin and elevated serum visfatin, IL-6, TNF-a were associated with an increased likelihood of exhibiting NAFLD. NAFLD discriminant score was developed as the following: [(−0.298 × adiponectin) + (0.022 × TNF-a) + (1.021 × Log visfatin) + (0.709 × Log IL-6) + 1.154]. In NAFLD discriminant score, 86.4% of original grouped cases were correctly classified. Discriminant score threshold value of (−0.29) yielded a sensitivity and specificity of 91% and 83% respectively, for discriminating NAFLD from healthy controls. Decreased serum adiponectin and elevated serum visfatin, IL-8, TNF-a were correlated with an increased probability of NASH. NASH discriminant score was proposed as the following: [(−0.091 × adiponectin) + (0.044 × TNF-a) + (1.017 × Log visfatin) + (0.028 × Log IL-8) − 1.787] In NASH model, 84% of original cases were correctly classified. Discriminant score threshold value of (−0.22) yielded a

  3. 77 FR 24451 - Direct Final Approval of Hospital/Medical/Infectious Waste Incinerators State Plan for Designated...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-24

    ...) 886-6030. 4. Mail: Carlton T. Nash, Chief, Toxics and Global Atmosphere Section, Air Toxics and..., Illinois 60604. 5. Hand Delivery: Carlton T. Nash, Chief, Toxics and Global Atmosphere Section, Air Toxics...

  4. Utility of the ELF Test for Detecting Steatohepatitis in Morbid Obese Patients with Suspicion of Nonalcoholic Fatty Liver Disease.

    PubMed

    López, Iria Cebreiros; Aroca, Florentina Guzmán; Bernal, Maria Dolores Frutos; Mompeán, Juan Antonio Luján; Bernal, Águeda Bas; Martínez, Antonio Miguel Hernández; Barba, Enrique Martínez; Velasco, Jose Antonio Noguera; Paricio, Pascual Parilla

    2017-09-01

    Morbid obese patients have a high rate of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). NASH is related to the progression and poor evolution of chronic hepatopathy in NAFLD, so that its detection makes it possible to identify the subjects who are most at risk in order to prioritize treatment. The ELF test (Enhanced Liver Fibrosis test; Siemens Diagnostics, NY, USA) has been assessed for its capacity to detect fibrosis in patients with NAFLD, but its capacity for diagnosing NASH has not been checked. Our objective is to determine the utility of the ELF test for detecting NASH in morbid obese patients with suspected NAFLD. ELF values were determined in a cohort of obese patients who underwent bariatric surgery with suspected NAFLD. Liver biopsy was used as the reference standard. The values of ELF were significantly higher in patients with NASH (p = 0.002) and in those who presented with metabolic syndrome (p = 0.047). An ELF cut-off point of 8.72 allows the detection of patients with NASH with a sensitivity of 71.4% and a specificity of 74.1% (AUC = 0.742, p = 0.002). The ELF test is efficient for the identification of obese patients with NAFLD and early signs of steatohepatitis and fibrosis.

  5. [Metabolic parameters in patients with steatosis non alcoholic liver and controlled diabetes type 2 versus uncontrolled diabetes type 2].

    PubMed

    Miranda Manrique, Gonzalo

    2016-01-01

    Non-alcoholic fatty liver (NASH) is widely distributed around the world and is more common in subjects with dyslipidemia, metabolic syndrome obese and DM2 (34-74%). However, the prevalence of cirrhosis by NASH in general population is unknown which is still subject of research. To determine if there are significant differences between metabolic parameters of non-alcoholic fatty liver in controlled versus uncontrolled diabetes type 2 of recent diagnosis. retrospective case-control study, performed in the Hospital Guillermo Almenara Irigoyen, Lima, Peru from November 2014 to February 2015.This study included 231 patients: 147 patients (NASH with DM2 of recent diagnosis and poor control) and 84 patients (NASH with DM2 ofrecent diagnosis and adequate control). Levene test for evaluating homogeneity of variances intra groups and parametric test for independent samples. After applying Levene test of homogeneity and student test, significant metabolic parameters were the triglycerides, HbA1C level, metformin dose and gender. It is important in diabetic patients to diagnose NASH early for a tighter control, not only of glucose but other metabolic parameters mainly triglycerides which strongly supports existing concept of "multiple hits" which considers NASH affects glucose homeostasis, and it could be the starting point of new research to improve interventions for decreasing progression from to cirrhosis in diabetic patients and also to delay progression of diabetes mellitus in patients with non alcoholic steatohepatitis.

  6. 78 FR 34973 - Proposal for Sewage Sludge Incinerators State Plan for Designated Facilities and Pollutants; Indiana

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-11

    [email protected] . 3. Fax: (312) 692-2543. 4. Mail: Carlton T. Nash, Chief, Toxics and Global Atmosphere... Boulevard, Chicago, Illinois 60604. 5. Hand Delivery: Carlton T. Nash, Chief, Toxics and Global Atmosphere...

  7. 78 FR 72611 - Proposal for Hospital/Medical/Infectious Waste Incinerator Negative Declaration for Designated...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-03

    [email protected] . 3. Fax: (312) 692-2543. 4. Mail: Carlton T. Nash, Chief, Toxics and Global Atmosphere... Boulevard, Chicago, Illinois 60604. 5. Hand Delivery: Carlton T. Nash, Chief, Toxics and Global Atmosphere...

  8. PNPLA3 genotype increases susceptibility of nonalcoholic steatohepatitis among obese patients with nonalcoholic fatty liver disease.

    PubMed

    Tai, Chi-Ming; Huang, Chih-Kun; Tu, Hung-Pin; Hwang, Jau-Chung; Chang, Chi-Yang; Yu, Ming-Lung

    2015-01-01

    The patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 variant is associated with histologic disease severity in patients with nonalcoholic fatty liver disease (NAFLD); however, whether the PNPLA3 genotype has an effect on susceptibility of nonalcoholic steatohepatitis (NASH) from NAFLD among severely obese patients remains unclear. The objective of this study was to investigate the role of the PNPLA3 genotype on NASH in severely obese Asian patients with NAFLD. The PNPLA3 rs738409 genotype was determined in 181 severely obese patients who underwent bariatric surgery. The diagnosis of NASH and the NAFLD activity score (NAS) were determined by liver histopathology. Of the 181 patients, 29 (16.0%), 60 (33.2%), and 92 (50.8%) were in the non-NAFLD, steatosis, and NASH groups, respectively. The PNPLA3 rs738409 GG genotype was associated with higher liver enzymes and a higher risk for NASH (odds ratio [OR], 3.72; 95% CI, 1.25-11.05). The GG genotype was also associated with histologic severity of NAFLD, including higher steatosis grade (OR, 9.94; 95% CI, 2.20-44.83 for patients with grade 3 steatosis) and NAS (OR, 11.49; 95% CI, 2.50-52.83 for patients with a NAS ≥5). Finally, multiple logistic regression also showed that the GG genotype was an independent risk factor for NASH (OR, 3.58; 95% CI, 1.15-11.12) in NAFLD patients. The PNPLA3 rs738409 GG genotype increases susceptibility of NASH in severely obese Asians with NAFLD and correlates to histologic severity of NAFLD. Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  9. Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis.

    PubMed

    Glass, Lisa M; Dickson, Rolland C; Anderson, Joseph C; Suriawinata, Arief A; Putra, Juan; Berk, Brian S; Toor, Arifa

    2015-04-01

    Given the rising epidemics of obesity and metabolic syndrome, nonalcoholic steatohepatitis (NASH) is now the most common cause of liver disease in the developed world. Effective treatment for NASH, either to reverse or prevent the progression of hepatic fibrosis, is currently lacking. To define the predictors associated with improved hepatic fibrosis in NASH patients undergoing serial liver biopsies at prolonged biopsy interval. This is a cohort study of 45 NASH patients undergoing serial liver biopsies for clinical monitoring in a tertiary care setting. Biopsies were scored using the NASH Clinical Research Network guidelines. Fibrosis regression was defined as improvement in fibrosis score ≥1 stage. Univariate analysis utilized Fisher's exact or Student's t test. Multivariate regression models determined independent predictors for regression of fibrosis. Forty-five NASH patients with biopsies collected at a mean interval of 4.6 years (±1.4) were included. The mean initial fibrosis stage was 1.96, two patients had cirrhosis and 12 patients (26.7 %) underwent bariatric surgery. There was a significantly higher rate of fibrosis regression among patients who lost ≥10 % total body weight (TBW) (63.2 vs. 9.1 %; p = 0.001) and who underwent bariatric surgery (47.4 vs. 4.5 %; p = 0.003). Factors such as age, gender, glucose intolerance, elevated ferritin, and A1AT heterozygosity did not influence fibrosis regression. On multivariate analysis, only weight loss of ≥10 % TBW predicted fibrosis regression [OR 8.14 (CI 1.08-61.17)]. Results indicate that regression of fibrosis in NASH is possible, even in advanced stages. Weight loss of ≥10 % TBW predicts fibrosis regression.

  10. Hepatocyte nuclear receptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis.

    PubMed

    Zou, An; Magee, Nancy; Deng, Fengyan; Lehn, Sarah; Zhong, Cuncong; Zhang, Yuxia

    2018-06-01

    Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide, ranging from nonalcoholic fatty liver (NAFL, steatosis without hepatocellular injury) to the more aggressive nonalcoholic steatohepatitis (NASH, steatosis with ballooning, inflammation, or fibrosis). Although many studies have greatly contributed to the elucidation of NAFLD pathogenesis, the disease progression from NAFL to NASH remains incompletely understood. Nuclear receptor small heterodimer partner (Nr0b2, SHP ) is a transcriptional regulator critical for the regulation of bile acid, glucose, and lipid metabolism. Here, we show that SHP levels are decreased in the livers of patients with NASH and in diet-induced mouse NASH. Exposing primary mouse hepatocytes to palmitic acid and lipopolysaccharide in vitro , we demonstrated that the suppression of Shp expression in hepatocytes is due to c-Jun N-terminal kinase (JNK) activation, which stimulates c-Jun-mediated transcriptional repression of Shp Interestingly, in vivo induction of hepatocyte-specific SHP in steatotic mouse liver ameliorated NASH progression by attenuating liver inflammation and fibrosis, but not steatosis. Moreover, a key mechanism linking the anti-inflammatory role of hepatocyte-specific SHP expression to inflammation involved SHP-induced suppression of NF-κB p65-mediated induction of chemokine (C-C motif) ligand 2 (CCL2), which activates macrophage proinflammatory polarization and migration. In summary, our results indicate that a JNK/SHP/NF-κB/CCL2 regulatory network controls communications between hepatocytes and macrophages and contributes to the disease progression from NAFL to NASH. Our findings may benefit the development of new management or prevention strategies for NASH. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Autoimmune Hepatitis

    MedlinePlus

    ... Living with a Liver Transplant Clinical Trials Nonalcoholic Fatty Liver Disease & NASH Definition & Facts Symptoms & Causes Diagnosis Treatment Eating, Diet, & Nutrition Clinical Trials Nonalcoholic Fatty Liver Disease & NASH in Children Definition & Facts Symptoms & Causes ...

  12. Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation

    PubMed Central

    Ibrahim, Samar H; Hirsova, Petra; Gores, Gregory J

    2018-01-01

    A subset of patients with non-alcoholic fatty liver disease develop an inflammatory condition, termed nonalcoholic steatohepatitis (NASH). NASH is characterised by hepatocellular injury, innate immune cell-mediated inflammation and progressive liver fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but appear to be linked to the proinflammatory microenvironment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. In this review, we discuss the signalling pathways induced by sublethal hepatocyte lipid overload that contribute to the pathogenesis of NASH. Furthermore, we will review the role of proinflammatory, proangiogenic and profibrotic hepatocyte-derived extracellular vesicles as disease biomarkers and pathogenic mediators during lipotoxicity. We also review the potential therapeutic strategies to block the feed-forward loop between sublethal hepatocyte injury and liver inflammation. PMID:29367207

  13. Clinical features and treatment of nonalcoholic fatty liver disease across the Asia Pacific region-the GO ASIA initiative.

    PubMed

    Chan, W-K; Treeprasertsuk, S; Imajo, K; Nakajima, A; Seki, Y; Kasama, K; Kakizaki, S; Fan, J-G; Song, M J; Yoon, S K; Dan, Y-Y; Lesmana, L; Ho, K-Y; Goh, K-L; Wong, V W-S

    2018-03-01

    The Gut and Obesity Asia (GO ASIA) workgroup was formed to study the relationships between obesity and gastrointestinal diseases in the Asia Pacific region. To study factors associated with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, and medical treatment of biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients. Retrospective study of biopsy-proven NAFLD patients from centres in the GO ASIA Workgroup. Independent factors associated with NASH and with advanced fibrosis on binary logistic regression analyses in a training cohort were used for the development of their corresponding risk score, which were validated in a validation cohort. We included 1008 patients from nine centres across eight countries (NASH 62.9%, advanced fibrosis 17.2%). Independent predictors of NASH were body mass index ≥30 kg/m 2 , diabetes mellitus, dyslipidaemia, alanine aminotransferase ≥88 U/L and aspartate aminotransferase ≥38 U/L, constituting the Asia Pacific NASH risk score. A high score has a positive predictive value of 80%-83% for NASH. Independent predictors of advanced fibrosis were age ≥55 years, diabetes mellitus and platelet count <150 × 10 9 /L, constituting the Asia-Pacific NAFLD advanced fibrosis risk score. A low score has a negative predictive value of 95%-96% for advanced fibrosis. Only 1.7% of patients were referred for structured lifestyle program, 4.2% were on vitamin E, and 2.4% were on pioglitazone. More severe liver disease can be suspected or ruled out based on factors identified in this study. Utilisation of structured lifestyle program, vitamin E and pioglitazone was limited despite this being a cohort of biopsy-proven NAFLD patients with majority of patients having NASH. © 2018 John Wiley & Sons Ltd.

  14. Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid.

    PubMed

    Yoo, Wonbeak; Gjuka, Donjeta; Stevenson, Heather L; Song, Xiaoling; Shen, Hong; Yoo, Suk Young; Wang, Jing; Fallon, Michael; Ioannou, George N; Harrison, Stephen A; Beretta, Laura

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD) NASH mouse model. We identified six fatty acids that could serve as non-invasive markers of NASH in patients with NAFLD. Serum levels of 15:0, 17:0 and 16:1n7t negatively correlated with NAFLD activity scores and hepatocyte ballooning scores, while 18:1n7c serum levels strongly correlated with fibrosis stage and liver inflammation. Serum levels of 15:0 and 17:0 also negatively correlated with fasting glucose and AST, while 16:1n7c and 18:1n7c levels positively correlated with AST and ferritin, respectively. Inclusion of demographic and clinical parameters improved the performance of the fatty acid panels in detecting NASH in NAFLD patients. The panel [15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin and APRI] predicted intermediate or advanced fibrosis in NAFLD patients, with 82% sensitivity at 90% specificity [AUROC = 0.92]. 15:0 and 18:1n7c were further selected for functional studies in vivo. Mice treated with 15:0-supplemented MCD diet showed reduced AST levels and hepatic infiltration of ceroid-laden macrophages compared to MCD-treated mice, suggesting that 15:0 deficiency contributes to liver injury in NASH. In contrast, 18:1n7c-supplemented MCD diet didn't affect liver pathology. In conclusion, 15:0 may serve as a promising biomarker or therapeutic target in NASH, opening avenues for the integration of diagnosis and treatment.

  15. The selective peroxisome proliferator–activated receptor‐delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice

    PubMed Central

    Haczeyni, Fahrettin; Wang, Hans; Barn, Vanessa; Mridha, Auvro R.; Yeh, Matthew M.; Haigh, W. Geoffrey; Ioannou, George N.; Choi, Yun‐Jung; McWherter, Charles A.; Teoh, Narcissus C.‐H.

    2017-01-01

    Lipotoxicity associated with insulin resistance is central to nonalcoholic steatohepatitis (NASH) pathogenesis. To date, only weight loss fully reverses NASH pathology, but mixed peroxisome proliferator–activated receptor‐alpha/delta (PPAR‐α/δ) agonists show some efficacy. Seladelpar (MBX‐8025), a selective PPAR‐δ agonist, improves atherogenic dyslipidemia. We therefore used this agent to test whether selective PPAR‐δ activation can reverse hepatic lipotoxicity and NASH in an obese, dyslipidemic, and diabetic mouse model. From weaning, female Alms1 mutant (foz/foz) mice and wild‐type littermates were fed an atherogenic diet for 16 weeks; groups (n = 8‐12) were then randomized to receive MBX‐8025 (10 mg/kg) or vehicle (1% methylcellulose) by gavage for 8 weeks. Despite minimally altering body weight, MBX‐8025 normalized hyperglycemia, hyperinsulinemia, and glucose disposal in foz/foz mice. Serum alanine aminotransferase ranged 300‐600 U/L in vehicle‐treated foz/foz mice; MBX‐8025 reduced alanine aminotransferase by 50%. In addition, MBX‐8025 normalized serum lipids and hepatic levels of free cholesterol and other lipotoxic lipids that were increased in vehicle‐treated foz/foz versus wild‐type mice. This abolished hepatocyte ballooning and apoptosis, substantially reduced steatosis and liver inflammation, and improved liver fibrosis. In vehicle‐treated foz/foz mice, the mean nonalcoholic fatty liver disease activity score was 6.9, indicating NASH; MBX‐8025 reversed NASH in all foz/foz mice (nonalcoholic fatty liver disease activity score 3.13). Conclusion: Seladelpar improves insulin sensitivity and reverses dyslipidemia and hepatic storage of lipotoxic lipids to improve NASH pathology in atherogenic diet–fed obese diabetic mice. Selective PPAR‐δ agonists act independently of weight reduction, but counter lipotoxicity related to insulin resistance, thereby providing a novel therapy for NASH. (Hepatology Communications 2017

  16. Relationship between obstructive sleep apnea and liver abnormalities in morbidly obese patients: a prospective study.

    PubMed

    Jouët, Pauline; Sabaté, Jean-Marc; Maillard, Dominique; Msika, Simon; Mechler, Charlotte; Ledoux, Séverine; Harnois, Florence; Coffin, Benoit

    2007-04-01

    Morbid obesity is a risk factor of nonalcoholic steatohepatitis (NASH). Obstructive sleep apnea (OSA) could also be an independent risk factor for elevated liver enzymes and NASH. The relationships between liver injuries and OSA in morbidly obese patients requiring bariatric surgery were studied prospectively. Every consecutive morbidly obese patient (BMI > or =40 kg/m2 or > or =35 kg/m2 with severe comorbidities) requiring bariatric surgery was included between January 2003 and October 2004. Polygraphic recording, serum aminotransferases (ALT, AST), gamma-glutamyltransferase (GGT) and liver biopsy were systematically performed. OSA was present when the apnea-hypopnea index (AHI) was >10/h. 62 patients (54 F; age 38.5 +/- 11.0 (SD) yrs; BMI 47.8 +/- 8.4 kg/m2) were included. Liver enzymes (AST, ALT or GGT) were increased in 46.6%. NASH was present in 34.4% and OSA in 84.7%. Patients with OSA were significantly older (P = 0.015) and had a higher BMI (P = 0.003). In multivariate analysis, risk factors for elevated liver enzymes were the presence of OSA and male sex. The presence of NASH was similar in patients with or without OSA (32.7% vs 44.4% of patients, P = 0.76). In this cohort of morbidly obese patients requiring bariatric surgery, one-third of patients had NASH, a prevalence similar to previous studies. OSA was found to be a risk factor for elevated liver enzymes but not for NASH.

  17. On Social Optima of Non-Cooperative Mean Field Games

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Li, Sen; Zhang, Wei; Zhao, Lin

    This paper studies the social optima in noncooperative mean-field games for a large population of agents with heterogeneous stochastic dynamic systems. Each agent seeks to maximize an individual utility functional, and utility functionals of different agents are coupled through a mean field term that depends on the mean of the population states/controls. The paper has the following contributions. First, we derive a set of control strategies for the agents that possess *-Nash equilibrium property, and converge to the mean-field Nash equilibrium as the population size goes to infinity. Second, we study the social optimal in the mean field game. Wemore » derive the conditions, termed the socially optimal conditions, under which the *-Nash equilibrium of the mean field game maximizes the social welfare. Third, a primal-dual algorithm is proposed to compute the *-Nash equilibrium of the mean field game. Since the *-Nash equilibrium of the mean field game is socially optimal, we can compute the equilibrium by solving the social welfare maximization problem, which can be addressed by a decentralized primal-dual algorithm. Numerical simulations are presented to demonstrate the effectiveness of the proposed approach.« less

  18. Nonalcoholic steatohepatitis in bariatric patients with a diagnosis of obstructive sleep apnea.

    PubMed

    Weingarten, Toby N; Mantilla, Carlos B; Swain, James M; Kendrick, Michael L; Oberhansley, Jeff M; Burcham, Robert J; Ribeiro, Tarsila C R; Watt, Kymberly D; Schroeder, Darrell R; Narr, Bradly J; Sprung, Juraj

    2012-01-01

    To study a possible association between obstructive sleep apnea (OSA) severity, managed with noninvasive ventilation, and nonalcoholic steatohepatitis (NASH) in bariatric surgical patients. Medical records of 218 bariatric surgical patients who underwent liver biopsy were reviewed. OSA severity was determined from preoperative polysomnography (apnea-hypopnea index (AHI) ≤ 15 no/mild OSA vs. AHI ≥ 16 moderate/severe OSA). Patients diagnosed with OSA were prescribed noninvasive ventilation. Patients were categorized according to liver histopathology into 3 groups: (i) no liver disease or simple steatosis, (ii) mild NASH (steatosis with necroinflammation and mild fibrosis (stage 0-1)), and iii) advanced NASH (steatosis with necroinflammation and more advanced fibrosis (stage ≥ 2)). 125 patients (57%) had no/mild OSA, and 93 (43%) had moderate/severe OSA. There was no difference in serum aminotransferases between patients by OSA severity classification. There was a high prevalence of hepatic histopathological abnormalities: 84% patients had steatosis, 57% had necroinflammation, 34% had fibrotic changes, and 14% had advanced NASH. There was no association between severity of NASH and severity of OSA. There is no association between stage of steatohepatitis and OSA severity among morbidly obese patients managed with noninvasive ventilation.

  19. Melatonin ameliorates methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis in rats.

    PubMed

    Tahan, Veysel; Atug, Ozlen; Akin, Hakan; Eren, Fatih; Tahan, Gulgun; Tarcin, Ozlem; Uzun, Hafize; Ozdogan, Osman; Tarcin, Orhan; Imeryuz, Nese; Ozguner, Fehmi; Celikel, Cigdem; Avsar, Erol; Tozun, Nurdan

    2009-05-01

    Nonalcoholic steatohepatitis (NASH) may progress to advanced fibrosis and cirrhosis. Mainly, oxidative stress and excessive hepatocyte apoptosis are implicated in the pathogenesis of progressive NASH. Melatonin is not only a powerful antioxidant but also an anti-inflammatory and anti-apoptotic agent. We aimed to evaluate the effects of melatonin on methionine- and choline-deficient diet (MCDD)-induced NASH in rats. Thirty-two male Wistar rats were divided into four groups. Two groups were fed with MCDD while the other two groups were fed a control diet, pair-fed. One of the MCDD groups and one of the control diet groups were administered melatonin 50 mg/kg/day intraperitoneally, and the controls were given a vehicle. After 1 month the liver tissue oxidative stress markers, proinflammatory cytokines and hepatocyte apoptosis were studied by commercially available kits. For grading and staging histological lesions, Brunt et al.'s system was used. Melatonin decreased oxidative stress, proinflammatory cytokines and hepatocyte apoptosis. The drug ameliorated the grade of NASH. The present study suggests that melatonin functions as a potent antioxidant, anti-inflammatory and antiapoptotic agent in NASH and may be a therapeutic option.

  20. Numerical and Statistical Analysis of Fractures in Mechanically Dissimilar Rocks of Limestone Interbedded with Shale from Nash Point in Bristol Channel, South Wales, UK.

    NASA Astrophysics Data System (ADS)

    Adeoye-Akinde, K.; Gudmundsson, A.

    2017-12-01

    Heterogeneity and anisotropy, especially with layered strata within the same reservoir, makes the geometry and permeability of an in-situ fracture network challenging to forecast. This study looks at outcrops analogous to reservoir rocks for a better understanding of in-situ fracture networks and permeability, especially fracture formation, propagation, and arrest/deflection. Here, fracture geometry (e.g. length and aperture) from interbedded limestone and shale is combined with statistical and numerical modelling (using the Finite Element Method) to better forecast fracture network properties and permeability. The main aim is to bridge the gap between fracture data obtained at the core level (cm-scale) and at the seismic level (km-scale). Analysis has been made of geometric properties of over 250 fractures from the blue Lias in Nash Point, UK. As fractures propagate, energy is required to keep them going, and according to the laws of thermodynamics, this energy can be linked to entropy. As fractures grow, entropy increases, therefore, the result shows a strong linear correlation between entropy and the scaling exponent of fracture length and aperture-size distributions. Modelling is used to numerically simulate the stress/fracture behaviour in mechanically dissimilar rocks. Results show that the maximum principal compressive stress orientation changes in the host rock as the fracture-induced stress tip moves towards a more compliant (shale) layer. This behaviour can be related to the three mechanisms of fracture arrest/deflection at an interface, namely: elastic mismatch, stress barrier and Cook-Gordon debonding. Tensile stress concentrates at the contact between the stratigraphic layers, ahead of and around the propagating fracture. However, as shale stiffens with time, the stresses concentrated at the contact start to dissipate into it. This can happen in nature through diagenesis, and with greater depth of burial. This study also investigates how induced

  1. Probiotics in Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, and Cirrhosis.

    PubMed

    Qamar, Amir A

    2015-01-01

    With the growing epidemic of obesity, the incidence of both nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH) is increasing. The intestinal microbiota differs between individuals who are obese or have normal body mass indices. Animal studies have shown increased intestinal permeability in NAFL, NASH, and cirrhosis. This increases the risk of oxidative and inflammatory injury to the liver from intestinal microbacteria. It may also increase the risk of fatty acid injury and fatty deposition. Bacterial translocation is associated with increased portal hypertension and hepatic encephalopathy in cirrhosis. By preventing bacterial adhesion and translocation, probiotics may have a role in the management of patients with NAFL, NASH, and cirrhosis. Multiple small studies have suggested that probiotics improve some of the clinical markers of activity in patients with NAFL and NASH. Controlled studies have also shown improved outcomes in patients with cirrhosis who were treated with probiotics.

  2. Activation of the Nrf2-ARE Pathway in Hepatocytes Protects Against Steatosis in Nutritionally Induced Non-alcoholic Steatohepatitis in Mice

    PubMed Central

    Lee, Lung-Yi; Köhler, Ulrike A.; Zhang, Li; Roenneburg, Drew; Werner, Sabine; Johnson, Jeffrey A.; Foley, David P.

    2014-01-01

    Oxidative stress is implicated in the development of non-alcoholic steatohepatitis (NASH). The Nrf2-antioxidant response element pathway protects cells from oxidative stress. Studies have shown that global Nrf2 deficiency hastens the progression of NASH. The purpose of this study was to determine whether long-term hepatocyte-specific activation of Nrf2 mitigates NASH progression. Transgenic mice expressing a constitutively active Nrf2 construct in hepatocytes (AlbCre+/caNrf2+) and littermate controls were generated. These mice were fed standard or methionine-choline-deficient (MCD) diet, a diet used to induce NASH development in rodents. After 28 days of MCD dietary feeding, mice developed significant increases in steatosis, inflammation, oxidative stress, and HSC activation compared with those mice on standard diet. AlbCre+/caNrf2+ animals had significantly decreased serum transaminases and reduced steatosis when compared with the AlbCre+/caNrf2− animals. This significant reduction in steatosis was associated with increased expression of genes involved in triglyceride export (MTTP) and β-oxidation (CPT2). However, there were no differences in the increased oxidative stress, inflammation, and HSC activation from MCD diet administration between the AlbCre+/caNrf2− and AlbCre+/caNrf2+ animals. We conclude that hepatocyte-specific activation of Nrf2-mediated gene expression decreased hepatocellular damage and steatosis in a dietary model of NASH. However, hepatocyte-specific induction of Nrf2-mediated gene expression alone is insufficient to mitigate inflammation, oxidative stress, and HSC activation in this nutritional NASH model. PMID:25294219

  3. Battle for Climate and Scarcity Rents: Beyond the Linear-Quadratic Case.

    PubMed

    Kagan, Mark; van der Ploeg, Frederick; Withagen, Cees

    Industria imports oil, produces final goods and wishes to mitigate global warming. Oilrabia exports oil and buys final goods from the other country. Industria uses the carbon tax to impose an import tariff on oil and steal some of Oilrabia's scarcity rent. Conversely, Oilrabia has monopoly power and sets the oil price to steal some of Industria's climate rent. We analyze the relative speeds of oil extraction and carbon accumulation under these strategic interactions for various production function specifications and compare these with the efficient and competitive outcomes. We prove that for the class of HARA production functions, the oil price is initially higher and subsequently lower in the open-loop Nash equilibrium than in the efficient outcome. The oil extraction rate is thus initially too low and in later stages too high. The HARA class includes linear, loglinear and semi-loglinear demand functions as special cases. For non-HARA production functions, Oilrabia may in the open-loop Nash equilibrium initially price oil lower than the efficient level, thus resulting in more oil extraction and climate damages. We also contrast the open-loop Nash and efficient outcomes numerically with the feedback Nash outcomes. We find that the optimal carbon tax path in the feedback Nash equilibrium is flatter than in the open-loop Nash equilibrium. It turns out that for certain demand functions using the carbon tax as an import tariff may hurt consumers' welfare as the resulting user cost of oil is so high that the fall in welfare wipes out the gain from higher tariff revenues.

  4. NASH in Nondiabetic Endocrine Disorders.

    PubMed

    Wang, Timothy; Yang, Wei; Karakas, Sidika; Sarkar, Souvik

    2018-06-06

    Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease, including hepatic steatosis, inflammation, and fibrosis. NAFLD carries the risk of progression to cirrhosis with its associated complications and hepatocellular carcinoma. It is now the most common liver disease in the Western world and its prevalence is increasing. While the association between NAFLD and type 2 diabetes has been well documented, there is significantly less understanding of the pathophysiology and progression of NAFLD in patients with other endocrine disorders affecting metabolism in various ways. Some of the more common endocrine disorders such as polycystic ovarian syndrome, growth hormone deficiency, hypothyroidism, and hypogonadism are known in clinical practice to be associated with NAFLD. Medications that alter the endocrine system such as tamoxifen and adrenal steroids have also been attributed to significant NAFLD. The key to management of NAFLD at this time are dietary changes and exercise to achieve weight loss. Unfortunately, a large proportion of the patients with these endocrine disorders are unable to achieve either. This review aims to examine and summarize the current published literature that have evaluated the association between NAFLD and the above endocrine disorders and potential therapeutic interventions in each case.

  5. J.B. Nash Lecture Series.

    ERIC Educational Resources Information Center

    Gray, Howard R., Comp.; And Others

    The following lectures are presented in this publication: (1) "The Dynamics of Recreation" (Betty Van der Smissen); (2) "Recreation Prospects" (Edith L. Ball); (3) "A View of the Past--A Bridge to the Future" (Allen V. Sapora); (4) "Coming to Grips with the New Leisure" (Richard G. Kraus); (5) "The Mild Blue Yonder--Changing Lifestyles and…

  6. Nonalcoholic Fatty Liver Disease & NASH

    MedlinePlus

    ... Process Research Training & Career Development Funded Grants & Grant History Research Resources Research at NIDDK Technology Advancement & Transfer Meetings & Workshops Health Information Diabetes Digestive ...

  7. What Is NAFLD and NASH?

    MedlinePlus

    ... Process Research Training & Career Development Funded Grants & Grant History Research Resources Research at NIDDK Technology Advancement & Transfer Meetings & Workshops Health Information Diabetes Digestive ...

  8. Nonalcoholic Steatohepatitis Induced by a High-Fat Diet Promotes Diethylnitrosamine Initiated Early Hepatocarcinogenesis in Rats

    USDA-ARS?s Scientific Manuscript database

    It has been suggested that patients with nonalcoholic steatohepatitis (NASH) have a high risk for liver cancer. However, it is unknown whether high-fat diet induced NASH promotes chemical carcinogen-initiated hepatocarcinogenesis. In the present study, Sprague-Dawley rats were injected with a low d...

  9. Two Different Approaches to Nonzero-Sum Stochastic Differential Games

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rainer, Catherine

    2007-06-15

    We make the link between two approaches to Nash equilibria for nonzero-sum stochastic differential games: the first one using backward stochastic differential equations and the second one using strategies with delay. We prove that, when both exist, the two notions of Nash equilibria coincide.

  10. Remarks on Hierarchic Control for a Linearized Micropolar Fluids System in Moving Domains

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jesus, Isaías Pereira de, E-mail: isaias@ufpi.edu.br

    We study a Stackelberg strategy subject to the evolutionary linearized micropolar fluids equations in domains with moving boundaries, considering a Nash multi-objective equilibrium (non necessarily cooperative) for the “follower players” (as is called in the economy field) and an optimal problem for the leader player with approximate controllability objective. We will obtain the following main results: the existence and uniqueness of Nash equilibrium and its characterization, the approximate controllability of the linearized micropolar system with respect to the leader control and the existence and uniqueness of the Stackelberg–Nash problem, where the optimality system for the leader is given.

  11. Hepatic Transcriptome Profiles of Mice with Diet-Induced Nonalcoholic Steatohepatitis Treated with Astaxanthin and Vitamin E

    PubMed Central

    Kobori, Masuko; Takahashi, Yumiko; Sakurai, Mutsumi; Ni, Yinhua; Chen, Guanliang; Nagashimada, Mayumi; Kaneko, Shuichi; Ota, Tsuguhito

    2017-01-01

    Astaxanthin alleviates hepatic lipid accumulation and peroxidation, inflammation, and fibrosis in mice with high-cholesterol, high-cholate, and high-fat (CL) diet-induced nonalcoholic steatohepatitis (NASH). It has been proposed as a potential new treatment to inhibit the progression of NASH in humans. In this study, we compared hepatic gene expression profiles after treatment with astaxanthin or the antioxidant vitamin E in mice with CL diet-induced NASH. Comprehensive gene expression analyses of the livers of mice fed a standard, CL, or CL diet containing astaxanthin or vitamin E for 12 weeks were performed using a DNA microarray. Both astaxanthin and vitamin E effectively improved gene expression associated with eukaryotic initiation factor-2 (EIF2) signaling, which is suppressed in NASH by endoplasmic reticulum (ER) stress in the liver. However, astaxanthin did not improve the expression of genes associated with mitochondrial dysfunction. Astaxanthin, but not vitamin E, was predicted to suppress the actions of ligand-dependent nuclear receptors peroxisome proliferator-activated receptors, (PPAR) α (PPARA) and PPARδ (PPARD), and to affect related molecules. Establishing a new therapy using astaxanthin will require elucidation of astaxanthin’s molecular action on the functions of PPARα and related molecules in the livers of mice with diet-induced NASH. PMID:28282876

  12. Gender and racial differences in nonalcoholic fatty liver disease.

    PubMed

    Pan, Jen-Jung; Fallon, Michael B

    2014-05-27

    Due to the worldwide epidemic of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of elevated liver enzymes. NAFLD represents a spectrum of liver injury ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may progress to advanced fibrosis and cirrhosis. Individuals with NAFLD, especially those with metabolic syndrome, have higher overall mortality, cardiovascular mortality, and liver-related mortality compared with the general population. According to the population-based studies, NAFLD and NASH are more prevalent in males and in Hispanics. Both the gender and racial ethnic differences in NAFLD and NASH are likely attributed to interaction between environmental, behavioral, and genetic factors. Using genome-wide association studies, several genetic variants have been identified to be associated with NAFLD/NASH. However, these variants account for only a small amount of variation in hepatic steatosis among ethnic groups and may serve as modifiers of the natural history of NAFLD. Alternatively, these variants may not be the causative variants but simply markers representing a larger body of genetic variations. In this article, we provide a concise review of the gender and racial differences in the prevalence of NAFLD and NASH in adults. We also discuss the possible mechanisms for these disparities.

  13. United States Navy Oceanic Armed Reconnaissance System

    DTIC Science & Technology

    2011-12-12

    This report was prepared by: Rahul Petrie Daniel Reese Kurtis Hoots Robert Taylor Drew Nash Bunny Cooper Jonathan Trdan-Schmidt Marshall...NPS – Cohort 311-102S, Team OARS: Mr. Marshall Rice, Mr. Rahul Petrie, Mr. Daniel Reese, Mr. Kurtis Hoots, Mr. Robert Taylor, Mr. Drew Nash

  14. Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine initiated early hepatocarcinogenesis in rats

    USDA-ARS?s Scientific Manuscript database

    It has been suggested that patients with nonalcoholic steatohepatitis (NASH) are at a high risk for liver cancer. However, it is unknown whether high-fat diet induced NASH promotes hepatocarcinogenesis. In the present study, Sprague-Dawley rats were injected with a low dose of hepatic carcinogen die...

  15. Hepatic manifestations of women with polycystic ovary syndrome.

    PubMed

    Chen, Mei-Jou; Ho, Hong-Nerng

    2016-11-01

    Women with polycystic ovary syndrome (PCOS) have a higher prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) than the general population. The link between NAFLD/NASH and PCOS is not just a coincidence. Indeed, both of these disorders comprise common risk factors, including central obesity, insulin resistance, chronic low-grade inflammation, and hyperandrogenemia. The characteristics of hyperandrogenemia in women with PCOS include elevated total and free testosterone levels and low sex hormone-binding globulin levels and are reported to be associated with NAFLD and elevated liver enzymes; however, not all elevated androgen levels in women with PCOS have the same adverse effects on the liver. With the exception of weight loss and encouraging exercise in obese women, few evidence-based effective treatments target NAFLD/NASH in women with PCOS. Selective antiandrogens and insulin sensitizers might be beneficial in treating NAFLD/NASH in women with PCOS, but further elucidation is needed. Copyright © 2016. Published by Elsevier Ltd.

  16. Rosiglitazone attenuates liver inflammation in a rat model of nonalcoholic steatohepatitis.

    PubMed

    Tahan, Veysel; Eren, Fatih; Avsar, Erol; Yavuz, Dilek; Yuksel, Meral; Emekli, Ebru; Imeryuz, Nese; Celikel, Cigdem; Uzun, Hafize; Haklar, Goncagul; Tozun, Nurdan

    2007-12-01

    Rosiglitazone is an insulin-sensitizing agent. We aimed to assess the effects of rosiglitazone on a methionine- and choline-deficient diet (MCDD) model of nonalcoholic steatohepatitis (NASH) in rats. Wistar rats were fed either MCDD or a control diet in the 4-week induction study; they were given saline or 4 mg/kg/day rosiglitazone. After the induction study period, the rats were divided into four groups and fed MCDD or given a control diet for an additional 8 weeks and received saline or rosiglitazone. Serum and tissue samples were obtained. Rosiglitazone improved inflammation in NASH and improved ALT, alkaline phosphatase, and interleukin-6 levels in the induction study and interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha levels in the treatment study. Our preliminary study is the first to show the anti-inflammatory effects of rosiglitazone in NASH. Rosiglitazone's effect on cytokines may be a key mechanism of its anti-inflammatory effect in NASH.

  17. Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis.

    PubMed

    Dzierlenga, Anika L; Cherrington, Nathan J

    2018-03-01

    Nonalcoholic steatohepatitis (NASH) remodels the expression and function of genes and proteins that are critical for drug disposition. This study sought to determine whether disruption of membrane protein trafficking pathways in human NASH contributes to altered localization of multidrug resistance-associated protein 2 (MRP2). A comprehensive immunoblot analysis assessed the phosphorylation, membrane translocation, and expression of transporter membrane insertion regulators, including several protein kinases (PK), radixin, MARCKS, and Rab11. Radixin exhibited a decreased phosphorylation and total expression, whereas Rab11 had an increased membrane localization. PKCδ, PKCα, and PKA had increased membrane activation, whereas PKCε had a decreased phosphorylation and membrane expression. Radixin dephosphorylation may activate MRP2 membrane retrieval in NASH; however, the activation of Rab11/PKCδ and PKA/PKCα suggest an activation of membrane insertion pathways as well. Overall these data suggest an altered regulation of protein trafficking in human NASH, although other processes may be involved in the regulation of MRP2 localization. © 2018 Wiley Periodicals, Inc.

  18. Expression of genes for microRNA-processing enzymes is altered in advanced non-alcoholic fatty liver disease.

    PubMed

    Sharma, Haveesh; Estep, Michael; Birerdinc, Aybike; Afendy, Arian; Moazzez, Amir; Elariny, Hazem; Goodman, Zachary; Chandhoke, Vikas; Baranova, Ancha; Younossi, Zobair M

    2013-08-01

    Recently, microRNAs (miRNA) have been linked to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH). First transcribed as pri-miRNA, these molecules are further processed by a complex of endonuclear and cytosolic RNA binding molecules to form mature miRNAs. The aim of this study is to investigate mechanisms of miRNA regulation in the visceral adipose of obese NAFLD patients via measuring expression of miRNA processing enzymes and pri-miRNA. Total RNAs were extracted from visceral adipose tissue (VAT) samples collected from patients undergoing bariatric surgery. All patients had biopsy-proven NAFLD (NASH patients [n = 12] and non-NASH NAFLD [n = 12]). For each patient, we profiled mRNA levels for three miRNA processing elements (Drosha, DGCR8, and Dicer1) and seven pri-miRNAs (pri-miR-125b-2, pri-miR-16-2, pri-miR-26a-1, pri-miR-26a-2, pri-miR-7-1, pri-miR-7-2, and pri-miR-7-3). Expression of Dicer1, Drosha and DGCR8 was significantly increased within the NASH cohort along with expression of pri-miR-7-1. The presence of focal necrosis on the liver biopsy correlated significantly with levels of Dicer1 and DGRC8. Both NASH and ballooning degeneration of hepatocytes correlated negatively with the expression levels of hsa-miR-125b. Histologic NASH correlated positively with the expression levels of pri-miR-16-2 and pri-miR-7-1. The presence of the hepatocyte's ballooning degeneration in the liver biopsy correlated positively with pri-miR-26a-1 and pri-miR-7-1. The expression profile of pri-miR-125b-2 also correlated positively with body mass index. Our findings support the hypothesis that VAT-derived miRNA may contribute to the pathogenesis of NASH in obese patients. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  19. An estrogen receptor β-selective agonist inhibits non-alcoholic steatohepatitis in preclinical models by regulating bile acid and xenobiotic receptors.

    PubMed

    Ponnusamy, Suriyan; Tran, Quynh T; Thiyagarajan, Thirumagal; Miller, Duane D; Bridges, Dave; Narayanan, Ramesh

    2017-03-01

    Non-alcoholic steatohepatitis (NASH) affects 8-10 million people in the US and up to 75% of obese individuals. Despite this, there are no approved oral therapeutics to treat NASH and therefore the need for novel approaches exists. The estrogen receptor β (ER-β)-selective agonist, β-LGND2, inhibits body weight and white adipose tissue, and increases metabolism, resulting in higher energy expenditure and thermogenesis. Due to favorable effects of β-LGND2 on obesity, we hypothesized that β-LGND2 will prevent NASH directly by reducing lipid accumulation in the liver or indirectly by favorably changing body composition. Male C57BL/6 mice fed with high fat diet (HFD) for 10 weeks or methionine choline-deficient diet for four weeks and treated with vehicle exhibited altered liver weights by twofold and increased serum transaminases by 2-6-folds. These changes were not observed in β-LGND2-treated animals. Infiltration of inflammatory cells and collagen deposits, an indication of fibrosis, were observed in the liver of mice fed with HFD for 10 weeks, which were effectively blocked by β-LGND2. Gene expression studies in the liver indicate that pregnane X receptor target genes were significantly increased by HFD, and the increase was inhibited by β-LGND2. On the other hand, metabolomics indicate that bile acid metabolites were significantly increased by β-LGND2. These studies demonstrate that an ER-β agonist might provide therapeutic benefits in NASH by directly modulating the function of xenobiotic and bile acid receptors in the liver, which have important functions in the liver, and indirectly, as demonstrated before, by inhibiting adiposity. Impact statement Over 75-90% of those classified as clinically obese suffer from co-morbidities, the most common of which is non-alcoholic steatohepatitis (NASH). While there are currently no effective treatment approaches for NASH, data presented here provide preliminary evidence that an estrogen receptor β-selective ligand

  20. Modeling NAFLD Disease Burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.

    PubMed

    Estes, Chris; Anstee, Quentin M; Arias-Loste, Maria Teresa; Bantel, Heike; Bellentani, Stefeno; Caballeria, Joan; Colombo, Massimo; Craxi, Antonio; Crespo, Javier; Day, Christopher P; Geier, Andreas; Kondili, Loreta A; Lazarus, Jeffrey V; Loomba, Rohit; Manns, Michael P; Marchesini, Giulio; Negro, Francesco; Petta, Salvatore; Ratziu, Vlad; Romero-Gomez, Manuel; Sanyal, Arun; Schattenberg, Jörn M; Tacke, Frank; Trautwein, Christian; Wei, Lai; Zeuzem, Stefan; Razavi, Homie

    2018-06-07

    Nonalcoholic fatty liver disease (NAFLD) with resulting nonalcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma (HCC) globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. A model was used to estimate NAFLD and NASH disease progression in 8 countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as result of urbanization and the lowest growth in Japan as result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as result of an aging/increasing population. NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) can lead to advanced liver disease, and are occurring in increasing numbers in tandem with epidemics of obesity and diabetes. A mathematical model was built to understand how the disease burden associated with NAFLD and NASH will change over time. Results suggest increasing numbers of cases of advanced liver disease and liver-related mortality in the coming years

  1. p38 MAPK signal pathway involved in anti-inflammatory effect of Chaihu-Shugan-San and Shen-ling-bai-zhu-San on hepatocyte in non-alcoholic steatohepatitis rats.

    PubMed

    Yang, QinHe; Xu, YongJian; Feng, GaoFei; Hu, ChaoFeng; Zhang, YuPei; Cheng, ShaoBing; Wang, YanPing; Gong, XiangWen

    2014-01-01

    Traditional Chinese Medicine (TCM), has over thousands-of-years history of use. Chaihu-Shugan-San (CSS), and Shen-ling-bai-zhu-San (SLBZS), are famous traditional Chinese herbal medicine formulas, which have been used in China, for the treatment of many chronic diseases. This study investigated the anti-inflammatory effects of CSS and SLBZS on signaling molecules involved in p38 mitogen-activated protein kinase (p38 MAPK), pathway on hepatocytes of non-alcoholic steatohepatitis (NASH), rats induced by high fat diet. SD male rats were randomly divided into 8 groups: negative control group, model control group, high (9.6g/kg/day)/low (3.2g/kg/day)-dose CSS group, high (30g/kg/day)/low (10g/kg/day)-dose SLBZS group, high (39.6g/kg/day)/low (13.2g/kg/day)-dose integrated group. The rats of NASH model were induced by feeding a high-fat diet. After 16, wks, Hepatocytes were isolated from 6, rats in each group by collagenase perfusion. The liver histopathological changes and serum inflammatory cytokines TNF-α, IL-6 were determined. The proteins of TLR4, phosphor-p38 MAPK and p38 MAPK involved in p38 MAPK signal pathway were assayed. The statistical data indicated the NASH model rats reproduced typical histopathological features of NASH in human. CSS and SLBZS ameliorated lipid metabolic disturbance, attenuated NASH progression, decreased the levels of TNF-α and IL-6 in serum, as well as inhibited TLR4 protein expression, p38 MAPK phosphorylation, and activation of p38 MAPK. In conclusion, CSS and SLBZS might work as a significant anti-inflammatory effect on hepatocyte of NASH by inhibiting the activation of TLR4, p-p38 MAPK and p38 MAPK involved in p38 MAPK signal pathway. To some extent, CSS and SLBZS may be a potential alternative and complementary medicine to protect against liver injury, alleviate the inflammation reaction, moderate NASH progression.

  2. Bountiful health care and A Beautiful Mind.

    PubMed

    Flower, Joe

    2002-01-01

    The Nash Equilibrium (put forward by John Nash and celebrated in the film, A Beautiful Mind) mathematically describes multi-player, infinite games. It is a general description of large human transactions, such as health care. Learn how new inputs, new players or new resources can disrupt these transactions.

  3. Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: Analysis of isolated hepatic stellate cells

    PubMed Central

    KIM, MINA; YANG, SU-GEUN; KIM, JOON MI; LEE, JIN-WOO; KIM, YOUNG SOO; LEE, JUNG IL

    2012-01-01

    Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular injury and initial fibrosis severity has been suggested as an important prognostic factor of NASH. Silymarin was reported to improve carbon tetrachloride-induced liver fibrosis and reduce the activation of hepatic stellate cells (HSC). We investigated whether silymarin could suppress the activation of HSCs in NASH induced by methionine- and choline-deficient (MCD) diet fed to insulin-resistant rats. NASH was induced by feeding MCD diet to obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with standard chow and served as the control. OLETF rats were fed on either standard laboratory chow, or MCD diet or MCD diet mixed with silymarin. Histological analysis of the liver showed improved non-alcoholic fatty liver disease (NAFLD) activity score in silymarin-fed MCD-induced NASH. Silymarin reduced the activation of HSCs, evaluated by counting α-smooth muscle actin (SMA)-positive cells and measuring α-SMA mRNA expression in the liver lysates as well as in HSCs isolated from the experimental animals. Although silymarin decreased α1-procollagen mRNA expression in isolated HSCs, the anti-fibrogenic effect of silymarin was not prominent so as to show significant difference under histological analysis. Silymarin increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreased tumor necrosis factor (TNF)-α mRNA expression in the liver. Our study suggested that the possible protective effect of silymarin in diet induced NASH by suppressing the activation of HSCs and disturbing the role of the inflammatory cytokine TNF-α. PMID:22710359

  4. Effects of dark chocolate on NOX-2-generated oxidative stress in patients with non-alcoholic steatohepatitis.

    PubMed

    Loffredo, L; Del Ben, M; Perri, L; Carnevale, R; Nocella, C; Catasca, E; Baratta, F; Ceci, F; Polimeni, L; Gozzo, P; Violi, F; Angelico, F

    2016-08-01

    Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is considered a pathogenetic mechanism determining fibrosis and disease progression in non-alcoholic steatohepatitis (NASH). Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans. To analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH. In a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (>85% cocoa) or 40 g/day of milk chocolate (<35% cocoa), for 2 weeks. sNOX2-dp, serum isoprostanes and CK-18 were assessed at baseline and after 2 weeks of chocolate intake. Compared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels. A significant difference for treatments was found in subjects with respect to sNOX2-dp, serum isoprostanes and serum CK-18. The pairwise comparisons showed that, compared to baseline, after 14 days of dark chocolate intake, a significant reduction in sNOX2-dp serum isoprostanes and CK-18 M30 was found. No change was observed after milk chocolate ingestion. A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes. Cocoa polyphenols exert an antioxidant activity via NOX2 down-regulation in NASH patients. © 2016 John Wiley & Sons Ltd.

  5. Histological improvement of non-alcoholic steatohepatitis with a prebiotic: a pilot clinical trial.

    PubMed

    Bomhof, Marc R; Parnell, Jill A; Ramay, Hena R; Crotty, Pam; Rioux, Kevin P; Probert, Chris S; Jayakumar, Saumya; Raman, Maitreyi; Reimer, Raylene A

    2018-05-19

    In obesity and diabetes the liver is highly susceptible to abnormal uptake and storage of fat. In certain individuals hepatic steatosis predisposes to the development of non-alcoholic steatohepatitis (NASH), a disease marked by hepatic inflammation and fibrosis. Although the precise pathophysiology of NASH is unknown, it is believed that the gut microbiota-liver axis influences the development of this disease. With few treatment strategies available for NASH, exploration of gut microbiota-targeted interventions is warranted. We investigated the therapeutic potential of a prebiotic supplement to improve histological parameters of NASH. In a placebo-controlled, randomized pilot trial, 14 individuals with liver-biopsy-confirmed NASH [non-alcoholic fatty liver activity score (NAS) ≥ 5] were randomized to receive oligofructose (8 g/day for 12 weeks followed by 16 g/day for 24 weeks) or isocaloric placebo for 9 months. The primary outcome measure was the change in liver biopsy NAS score and the secondary outcomes included changes in body weight, body composition, glucose tolerance, inflammatory markers, and gut microbiota. Independent of weight loss, oligofructose improved liver steatosis relative to placebo and improved overall NAS score (P = 0.016). Bifidobacterium was enhanced by oligofructose, whereas bacteria within Clostridium cluster XI and I were reduced with oligofructose (P < 0.05). There were no adverse side effects that deterred individuals from consuming oligofructose for treatment of this disease. Independent of other lifestyle changes, prebiotic supplementation reduced histologically-confirmed steatosis in patients with NASH. Larger follow-up studies are warranted. This trial was registered at Clinicaltrials.com as NCT03184376.

  6. Alisol A 24-acetate ameliorates nonalcoholic steatohepatitis by inhibiting oxidative stress and stimulating autophagy through the AMPK/mTOR pathway.

    PubMed

    Wu, Chenqu; Jing, Menghui; Yang, Lijuan; Jin, Lei; Ding, Yicun; Lu, Juan; Cao, Qin; Jiang, Yuanye

    2018-06-05

    Alisol A 24-acetate (AA), a natural triterpenoid isolated from the traditional Chinese medicine Rhizoma Alismatis, has various therapeutic effects. We investigated the anti-nonalcoholic steatohepatitis (NASH) effect of AA and its underlying mechanisms in vitro and in vivo. C57BL/6 mice were fed a methionine and choline-deficient (MCD) diet for 4 weeks to induce NASH. The mice were simultaneously treated with a daily dose of AA (15, 30, and 60 mg kg -1 , ig) for 4 weeks. On the last day, the animals were sacrificed and plasma and liver tissue were collected. Serum and liver tissue biochemical analyses and histological observation were performed. The human hepatic stellate cell line LX-2 was used to build NASH models by culturing with conditioned medium from WRL-68 liver cells after exposure to MCD medium in vitro. Liver oxidative stress and inflammatory indices and autophagy markers were examined. The results showed that AA suppressed reactive oxygen species (ROS) and inflammation in a NASH mouse model and inhibited the expression of inflammatory cytokines and ROS in LX-2 cells in MCD medium. Furthermore, we found AA stimulated autophagy in mice liver and LX-2, which could be the underlying mechanism of AA in NASH. To further investigate the role of autophagy in LX-2 cells, we found that AA regulated autophagy via the AMPK/mTOR/ULK1 pathway and dorsomorphin, a selective AMPK inhibitor, led to the suppression of AA-induced autophagy. Taken together, our results indicate that AA could be a possible therapy for NASH by inhibiting oxidative stress and stimulating autophagy. Copyright © 2018. Published by Elsevier B.V.

  7. Verification of B-lymphocyte activating factor's involvement in the exacerbation of insulin resistance as well as an autoimmune response in patients with nonalcoholic steatohepatitis and patients with HCV-related chronic liver disease.

    PubMed

    Himoto, Takashi; Fujita, Koji; Nomura, Takako; Tani, Joji; Morishita, Asahiro; Yoneyama, Hirohito; Haba, Reiji; Masaki, Tsutomu

    2017-01-01

    Ten to forty percent of nonalcoholic steatohepatitis (NASH) and HCV-related chronic liver disease (CLD-C) patients have antinuclear antibodies (ANAs). However, the relationship between autoimmune response and insulin resistance remains uncertain among those patients. The primary purpose of this study was to investigate whether or not ANA status was associated with the development of insulin resistance and obesity in NASH and CLD-C patients. Degrees of hepatic fibrosis and steatosis were evaluated by the classification proposed by Brunt et al. Obesity and insulin resistance were estimated by calculating body mass index and the value of homeostasis model of for assessment of insulin resistance (HOMA-IR), respectively. A revised scoring system was applied to the diagnosis of autoimmune hepatitis (AIH). Serum B-lymphocyte activating factor (BAFF) levels were determined, using an ELISA technique. Ten of 25 (40%) NASH patients and 9 of 22 (41%) CLD-C patients had ANAs, though the titers were weak in most patients. Only one NASH patient met the category of "definite" AIH among the enrolled patients. Serum IgG levels were significantly higher in NASH and CLD-C patients with ANAs than in those without ANAs, and NASH and CLD-C patients with ANAs had significantly higher HOMA-IR values than those without ANAs (6.81 ± 3.36 vs. 4.00 ± 2.57, p = 0.0305, 3.01 ± 1.31 vs. 1.28 ± 0.50, p = 0.0011). CLD-C patients with ANAs had more advanced hepatic fibrosis and steatosis than those without ANAs, while ANA status was not associated with hepatic fibrosis or steatosis in NASH patients. Obesity was independent of ANA status in both subjects. Serum BAFF levels were significantly higher in CLD-C patients with ANAs than those in CLD-C patients without ANAs (1303 ± 268 vs. 714 ± 143 pg/ml, p = 0.0036). A close correlation between serum BAFF level and the HOMA-IR value was observed in CLD-C patients (r = 0.467, p = 0.0485). Our data suggest that NASH and CLD

  8. Effects of dark chocolate on endothelial function in patients with non-alcoholic steatohepatitis.

    PubMed

    Loffredo, L; Baratta, F; Ludovica, P; Battaglia, S; Carnevale, R; Nocella, C; Novo, M; Pannitteri, G; Ceci, F; Angelico, F; Violi, F; Del Ben, M

    2018-02-01

    Oxidative stress plays a pivotal role in inducing endothelial dysfunction and progression from simple fatty liver steatosis (FLD) to non-alcoholic steatohepatitis (NASH). Polyphenols could reduce oxidative stress and restore endothelial function by inhibiting the nicotinamide-adenine-dinucleotide-phosphate (NADPH) oxidase isoform Nox2. The aim of this study was to assess endothelial function and oxidative stress in a population affected by simple FLD and NASH. Furthermore, we analysed the effect of high vs low content of cocoa polyphenols on endothelial function and oxidative stress in patients with NASH. In a cross-sectional study we analysed endothelial function, as assessed by flow-mediated dilation (FMD), and oxidative stress, as assessed by Nox2 activation, serum isoprostanes and nitric oxide bioavailability (NOx), in patients with NASH (n = 19), FLD (n = 19) and controls (n = 19). Then, we performed a randomized, cross-over study in 19 subjects with NASH comparing the effect of 14-days administration of 40 g of chocolate at high (dark chocolate, cocoa >85%) versus low content (milk chocolate, cocoa <35%) of polyphenols on FMD and oxidative stress. Compared to controls, NASH and FLD patients had higher Nox2 activity and isoprostanes levels and lower FMD and NOx, with a significant gradient between FLD and NASH. The interventional study showed that, compared to baseline, FMD and NOx increased (from 2.9 ± 2.4 to 7.2 ± 3.0% p < 0.001 and from 15.9 ± 3.6 to 20.6 ± 4.9 μM, p < 0.001, respectively) in subjects given dark but not in those given milk chocolate. A simple linear regression analysis showed that Δ (expressed by difference of values between before and after 14 days of chocolate assumption) of FMD was associated with Δ of Nox2 activity (Rs = -0.323; p = 0.04), serum isoprostanes (Rs: -0.553; p < 0.001) and NOx (Rs: 0.557; p < 0.001). Cocoa polyphenols improve endothelial function via Nox2 down-regulation in NASH patients

  9. Exercise Reduces Liver Lipids and Visceral Adiposity in Patients With Nonalcoholic Steatohepatitis in a Randomized Controlled Trial.

    PubMed

    Houghton, David; Thoma, Christian; Hallsworth, Kate; Cassidy, Sophie; Hardy, Timothy; Burt, Alastair D; Tiniakos, Dina; Hollingsworth, Kieren G; Taylor, Roy; Day, Christopher P; McPherson, Stuart; Anstee, Quentin M; Trenell, Michael I

    2017-01-01

    Pharmacologic treatments for nonalcoholic steatohepatitis (NASH) are limited. Lifestyle interventions are believed to be effective in reducing features of NASH, although the effect of regular exercise, independent of dietary change, is unclear. We performed a randomized controlled trial to study the effect of exercise on hepatic triglyceride content (HTGC) and biomarkers of fibrosis in patients with NASH. Twenty-four patients (mean age, 52 ± 14 y; body mass index, 33 ± 6 kg/m 2 ) with sedentary lifestyles (<60 min/wk of moderate-vigorous activity) and biopsy-proven NASH were assigned randomly to groups that exercised (n = 12) or continued standard care (controls, n = 12) for 12 weeks while maintaining their weight. The exercise (cycling and resistance training) was supervised at an accredited sports center and supervised by a certified exercise specialist and recorded 3 times per week on nonconsecutive days. We measured HTGC, body composition, circulating markers of inflammation, fibrosis, and glucose tolerance at baseline and at 12 weeks. Compared with baseline, exercise significantly reduced HTGC (reduction of 16% ± 24% vs an increase of 9% ± 15% for controls; P < .05), visceral fat (reduction of 22 ± 33 cm 2 vs an increase of 14 ± 48 cm 2 for controls; P < .05), plasma triglycerides (reduction of 0.5 ± 1.0 mmol/L vs an increase of 0.3 ± 0.4 mmol/L for controls; P < .05), and γ-glutamyltransferase (reduction of 10 ± 28 U/L - 1 vs a reduction of 17 ± 38 U/L -1 for controls; P < .05). There were no effects of exercise on liver enzyme levels, metabolic parameters, circulatory markers of inflammation (levels of interleukin 6, tumor necrosis factor-α, or C-reactive protein) and fibrosis. In a randomized controlled trial, 12 weeks of exercise significantly reduced HTGC, visceral fat, and plasma triglyceride levels in patients with NASH, but did not affect circulating markers of inflammation or fibrosis. Exercise without weight loss therefore affects some

  10. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials.

    PubMed

    Sato, Ken; Gosho, Masahiko; Yamamoto, Takaya; Kobayashi, Yuji; Ishii, Norimitsu; Ohashi, Tomohiko; Nakade, Yukiomi; Ito, Kiyoaki; Fukuzawa, Yoshitaka; Yoneda, Masashi

    2015-01-01

    Vitamin E is often used in the treatment of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH); however, the magnitude of treatment response associated with vitamin E in improving liver function and histology in NAFLD/NASH has not, to our knowledge, been quantified systematically. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) using vitamin E in the treatment of NAFLD/NASH. PubMed, Medline, and Cochrane Library Full Text Database, and Japan Medical-Literature Database (Igaku Chuo Zasshi) were searched until March 2014, and five RCTs were identified for meta-analysis. According to a random effect model analysis of the five studies, vitamin E significantly reduced aspartate transaminase (AST) by -19.43 U/L, alanine aminotransferase (ALT) by -28.91 U/L, alkaline phosphatase (ALP) by -10.39 U/L, steatosis by -0.54 U/L, inflammation by -0.20 U/L, and hepatocellular ballooning by -0.34 U/L compared with the control group. Vitamin E treatment with NASH adult patients showed obvious reductions in not only AST of -13.91 U/L, ALT by -22.44 U/L, steatosis of -0.67 U/L, inflammation of -0.20 U/L, but also fibrosis of -0.30 U/L compared to the control treatment. Vitamin E significantly improved liver function and histologic changes in patients with NAFLD/NASH. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. A dietary restriction influences the progression but not the initiation of MSG-Induced nonalcoholic steatohepatitis.

    PubMed

    Fujimoto, Makoto; Tsuneyama, Koichi; Nakanishi, Yuko; Salunga, Thucydides L; Nomoto, Kazuhiro; Sasaki, Yoshiyuki; Iizuka, Seiichi; Nagata, Mitsunobu; Suzuki, Wataru; Shimada, Tsutomu; Aburada, Masaki; Shimada, Yutaka; Gershwin, M Eric; Selmi, Carlo

    2014-03-01

    The metabolic syndrome is a major worldwide health care issue and a dominant risk factor for cardiovascular disease. The liver manifestations of this syndrome include nonalcoholic fatty liver disease (NAFLD) and its progressive variant nonalcoholic steatohepatitis (NASH). Although significant research has been performed, the basic pathogenesis of NAFLD/NASH remains controversial and effective treatments are still unavailable. We have previously reported on a murine model of NASH induced by the neonatal injection of monosodium glutamate (MSG), which includes the clinical manifestations of central obesity, diabetes, hyperlipidemia, and ultimately liver inflammation, fibrosis, and cancer. Although MSG is considered a safe food additive, its administration to pregnant rats increases the voracity and growth hormone levels in the offspring. To further understand the biology of this model, we have investigated the influence of the calorie intake on these clinical manifestations by feeding animals a restrictive diet. MSG-treated animals fed a restrictive diet continue to manifest obesity and early stage NASH but have improvements in serum lipid profiles. At 12 months of age, mice had manifestations of obesity, whether animals were fed a restricted or control diet, but animals fed a restrictive diet had a reduction in the progression of NASH. In conclusion, MSG appears to be a critical factor in the initiation of obesity, whereas calorie intake may modulate the progression of disease.

  12. Monosodium glutamate (MSG): a villain and promoter of liver inflammation and dysplasia.

    PubMed

    Nakanishi, Yuko; Tsuneyama, Koichi; Fujimoto, Makoto; Salunga, Thucydides L; Nomoto, Kazuhiro; An, Jun-Ling; Takano, Yasuo; Iizuka, Seiichi; Nagata, Mitsunobu; Suzuki, Wataru; Shimada, Tsutomu; Aburada, Masaki; Nakano, Masayuki; Selmi, Carlo; Gershwin, M Eric

    2008-01-01

    Chronic inflammation is a common theme in a variety of disease pathways, including autoimmune diseases. The pathways of chronic inflammation are well illustrated by nonalcoholic steatohepatitis (NASH), which is of a serious concern due to its increasing prevalence in the westernized world and its direct correlation with lifestyle factors, particularly diet. Importantly, NASH may ultimately lead to the development of hepatocellular carcinoma. We previously reported that injection of monosodium glutamate (MSG) in ICR mice leads to the development of significant inflammation, central obesity, and type 2 diabetes. To directly address the long-term consequences of MSG on inflammation, we have performed serial analysis of MSG-injected mice and focused in particular on liver pathology. By 6 and 12 months of age, all MSG-treated mice developed NAFLD and NASH-like histology, respectively. In particular, the murine steatohepatitis at 12 months was virtually undistinguishable from human NASH. Further, dysplastic nodular lesions were detected in some cases within the fibrotic liver parenchyma. We submit that MSG treatment of mice induces obesity and diabetes with steatosis and steatohepatitis resembling human NAFLD and NASH with pre-neoplastic lesions. These results take on considerable significance in light of the widespread usage of dietary MSG and we suggest that MSG should have its safety profile re-examined and be potentially withdrawn from the food chain.

  13. Network formation: neighborhood structures, establishment costs, and distributed learning.

    PubMed

    Chasparis, Georgios C; Shamma, Jeff S

    2013-12-01

    We consider the problem of network formation in a distributed fashion. Network formation is modeled as a strategic-form game, where agents represent nodes that form and sever unidirectional links with other nodes and derive utilities from these links. Furthermore, agents can form links only with a limited set of neighbors. Agents trade off the benefit from links, which is determined by a distance-dependent reward function, and the cost of maintaining links. When each agent acts independently, trying to maximize its own utility function, we can characterize “stable” networks through the notion of Nash equilibrium. In fact, the introduced reward and cost functions lead to Nash equilibria (networks), which exhibit several desirable properties such as connectivity, bounded-hop diameter, and efficiency (i.e., minimum number of links). Since Nash networks may not necessarily be efficient, we also explore the possibility of “shaping” the set of Nash networks through the introduction of state-based utility functions. Such utility functions may represent dynamic phenomena such as establishment costs (either positive or negative). Finally, we show how Nash networks can be the outcome of a distributed learning process. In particular, we extend previous learning processes to so-called “state-based” weakly acyclic games, and we show that the proposed network formation games belong to this class of games.

  14. Apnoeic-hypopnoeic episodes during obstructive sleep apnoea are associated with histological nonalcoholic steatohepatitis.

    PubMed

    Mishra, Poonam; Nugent, Clarke; Afendy, Arian; Bai, Chunhong; Bhatia, Priya; Afendy, Mariam; Fang, Yun; Elariny, Hazem; Goodman, Zachary; Younossi, Zobair M

    2008-09-01

    Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnoea are associated with metabolic syndrome and atherosclerotic heart disease. This study evaluates the potential association between the NAFLD subtypes and a number of polysomnographical (PSG) parameters. This study included patients undergoing bariatric surgery with extensive clinical and histological data for whom complete PSG data before surgery were also available. Excess alcohol intake and other causes of liver disease were excluded. Apnoea, hypopnoea and apnoea-hypopnoea index (AHI) were calculated as described previously. In this study, a total of 101 patients [77 nonalcoholic steatohepatitis (NASH) and 22 non-NASH controls] with PSG data were included (age 42.9 +/- 11.4 years, body mass index 51.6 +/- 9.5 kg/m(2), fasting serum glucose 117.4 +/- 53.4 mg/dl, fasting serum triglycerides 171.3 +/- 82.9 mg/dl, 58% hypertension and 33% diabetes mellitus). Subjects with histological NASH had significantly lower lowest desaturation (77 vs. 85%, P=0.006), lower mean nocturnal oxygen saturation (91 vs. 93%, P=0.05), higher AHI (35 vs. 22, P=0.03), higher respiratory disturbance index (46 vs. 21, P=0.02) and higher alanine aminotransferase/aspartate aminotransferase ratio (1.4 vs. 1.3, P=0.05) compared with non-NASH controls. In multivariate analysis, the lowest desaturation (P=0.04) was independently associated with histological NASH. Lowest desaturation and mean nocturnal oxygen saturation were significantly lower in subjects with fibrosis (76 vs. 85%, P=0.004 and 90.4 vs. 93.0%, P=0.02). Our results suggest that the frequent nocturnal hypoxic episodes in NAFLD patients may be a risk factor for developing NASH. Additional studies are needed to study the effect of optimizing sleep apnoea management on the outcomes of patients with NAFLD.

  15. Curcumin reduces the risk of chronic kidney damage in mice with nonalcoholic steatohepatitis by modulating endoplasmic reticulum stress and MAPK signaling.

    PubMed

    Afrin, Mst Rejina; Arumugam, Somasundaram; Rahman, Md Azizur; Karuppagounder, Vengadeshprabhu; Harima, Meilei; Suzuki, Hiroshi; Miyashita, Shizuka; Suzuki, Kenji; Ueno, Kazuyuki; Yoneyama, Hiroyuki; Watanabe, Kenichi

    2017-08-01

    Developing confirmation recommends that in patients with dynamic type of NAFLD, particularly nonalcoholic steatohepatitis (NASH) may have the pathogenic parts in the advancement of kidney damage. In this study we have examined the impact of curcumin on NASH instigated chronic kidney damage (CKD) and the putative mechanisms. To prepare this NASH model, neonatal C57BL/6J male mice were exposed to low-dose streptozotocin (STZ) and were fed high-fat diet (HFD) at the age of 4weeks and continued up to 14weeks, curcumin was given at 100mg/kg dose by oral gavage daily after 10weeks of STZ injection and continued for 4weeks along with HFD feeding. NASH incited mice demonstrated nephrotoxicity as proved by declining renal capacity, which was evaluated by measuring blood urea nitrogen and creatinine in serum and histopathological variations from the norm. These progressions were switched by curcumin treatment, which brought about huge change in renal capacity. Furthermore, curcumin markedly decreased NAD(P)H oxidase subunits (p67phox, p47phox, p22phox), nitrotyrosine and CYP2E1 renal protein expression as well as reduced pro-inflammatory cytokine expression (TNFα, IL-1β, IFNγ). Renal protein expression of mitogen activated protein kinases (MAPKs) (p-JNK, p-ERK1/2) and glucose regulated protein 78, CHOP were increased in NASH induced mice and curcumin treatment attenuated these increased expressions. In addition, curcumin treatment also decreased the apoptosis signaling proteins (cleaved caspase-3, cleaved caspase-12) in the NASH kidney. Taken together, our results suggest that curcumin preserves the renal function, probably by attenuating the ER stress mediated MAPK signaling. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Deletion of Smad4 attenuates the hepatic inflammation and fibrogenesis during nonalcoholic steatohepatitis progression.

    PubMed

    Qin, Geng; Wang, Guo Zhen; Guo, Dan Dan; Bai, Ru-Xue; Wang, Miao; Du, Shi Yu

    2018-04-25

    To explore the effects of Smad4 deletion on inflammation and fibrogenesis during nonalcoholic steatohepatitis (NASH) progression. We collected 56 liver tissues from NASH patients (NASH group) and 60 normal liver tissues from patients received liver resection for trauma (control group). Smad4 Co/Co mice and wild-type (WT) mice were used to construct NASH model by high-fat diet (HFD) or methionine- and choline-deficient (MCD) diet. Hematoxylin and eosin (HE) staining and Tunnel assay were performed to observe pathological changes and apoptosis of liver tissues, respectively, quantitative real-time polymerase chain reaction (qRT-PCR) to detect expressions of inflammatory, fibrogenesis and apoptosis-related genes, and immunohistochemistry to determine proteins expressions of Smad4, MCP-1 and α-SMA. Smad4 protein expression was significantly increased in NASH patients as compared with Control group. Besides, in terms of HFD- and MCD- fed mice, those in Smad4 Co/Co group showed reduction of hepatic steatosis, inflammatory, liver apoptosis and NAS scores, and presented a decrease in glucose, TG, FFAs, AST and ALT, a great up-regulation in adiponectin. Besides, as compared with the WT mice fed with HFD and MCD, Smad4 Co/Co decreased the expressions of inflammatory markers (TNF-α, MCP-1, IFN-γ), fibrogenesis markers (COL1A1, α-SMA and TGF-β1), lipogenic genes (SREBP1c, FAS and ACC) and proapoptotic genes (Bax and caspase 3) in liver tissues, but increased the expressions of β-oxidation genes (PPARα, CPT1 and ACO) and antiapoptotic gene Bcl-2. Smad4 deletion may inhibit lipogenesis, stimulateβ-oxidation, ameliorate lipid metabolism and liver function, alleviate inflammation, fibrosis, and reduce liver apoptosis during NASH. This article is protected by copyright. All rights reserved.

  17. Ultra-high-field magnetic resonance spectroscopy in non-alcoholic fatty liver disease: Novel mechanistic and diagnostic insights of energy metabolism in non-alcoholic steatohepatitis and advanced fibrosis.

    PubMed

    Traussnigg, Stefan; Kienbacher, Christian; Gajdošík, Martin; Valkovič, Ladislav; Halilbasic, Emina; Stift, Judith; Rechling, Christian; Hofer, Harald; Steindl-Munda, Petra; Ferenci, Peter; Wrba, Fritz; Trattnig, Siegfried; Krššák, Martin; Trauner, Michael

    2017-10-01

    With the rising prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) non-invasive tools obtaining pathomechanistic insights to improve risk stratification are urgently needed. We therefore explored high- and ultra-high-field magnetic resonance spectroscopy (MRS) to obtain novel mechanistic and diagnostic insights into alterations of hepatic lipid, cell membrane and energy metabolism across the spectrum of NAFLD. MRS and liver biopsy were performed in 30 NAFLD patients with NAFL (n=8) or NASH (n=22). Hepatic lipid content and composition were measured using 3-Tesla proton ( 1 H)-MRS. 7-Tesla phosphorus ( 31 P)-MRS was applied to determine phosphomonoester (PME) including phosphoethanolamine (PE), phosphodiester (PDE) including glycerophosphocholine (GPC), phosphocreatine (PCr), nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate (Pi), γ-ATP and total phosphorus (TP). Saturation transfer technique was used to quantify hepatic ATP flux. Hepatic steatosis in 1 H-MRS highly correlated with histology (P<.001) showing higher values in NASH than NAFL (P<.001) without differences in saturated or unsaturated fatty acid indices. PE/TP ratio increased with advanced fibrosis (F3/4) (P=.002) whereas GPC/PME+PDE decreased (P=.05) compared to no/mild fibrosis (F0-2). γ-ATP/TP was lower in advanced fibrosis (P=.049), while PCr/TP increased (P=.01). NADPH/TP increased with higher grades of ballooning (P=.02). Pi-to-ATP exchange rate constant (P=.003) and ATP flux (P=.001) were lower in NASH than NAFL. Ultra-high-field MRS, especially saturation transfer technique uncovers changes in energy metabolism including dynamic ATP flux in inflammation and fibrosis in NASH. Non-invasive profiling by MRS appears feasible and may assist further mechanistic and therapeutic studies in NAFLD/NASH. © 2017 The Authors Liver International Published by John Wiley & Sons Ltd.

  18. Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity.

    PubMed

    Guichelaar, M M J; Gawrieh, S; Olivier, M; Viker, K; Krishnan, A; Sanderson, S; Malinchoc, M; Watt, K D; Swain, J M; Sarr, M; Charlton, M R

    2013-09-01

    Allelic variation (rs738409C→G) in adiponutrin (patatin-like phospholipase domain-containing protein 3, PNPLA3) has been associated with hepatic steatosis and liver fibrosis. The physiologic impact of the PNPLA3 G allele may be exacerbated in patients with severe obesity. In this study, we investigated the interactions of PNPLA3 rs738409 with a broad panel of metabolic and histologic characteristics of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) in patients with medically complicated obesity. Consecutive patients undergoing bariatric surgery were selected for a prospective study. They underwent extensive laboratory and histologic (liver biopsy) assessment, as well as evaluation of rs738409 polymorphism by TaqMan assay. Only 12 (8.3%) of the 144 patients had normal liver histology, with 72 (50%) NASH, of whom 15 (10.4% of total patients) had fibrosis stage 2-3. PNPLA3 GG genotype correlated positively (P < 0.05) with serum levels of alanine aminotransferase (ALT), asparate aminotransferase (AST), glucose, fibrinogen, and insulin-dependent diabetes mellitus, homeostasis model assessment-insulin resistance, and presence of NASH. Multivariate analysis indicated that PNPLA3 rs738409 G versus C allele remained an (independent) risk factor for NASH, in addition to CK-18 >145 IU/l, glucose >100 mg/dl, and C-reactive protein (CRP) >0.8 mg/dl. The probability of NASH increased from 9% (no risk factor) to 82% if all four risk factors were present. In this cohort of patients with medically complicated obesity, PNPLA3 rs738409 G allelic expression is associated with hepatic (NASH) and nonhepatic complications of obesity, such as insulin resistance. These novel findings may be related to a greater impact of PNPLA3 variant in magnitude and scope in patients with severe obesity than in less obese populations. Further studies are needed to characterize the nature of these associations. Copyright © 2013 The Obesity Society.

  19. Hepatocellular carcinoma in a mouse model fed a choline-deficient, L-amino acid-defined, high-fat diet.

    PubMed

    Ikawa-Yoshida, Ayae; Matsuo, Saori; Kato, Atsuhiko; Ohmori, Yusuke; Higashida, Atsuko; Kaneko, Eiji; Matsumoto, Masahiko

    2017-08-01

    Hepatocellular carcinoma (HCC) is a common cancer worldwide and represents the outcome of the natural history of chronic liver disease. The growing rates of HCC may be partially attributable to increased numbers of people with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, details of the liver-specific molecular mechanisms responsible for the NAFLD-NASH-HCC progression remain unclear, and mouse models that can be used to explore the exact factors that influence the progression of NAFLD/NASH to the more chronic stages of liver disease and subsequent HCC are not yet fully established. We have previously reported a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) as a dietary NASH model with rapidly progressive liver fibrosis in mice. The current study in C57BL/6J mice fed CDAHFD provided evidence for the chronic persistence of advanced hepatic fibrosis in NASH and disease progression towards HCC in a period of 36 weeks. When mice fed CDAHFD were switched back to a standard diet, hepatic steatosis was normalized and NAFLD activity score improved, but HCC incidence increased and the phenotype of fibrosis-associated HCC development was observed. Moreover, when mice continued to be fed CDAHFD for 60 weeks, HCC further developed without severe body weight loss or carcinogenesis in other organs. The autochthonous tumours showed a variety of histological features and architectural patterns including trabecular, pseudoglandular and solid growth. The CDAHFD mouse model might be a useful tool for studying the development of HCC from NAFLD/NASH, and potentially useful for better understanding pathological changes during hepatocarcinogenesis. © 2017 The Authors. International Journal of Experimental Pathology published by John Wiley & Sons Ltd on behalf of Company of the International Journal of Experimental Pathology (CIJEP).

  20. Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet.

    PubMed

    Kong, Bo; Luyendyk, James P; Tawfik, Ossama; Guo, Grace L

    2009-01-01

    Nonalcoholic steatohepatitis (NASH) comprises dysregulation of lipid metabolism and inflammation. Identification of the various genetic and environmental susceptibility factors for NASH may provide novel treatments to limit inflammation and fibrosis in patients. This study utilized a mouse model of hypercholesterolemia, low-density lipoprotein receptor knockout (LDLr(-/-)) mice fed a high-fat diet for 5 months, to test the hypothesis that farnesoid X receptor (FXR) deficiency contributed to NASH development. Either the high-fat diet or FXR deficiency increased serum alanine aminotransferase activity, whereas only FXR deficiency increased bile acid and alkaline phosphatase levels. FXR deficiency and high-fat feeding increased serum cholesterol and triglycerides. Although high fat led to macrosteatosis and hepatocyte ballooning in livers of mice regardless of genotype, no inflammatory infiltrate was observed in the livers of LDLr(-/-) mice. In contrast, in the livers of LDLr(-/-)/FXR(-/-) mice, foci of inflammatory cells were observed occasionally when fed the control diet and were greatly increased when fed the high-fat diet. Consistent with enhanced inflammatory cells, hepatic levels of tumor necrosis factor alpha and intercellular adhesion molecule-1 mRNA were increased by the high-fat diet in LDLr(-/-)/FXR(-/-) mice. In agreement with elevated levels of procollagen 1 alpha 1 and TGF-beta mRNA, type 1 collagen protein levels were increased in livers of LDLr(-/-)/FXR(-/-) mice fed a high-fat diet. In conclusion, FXR deficiency induces pathologic manifestations required for NASH diagnosis in a mouse model of hypercholesterolemia, including macrosteatosis, hepatocyte ballooning, and inflammation, which suggest a combination of FXR deficiency and high-fat diet is a risk factor for NASH development, and activation of FXR may be a therapeutic intervention in the treatment of NASH.

  1. Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice.

    PubMed

    Jouihan, Hani; Will, Sarah; Guionaud, Silvia; Boland, Michelle L; Oldham, Stephanie; Ravn, Peter; Celeste, Anthony; Trevaskis, James L

    2017-11-01

    Nonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice. OCA and IP118 alone and in combination were sub-chronically administered to Lep ob /Lep ob mice with diet-induced NASH or diet-induced obese (DIO) mice. Metabolic (body weight and glucose) and liver (biochemical and histological) endpoints were assessed. NASH severity in Lep ob /Lep ob mice was graded using a customized integrated scoring system. OCA reduced liver weight and lipid in NASH mice (both by -17%) but had no effect on plasma ALT or AST levels. In contrast, IP118 significantly reduced liver weight (-21%), liver lipid (-15%), ALT (-29%), and AST (-27%). The combination of OCA + IP118 further reduced liver weight (-29%), liver lipid (-22%), ALT (-39%), and AST (-36%). Combination therapy was superior to monotherapies in reducing hepatic steatosis, inflammation, and fibrosis. Hepatic improvements with IP118 and OCA + IP118 were associated with reduced body weight (-4.3% and -3.5% respectively) and improved glycemic control in OCA + IP118-treated mice. In DIO mice, OCA + IP118 co-administration reduced body weight (-25.3%) to a greater degree than IP118 alone (-12.5%) and further improved glucose tolerance and reduced hepatic lipid. Our data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

  2. Peroxisome proliferator-activated receptor-α agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis.

    PubMed

    Larter, Claire Z; Yeh, Matthew M; Van Rooyen, Derrick M; Brooling, John; Ghatora, Kamaljit; Farrell, Geoffrey C

    2012-02-01

    Lipid accumulation precedes hepatocellular injury and liver inflammation in non-alcoholic steatohepatitis (NASH). The peroxisome proliferator-activated receptor (PPAR)α regulates hepatic lipid disposal. We studied whether pharmacological stimulation of PPARα reverses NASH associated with metabolic syndrome in high-fat (HF)-fed foz/foz obese/diabetic mice. Female foz/foz mice and wildtype (WT) littermates were fed HF diet for 16 weeks to initiate NASH then treated with Wy 14,643 (Wy) for 10 days or 20 days. Liver disease was assessed by histology, serum alanine aminotransferase, genes (real-time polymerase chain reaction) and proteins (Western blot, enzyme-linked immunosorbent assay) of interest and pro-inflammatory signaling pathways were determined. In diabetic foz/foz mice, NASH was associated with elevated serum MCP1 and hepatic activation of nuclear factor (NF)-κB and c-Jun N-terminal kinase, but not oxidative or endoplasmic reticulum stress. Wy treatment decreased steatosis and injury, although induction of PPARα-responsive fatty acid oxidation genes was proportionally less than in WT. The PPARα agonist lowered serum insulin, corrected hyperglycemia, and suppressed the carbohydrate-dependent lipogenic transcription factor, carbohydrate response element binding protein. Steatosis resolution was associated with suppression of NF-κB and JNK activation and decreased hepatic macrophages and neutrophils. Despite this, histology inflammation score remained high, associated with serum monocyte chemoattractant protein (MCP)1 elevation, a pro-inflammatory chemokine related to higher adipose, not liver MCP1 mRNA expression. Pharmacological activation of PPARα improves metabolic milieu, steatosis, ballooning, and combats NF-κB and JNK activation, neutrophil and F4/80 macrophage recruitment in diabetes-related NASH. However, persistent liver inflammation with high serum MCP1 due to unsuppressed adipose inflammation may limit PPARα agonists' efficacy as therapy for

  3. Nonalcoholic steatohepatitis and nonalcoholic Fatty liver disease in young women with polycystic ovary syndrome.

    PubMed

    Setji, Tracy L; Holland, Nicole D; Sanders, Linda L; Pereira, Kathy C; Diehl, Anna Mae; Brown, Ann J

    2006-05-01

    Nonalcoholic fatty liver disease and polycystic ovary syndrome (PCOS) are both associated with insulin resistance. Thus, women with PCOS may have an increased prevalence of nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH). The objective of the study was to determine the prevalence and characteristics of NASH and abnormal aminotransferase activity in women with PCOS. The study is a retrospective chart review. The setting is an academic endocrinology clinic. Patients were 200 women with PCOS, defined as irregular menses and hyperandrogenism. Biopsy-documented NASH and aminotransferase levels were the main outcome measures. Fifteen percent (29 of 200) had aspartate aminotransferase and/or alanine aminotransferase more than 60 U/liter. Women with aminotransferase elevations had lower high-density lipoprotein (HDL) (41 vs. 50 mg/dl, P = 0.006), higher triglycerides (174 vs. 129 mg/dl, P = 0.024), and higher fasting insulin (21 vs. 12 microIU/ml, P = 0.036) compared with women with normal aminotransferases. Six women (mean age 29 yr) with persistent aminotransferase elevations underwent liver biopsy. All six had NASH with fibrosis. Compared with the 194 of 200 PCOS women who did not undergo biopsy, women with biopsy-documented NASH had lower HDL (median 34 vs. 50 mg/dl, P < 0.001), and higher triglycerides (245 vs. 132 mg/dl, P = 0.025), fasting insulin (26 vs. 13 microIU/ml, P = 0.038), aspartate aminotransferase (144 vs. 22 U/liter, P < 0.001), and alanine aminotransferase (143 vs. 28 U/liter, P < 0.001). Abnormal aminotransferase activity is common in women with PCOS. Low HDL, high triglycerides, and high fasting insulin were associated with abnormal aminotransferase activity. Some women already had evidence of NASH with fibrosis. Further studies are needed to evaluate whether to screen PCOS women for liver disease at an earlier age than is currently recommended for the general population.

  4. A genetic risk score is associated with hepatic triglyceride content and non-alcoholic steatohepatitis in Mexicans with morbid obesity.

    PubMed

    León-Mimila, Paola; Vega-Badillo, Joel; Gutiérrez-Vidal, Roxana; Villamil-Ramírez, Hugo; Villareal-Molina, Teresa; Larrieta-Carrasco, Elena; López-Contreras, Blanca E; Kauffer, Luis R Macías; Maldonado-Pintado, Diana G; Méndez-Sánchez, Nahúm; Tovar, Armando R; Hernández-Pando, Rogelio; Velázquez-Cruz, Rafael; Campos-Pérez, Francisco; Aguilar-Salinas, Carlos A; Canizales-Quinteros, Samuel

    2015-04-01

    Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near/in PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes associated with non-alcoholic fatty liver disease (NAFLD) mainly in individuals of European ancestry. The aim of the study was to test whether these genetic variants and a genetic risk score (GRS) are associated with elevated liver fat content and non-alcoholic steatohepatitis (NASH) in Mexicans with morbid obesity. 130 morbidly obese Mexican individuals were genotyped for six SNPs in/near PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes. Hepatic fat content [triglyceride (HTG) and total cholesterol (HTC)] was quantified directly in liver biopsies and NASH was diagnosed by histology. A GRS was tested for association with liver fat content and NASH using logistic regression models. In addition, 95 ancestry-informative markers were genotyped to estimate population admixture proportions. After adjusting for age, sex and admixture, PNPLA3, LYPLAL1, GCKR and PPP1R3B polymorphisms were associated with higher HTG content (P < 0.05 for PNPLA3, LYPLAL1, GCKR polymorphisms and P = 0.086 for PPP1R3B). The GRS was significantly associated with higher HTG and HTC content (P = 1.0 × 10(-4) and 0.048, respectively), steatosis stage (P = 0.029), and higher ALT levels (P = 0.002). Subjects with GRS ≥ 6 showed a significantly increased risk of NASH (OR = 2.55, P = 0.045) compared to those with GRS ≤ 5. However, the GRS did not predict NASH status, as AUC of ROC curves was 0.56 (P = 0.219). NAFLD associated loci in Europeans and a GRS based on these loci contribute to the accumulation of hepatic lipids and NASH in morbidly obese Mexican individuals. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Inhibition of NLRP3 inflammasome by thioredoxin-interacting protein in mouse Kupffer cells as a regulatory mechanism for non-alcoholic fatty liver disease development

    PubMed Central

    He, Kun; Zhu, Xiwen; Liu, Yan; Miao, Chunmu; Wang, Tao; Li, Peizhi; Zhao, Lei; Chen, Yaxi; Gong, Junhua; Cai, Can; Li, Jinzheng; Li, Shengwei; Ruan, Xiong Z.; Gong, Jianping

    2017-01-01

    NOD-like receptor (NLR) NLRP3 inflammasome activation has been implicated in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It has been also shown that palmitic acid (PA) activates NLRP3 inflammasome and promotes interleukin-1β (IL-1β) secretion in Kupffer cells (KCs). However, the specific mechanism of the NLRP3 inflammasome activation is unclear. We studies the molecular mechanisms by investigating the roles of Thioredoxin-interacting protein (TXNIP) and NLRP3 on NAFLD development in patients, high-fat diet (HFD)-induced NAFL and methionine choline deficient (MCD) diet-induced NASH in wild type (WT), TXNIP−/− (thioredoxin-interacting protein) and NLRP3−/− mice, and isolated KCs. We found that the expressions of NLRP3 and TXNIP in human liver tissues were higher in NASH group than in NAFL group. Furthermore, co-immunoprecipitation analyses show that activation of the TXNIP-NLRP3 inflammasome protein complex occurred in KCs of NASH WT mice rather than NAFL WT mice, thus suggesting that the formation and activation of this protein complex is mainly involved in the development of NASH. NLRP3−/− mice exhibited less severe NASH than WT mice in MCD diet model, whereas TXNIP deficiency enhanced NLRP3 inflammasome activation and exacerbated liver injury. PA triggered the activation and co-localization of the NLRP3 inflammasome protein complex in KCs isolated from WT and TXNIP−/− but not NLRP3−/− mice, and most of the complex co-localized with mitochondria of KCs following PA stimulation. Taken together, our novel findings indicate that TXNIP plays a protective and anti-inflammatory role in the development of NAFLD through binding and suppressing NLRP3. PMID:28499273

  6. Mechanisms of the prevention and inhibition of the progression and development of non-alcoholic steatohepatitis by genetic and pharmacological decoy receptor 3 supplementation.

    PubMed

    Lee, Pei-Chang; Yang, Ling-Yu; Wang, Ying-Wen; Huang, Shiang-Fen; Lee, Kuei-Chuan; Hsieh, Yun-Cheng; Yang, Ying-Ying; Hsieh, Shie-Liang; Hou, Ming-Chih; Lin, Han-Chieh; Lee, Fa-Yuah; Lee, Shou-Dong

    2017-11-01

    Treatment of non-alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non-decoy effects of DcR3 on diet-induced NASH mice. Methionine- and choline-deficient (MCD) diet feeding for 9 weeks was applied to induce NASH in BALB/c mice. Decoy receptor 3 heterozygous transgenesis or pharmacological pretreatment with DcR3a for 1 month were designed as interventions. Intrahepatic inflammatory status as well as macrophage polarization, oxidative stress, and steatosis as well as lipogenic gene expression and fibrotic status were analyzed. Additionally, acute effects of DcR3a on HepG2 cells, Hep3B cells, and primary mouse hepatocytes in various MCD medium-stimulated changes were also evaluated. Both DcR3 genetic and pharmacologic supplement significantly reduced MCD diet-induced hepatic M1 polarization. In addition, DcR3 supplement attenuated MCD diet-increased hepatic inflammation, oxidative stress, adipocytokine imbalance, steatosis, and fibrogenesis. Moreover, acute DcR3a incubation in HepG2 cells, Hep3B cells, and mouse hepatocytes could normalize the expression of genes related to lipid oxidation along with inflammation and oxidative stress. The ability of DcR3 to attenuate hepatic steatosis and inflammation through its non-decoy effects of immune modulation and oxidative stress attenuation makes it a potential treatment for NASH. © 2017 The Japan Society of Hepatology.

  7. How Many Formative Assessment Angels Can Dance on the Head of a Meta-Analytic Pin: 0.2

    ERIC Educational Resources Information Center

    Kingston, Neal; Nash, Brooke

    2012-01-01

    In their critique of Kingston and Nash (2011), Briggs, Ruiz-Primo, Furtak, Shepard, and Yin (2012) make several major points. First, Kingston and Nash's conclusions about the state of research on the efficacy of formative assessment are similar to other researchers, "including some of the authors." Second, their research may be unique in that they…

  8. Bidding for Brains: Intellectual Property Rights and the International Migration of Knowledge Workers. NBER Working Paper No. 15486

    ERIC Educational Resources Information Center

    McAusland, Carol; Kuhn, Peter J.

    2009-01-01

    We introduce international mobility of knowledge workers into a model of Nash equilibrium IPR policy choice among countries. We show that governments have incentives to use IPRs in a bidding war for global talent, resulting in Nash equilibrium IPRs that can be too high, rather than too low, from a global welfare perspective. These incentives…

  9. Le Chatelier's principle in replicator dynamics

    NASA Astrophysics Data System (ADS)

    Allahverdyan, Armen E.; Galstyan, Aram

    2011-10-01

    The Le Chatelier principle states that physical equilibria are not only stable, but they also resist external perturbations via short-time negative-feedback mechanisms: a perturbation induces processes tending to diminish its results. The principle has deep roots, e.g., in thermodynamics it is closely related to the second law and the positivity of the entropy production. Here we study the applicability of the Le Chatelier principle to evolutionary game theory, i.e., to perturbations of a Nash equilibrium within the replicator dynamics. We show that the principle can be reformulated as a majorization relation. This defines a stability notion that generalizes the concept of evolutionary stability. We determine criteria for a Nash equilibrium to satisfy the Le Chatelier principle and relate them to mutualistic interactions (game-theoretical anticoordination) showing in which sense mutualistic replicators can be more stable than (say) competing ones. There are globally stable Nash equilibria, where the Le Chatelier principle is violated even locally: in contrast to the thermodynamic equilibrium a Nash equilibrium can amplify small perturbations, though both types of equilibria satisfy the detailed balance condition.

  10. Le Chatelier's principle in replicator dynamics.

    PubMed

    Allahverdyan, Armen E; Galstyan, Aram

    2011-10-01

    The Le Chatelier principle states that physical equilibria are not only stable, but they also resist external perturbations via short-time negative-feedback mechanisms: a perturbation induces processes tending to diminish its results. The principle has deep roots, e.g., in thermodynamics it is closely related to the second law and the positivity of the entropy production. Here we study the applicability of the Le Chatelier principle to evolutionary game theory, i.e., to perturbations of a Nash equilibrium within the replicator dynamics. We show that the principle can be reformulated as a majorization relation. This defines a stability notion that generalizes the concept of evolutionary stability. We determine criteria for a Nash equilibrium to satisfy the Le Chatelier principle and relate them to mutualistic interactions (game-theoretical anticoordination) showing in which sense mutualistic replicators can be more stable than (say) competing ones. There are globally stable Nash equilibria, where the Le Chatelier principle is violated even locally: in contrast to the thermodynamic equilibrium a Nash equilibrium can amplify small perturbations, though both types of equilibria satisfy the detailed balance condition.

  11. Drought in the northern Bahamas from 3300 to 2500 years ago

    NASA Astrophysics Data System (ADS)

    van Hengstum, Peter J.; Maale, Gerhard; Donnelly, Jeffrey P.; Albury, Nancy A.; Onac, Bogdan P.; Sullivan, Richard M.; Winkler, Tyler S.; Tamalavage, Anne E.; MacDonald, Dana

    2018-04-01

    Intensification and western displacement of the North Atlantic Subtropical High (NASH) is projected for this century, which can decrease Caribbean and southeastern American rainfall on seasonal and annual timescales. However, additional hydroclimate records are needed from the northern Caribbean to understand the long-term behavior of the NASH, and better forecast its future behavior. Here we present a multi-proxy sinkhole lake reconstruction from a carbonate island that is proximal to the NASH (Abaco Island, The Bahamas). The reconstruction indicates the northern Bahamas experienced a drought from ∼3300 to ∼2500 Cal yrs BP, which coincides with evidence from other hydroclimate and oceanographic records (e.g., Africa, Caribbean, and South America) for a synchronous southern displacement of the Intertropical Convergence Zone and North Atlantic Hadley Cell. The specific cause of the hydroclimate change in the northeastern Caribbean region from ∼3300 to 2500 Cal yrs BP was probably coeval southern or western displacement of the NASH, which would have increased northeastern Caribbean exposure to subsiding air from higher altitudes.

  12. Exacerbating the Tragedy of the Commons: Private Inefficient Outcomes and Peer Effect in Experimental Games with Fishing Communities

    PubMed Central

    2016-01-01

    Economic Experimental Games have shown that individuals make decisions that deviate down from the suboptimal Nash equilibrium. However, few studies have analyzed the case when deviation is above the Nash equilibrium. Extracting from above the Nash equilibrium is inefficient not only socially but also privately and it would exacerbate the tragedy of the commons. That would be the case of a race to the fish when stocks are becoming depleted or driver behavior on a highly congested road. The objective of this study is to analyze private inefficient extraction behavior in experimental games and to associate the type of player and the type of player group with such inefficient outcomes. To do this, we carried out economic experimental games with local coastal fishermen in Colombia, using a setting where the scarcity of the resource allows for an interior Nash equilibrium and inefficient over-extraction is possible. The state of the resource, the type of player and the composition of the group explain, in part, this inefficient behavior. PMID:26863228

  13. Nonalcoholic fatty liver disease: diagnosis, pathogenesis, and management.

    PubMed

    Başaranoğlu, Metin; Örmeci, Necati

    2014-04-01

    Nonalcoholic fatty liver disease (NAFLD) is an umbrella term that covers both a relatively benign condition, which is simple steatosis, and nonalcoholic steatohepatitis (NASH). NASH is characterized by a chronic and progressive liver pathology that may progress to cirrhosis, end-stage liver disease, hepatocellular carcinoma, and liver transplantation. Despite the growing body of evidence, one of the important and unresolved problems is the pathogenesis of NASH. It might be a metabolic disturbance as a primary abnormality in NAFLD. Insulin resistance is at the center of these metabolic abnormalities. Then, hepatocyte injury might be induced by oxidative stress. This ongoing process progresses to NASH, even to cirrhosis in some patients. In addition to oxidative stress, possibilities for the next hit are lipid peroxidation, reactive metabolites, adipose tissue products, transforming growth factor-β₁, Fas ligand, mitochondrial dysfunction, respiratory chain deficiency, and intestinal microbiota. Currently, there is no well-established and approved therapy. Recommendations are to improve existing co-morbidities, such as obesity, hyperlipidemia, or type 2 diabetes, and lifestyle modification with weight loss and exercise.

  14. Nifedipine prevents hepatic fibrosis in a non-alcoholic steatohepatitis model induced by an L-methionine-and choline-deficient diet.

    PubMed

    Nakagami, Hironori; Shimamura, Munehisa; Miyake, Takashi; Shimosato, Takashi; Minobe, Noriko; Moritani, Toshinori; Kiomy Osako, Mariana; Nakagami, Futoshi; Koriyama, Hiroshi; Kyutoku, Mariko; Shimizu, Hideo; Katsuya, Tomohiro; Morishita, Ryuichi

    2012-01-01

    Recent reports have shown that nifedipine, a calcium channel blocker, increases peroxisome proliferator-activated receptor-γ (PPARγ) activity. Since PPARγ agonists, such as pioglitazone and rosiglitazone, are effective in reducing non-alcoholic steatohepatitis (NASH) and cirrhosis in animal models, we examined the protective effects of nifedipine, as compared with bezafibrate, a PPARα agonist, in a NASH model induced by an L-methionine- and choline-deficient (MCD) diet. An MCD diet for 20 weeks changed the color of the rat liver to yellow with an irregular surface, whereas the color of the liver in both the bezafibrate and nifedipine treatment groups was markedly changed to yellow-brown with a smooth surface. Furthermore, nifedipine, as well as bezafibrate, significantly prevented liver fibrosis induced by an MCD diet, as assessed by Masson's trichrome staining, accompanied by a significant decrease in serum AST. Overall, nifedipine treatment resulted in an improvement in NASH, similar to bezafibrate, in a rat model. In hypertensive patients with metabolic syndrome, nifedipine may provide additional benefits, beyond its blood pressure-lowering effects, to prevent NASH and fatty liver disease.

  15. Advocacy, prejudice, and role modeling in the deaf community.

    PubMed

    Cumming, C E; Rodda, M

    1989-02-01

    Prejudiced attitudes toward deaf people are a well-established phenomenon (Higgins & Nash, 1982; Moores, 1982; Quigley & Kretschmer, 1982). In recent years, however, a new phenomenon has appeared, and some members of the deaf population now openly express prejudice against the hearing (Boros & Stuckless, 1982; Nash & Nash, 1981). The phenomenon may be an interesting example of Allport's (1954) classical analysis: The victims of the prejudice may tend to reciprocate and/or internalize the prejudice to which they have been exposed. The purpose of our analysis is to examine this phenomenon in more detail, particularly from the perspective of social learning theory as described by Bandura and Walters (1963), Walters (1966), and Bandura (1977).

  16. Studies of the Effect of Formative Assessment on Student Achievement: So Much More Is Needed

    ERIC Educational Resources Information Center

    McMillan, James H.; Venable, Jessica C.; Varier, Divya

    2013-01-01

    Kingston and Nash (2011) recently presented a meta-analysis of studies showing that the effect of formative assessment on K-12 student achievement may not be as robust as widely believed. This investigation analyzes the methodology used in the Kingston and Nash meta-analysis and provides further analyses of the studies included in the study. These…

  17. Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial

    PubMed Central

    Armstrong, Matthew J; Barton, Darren; Gaunt, Piers; Hull, Diana; Guo, Kathy; Stocken, Deborah; Gough, Stephen C L; Tomlinson, Jeremy W; Brown, Rachel M; Hübscher, Stefan G; Newsome, Philip N

    2013-01-01

    Introduction Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. Methods and analysis Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m2) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. Ethics and dissemination The protocol was approved by the National Research Ethics Service (East Midlands—Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52

  18. Simultaneous MR quantification of hepatic fat content, fatty acid composition, transverse relaxation time and magnetic susceptibility for the diagnosis of non-alcoholic steatohepatitis.

    PubMed

    Leporq, B; Lambert, S A; Ronot, M; Vilgrain, V; Van Beers, B E

    2017-10-01

    Non-alcoholic steatohepatitis (NASH) is characterized at histology by steatosis, hepatocyte ballooning and inflammatory infiltrates, with or without fibrosis. Although diamagnetic material in fibrosis and inflammation can be detected with quantitative susceptibility imaging, fatty acid composition changes in NASH relative to simple steatosis have also been reported. Therefore, our aim was to develop a single magnetic resonance (MR) acquisition and post-processing scheme for the diagnosis of steatohepatitis by the simultaneous quantification of hepatic fat content, fatty acid composition, T 2 * transverse relaxation time and magnetic susceptibility in patients with non-alcoholic fatty liver disease. MR acquisition was performed at 3.0 T using a three-dimensional, multi-echo, spoiled gradient echo sequence. Phase images were unwrapped to compute the B 0 field inhomogeneity (ΔB 0 ) map. The ΔB 0 -demodulated real part images were used for fat-water separation, T 2 * and fatty acid composition quantification. The external and internal fields were separated with the projection onto dipole field method. Susceptibility maps were obtained after dipole inversion from the internal field map with single-orientation Bayesian regularization including spatial priors. Method validation was performed in 32 patients with biopsy-proven, non-alcoholic fatty liver disease from which 12 had simple steatosis and 20 NASH. Liver fat fraction and T 2 * did not change significantly between patients with simple steatosis and NASH. In contrast, the saturated fatty acid fraction increased in patients with NASH relative to patients with simple steatosis (48 ± 2% versus 44 ± 4%; p < 0.05) and the magnetic susceptibility decreased (-0.30 ± 0.27 ppm versus 0.10 ± 0.14 ppm; p < 0.001). The area under the receiver operating characteristic curve for magnetic susceptibility as NASH marker was 0.91 (95% CI: 0.79-1.0). Simultaneous MR quantification of fat content, fatty acid

  19. Nucleus Accumbens Shell and mPFC but Not Insula Orexin-1 Receptors Promote Excessive Alcohol Drinking

    PubMed Central

    Lei, Kelly; Wegner, Scott A.; Yu, Ji Hwan; Mototake, Arisa; Hu, Bing; Hopf, Frederic W.

    2016-01-01

    Addiction to alcohol remains a major social and economic problem, in part because of the high motivation for alcohol that humans exhibit and the hazardous binge intake this promotes. Orexin-1-type receptors (OX1Rs) promote reward intake under conditions of strong drives for reward, including excessive alcohol intake. While systemic modulation of OX1Rs can alter alcohol drinking, the brain regions that mediate this OX1R enhancement of excessive drinking remain unknown. Given the importance of the nucleus accumbens (NAc) and anterior insular cortex (aINS) in driving many addictive behaviors, including OX1Rs within these regions, we examined the importance of OX1Rs in these regions on excessive alcohol drinking in C57BL/6 mice during limited-access alcohol drinking in the dark cycle. Inhibition of OX1Rs with the widely used SB-334867 within the medial NAc Shell (mNAsh) significantly reduced drinking of alcohol, with no effect on saccharin intake, and no effect on alcohol consumption when infused above the mNAsh. In contrast, intra-mNAsh infusion of the orexin-2 receptor TCS-OX2-29 had no impact on alcohol drinking. In addition, OX1R inhibition within the aINS had no effect on excessive drinking, which was surprising given the importance of aINS-NAc circuits in promoting alcohol consumption and the role for aINS OX1Rs in driving nicotine intake. However, OX1R inhibition within the mPFC did reduce alcohol drinking, indicating cortical OXR involvement in promoting intake. Also, in support of the critical role for mNAsh OX1Rs, SB within the mNAsh also significantly reduced operant alcohol self-administration in rats. Finally, orexin ex vivo enhanced firing in mNAsh neurons from alcohol-drinking mice, with no effect on evoked EPSCs or input resistance; a similar orexin increase in firing without a change in input resistance was observed in alcohol-naïve mice. Taken together, our results suggest that OX1Rs within the mNAsh and mPFC, but not the aINS, play a central role in

  20. Short-term therapy with peroxisome proliferation-activator receptor-alpha agonist Wy-14,643 protects murine fatty liver against ischemia-reperfusion injury.

    PubMed

    Teoh, Narci C; Williams, Jacqueline; Hartley, Jennifer; Yu, Jun; McCuskey, Robert S; Farrell, Geoffrey C

    2010-03-01

    Steatosis increases operative morbidity/mortality from ischemia-reperfusion injury (IRI); few pharmacological approaches have been protective. Using novel genetic/dietary models of nonalcoholic steatohepatitis (NASH) and simple steatosis (SS) in Alms1 mutant (foz/foz) mice, we characterized severity of IRI in NASH versus SS and lean liver and tested our hypothesis that the lipid-lowering effects of the peroxisome proliferation-activator receptor (PPAR)-alpha agonist Wy-14,643 would be hepatoprotective. Mice were subjected to 60-minute partial hepatic IRI. Microvascular changes were assessed at 15-minute reperfusion by in vivo microscopy, injury at 24 hours by serum alanine aminotransferase (ALT), and hepatic necrosis area. Injury and inflammation mediators were determined by way of immunoblotting for intercellular cellular adhesion molecule, vascular cellular adhesion molecule, p38, c-jun N-terminal kinase, IkappaB-alpha, interleukin (IL)-1a, IL-12, tumor necrosis factor-alpha (TNF-alpha) and IL-6, cell cycle by cyclin D1 and proliferating cell nuclear antigen immunohistochemistry. In foz/foz mice fed a high-fat diet (HFD) to cause NASH or chow (SS), IRI was exacerbated compared with HFD-fed or chow-fed wild-type littermates by ALT release; corresponding necrotic areas were 60 +/- 22% NASH, 29 +/- 9% SS versus 7 +/- 1% lean. Microvasculature of NASH or SS livers was narrowed by enormous lipid-filled hepatocytes, significantly reducing numbers of perfused sinusoids, all exacerbated by IRI. Wy-14,643 reduced steatosis in NASH and SS livers, whereas PPAR-alpha stimulation conferred substantial hepatoprotection against IRI by ALT release, with reductions in vascular cellular adhesion molecule-1, IL-1a, TNF-alpha, IL-12, activated nuclear factor-kappaB (NF-kappaB), p38, IL-6 production and cell cycle entry. NASH and SS livers are both more susceptible to IRI. Mechanisms include possible distortion of the microvasculature by swollen fat-laden hepatocytes, and enhanced

  1. Gd-EOB-DTPA-enhanced T1ρ imaging vs diffusion metrics for assessment liver inflammation and early stage fibrosis of nonalcoholic steatohepatitis in rabbits.

    PubMed

    Xie, Yuanliang; Zhang, Hongfeng; Jin, Chaoling; Wang, Xiang; Wang, Xiaoqi; Chen, Jingting; Xu, Yikai

    2018-05-01

    To assess the value of T1ρ,T1ρ on hepatobiliary phase (HBP) and diffusion metrics in staging of Non-alcoholic fatty liver disease (NAFLD) activity scores, inflammation, fibrosis in NASH rabbits model. Non-alcoholic steatohepatitis (NASH) rabbits model was induced by feeding a varied duration of high-fat, high-cholesterol diet. T1ρ,T1ρ (HBP) 20min after administration of Gd-EOB-DTPA, and Intravoxel incoherent motion imaging (IVIM) diffusion-weighted imaging were performed on a 3.0T magnetic resonance (MR) imaging unit. The diagnostic value of each parameter for NAS, inflammation and fibrosis severity were determined. T1ρ (r=0.658) and T1ρ (HBP) (r=0.750) have strong association with NASH overall activity, T1ρ (HBP) is strongly relevant to inflammation stage (r=0.812). There was negative association between f and inflammation (r=-0.480), whilst no significant relation between other three parameters (apparent diffusion coefficient (ADC), pseudo-diffusion coefficient (D*) and true diffusion coefficient (D)) and inflammation or overall activity. The areas under the receiver operating characteristic curves (AUCs) of f, ADC, T1ρ and T1ρ-HBP were 0.871, 0.728, 0.849 and 0.949 for differentiating NASH; 0.731, 0.552, 0.925 and 0.922 for G2-3 inflammation; and 0.767, 0.625, 0.816, and 0.882 for S1-2 fibrosis. Comparison of ROC curve showed T1ρ (HBP) had an optimal diagnostic performance for NASH [T1ρ (HBP) vs ADC, AUC:0.949 vs 0.728, P=0.043], inflammation [T1ρ (HBP) vs ADC, AUC:0.922 vs 0.552, P=0.003], fibrosis [T1ρ (HBP) vs ADC, AUC:0.882 vs 0.625, P=0.046]. The combination of T1ρ (HBP)+perfusion fraction (f) showed highest diagnostic value for NASH (AUC:0.971), inflammation (AUC:0.935). Among T1ρ imaging and IVIM diffusion metrics, combination of T1rho (HBP)+f was found to be superior noninvasive imaging biomarker for NASH activity assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. [Non-alcoholic fatty liver disease--new view].

    PubMed

    Raszeja-Wyszomirska, Joanna; Lawniczak, Małgorzata; Marlicz, Wojciech; Miezyńska-Kurtycz, Joanna; Milkiewicz, Piotr

    2008-06-01

    Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology--from steatosis alone, through the necroinflammatory disorder of non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. NAFLD/NASH is mostly related with visceral adiposity, obesity, type 2 diabetes melitus (DM t.2) and metabolic syndrome. Pathogenetic concepts of NAFLD include overnutrition and underactivity, insulin resistance (IR) and genetic factor. The prevalence of NAFLD has been estimated to be 17-33% in some countries, NASH may be present in about 1/3 of such cases, while 20-25% of NASH cases could progress to cirrhosis. NAFLD is now recognized as one of the most frequent reason of liver tests elevation without clinical symptoms. Insulin resistance is considering as having a central role in NAFLD pathogenesis. In hepatocytes, IR is related to hyperglycaemia and hyperinsulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. Early stages of fatty liver are clinically silent and include elevation of ALT and GGTP, hyperechogenic liver in USG and/or hepatomegaly. Among clinical symptoms, abdominal discomfort is relatively common as well as chronic fatigue. NAFLD/NASH is not a benign disease, progressive liver biopsy have shown histological progression of fibrosis in 32%, the estimated rate of cirrhosis development is 20% and a liver--related death is 12% over 10 years. No treatment has scientifically proved to ameliorate NAFLD or to avoid its progression. The various therapeutic alternatives are aimed at interfering with the risk factors involved in the pathogenesis of the disorder in order to prevent the progression to end-stage liver disease. The most important therapeutic measure is increasing insulin sensitivity by an attempt to change a lifestyle mostly by dieting and physical activity in order to loose weight. The most used agent is metformin, the others

  3. Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice

    PubMed Central

    Yamada, Shoji; Takashina, Yoko; Watanabe, Mitsuhiro; Nagamine, Ryogo; Saito, Yoshimasa; Kamada, Nobuhiko; Saito, Hidetsugu

    2018-01-01

    Gut microbiota plays a significant role in the development of hepatocellular carcinoma (HCC) in non-alcoholic steatohepatitis (NASH). However, understanding of the precise mechanism of this process remains incomplete. A new class steatohepatitis-inducing high-fat diet (HFD), namely STHD-01, can promote the development of HCC without the administration of chemical carcinogens. Using this diet, we comprehensively analyzed changes in the gut microbiota and its metabolic functions during the development of HCC in NASH. Mice fed the STHD-01 developed NASH within 9 weeks. NASH further progressed into HCC by 41 weeks. Treatment with antibiotics significantly attenuated liver pathology and suppressed tumor development, indicating the critical role of the gut microbiota in tumor development in this model. Accumulation of cholesterol and bile acids in the liver and feces increased after feeding the mice with STHD-01. Treatment with antibiotics did not reverse these phenotypes. In contrast, accumulation of secondary bile acids was dramatically reduced after the treatment with antibiotics, suggesting the critical role of the gut microbiota in the conversion of primary bile acids to secondary bile acids. Secondary bile acids such as deoxycholic acid activated the mTOR, pathway in hepatocytes. Activation of mTOR was observed in the liver of mice fed STHD-01, and the activation was reduced when mice were treated with antibiotics. Collectively, bile acid metabolism by the gut microbiota promotes HCC development in STHD-01-induced NASH. PMID:29515780

  4. The Art of Math

    ERIC Educational Resources Information Center

    Kim, Una; Stabley, Angela

    2010-01-01

    In the movie "A Beautiful Mind" there is a scene where future Nobel prize winner John Nash is captivated by a fellow student's tie. When asked about his behavior Nash quips, "There has to be a mathematical explanation for how bad that tie is." (Grazer & Howard, 2000) In this light moment, director Ron Howard attempts to show us that the mind of a…

  5. Resolution of non-alcoholic steatohepatitis after growth hormone replacement in a pediatric liver transplant patient with panhypopituitarism.

    PubMed

    Gilliland, Thomas; Dufour, Sylvie; Shulman, Gerald I; Petersen, Kitt Falk; Emre, Sukru H

    2016-12-01

    NAFLD is a common condition linked to obesity, type 2 diabetes, and metabolic syndrome. Simple hepatic steatosis is a risk factor for inflammatory reactions in the liver (NASH), which may lead to cirrhosis. While the mechanism is unclear, NAFLD and NASH are associated with panhypopituitarism, which in the pediatric population often results from craniopharyngioma or pituitary adenoma and the sequelae of treatment, causing hypothyroidism, adrenal insufficiency, hypogonadotropic hypogonadism, and GH deficiency. Refractory NAFLD in panhypopituitarism may be amenable to GH replacement. Here, we report a pediatric case of NASH secondary to panhypopituitarism from craniopharyngioma, which recurred by 11 months after LDLT. Despite low-dose GH replacement, the patient remained GH deficient. Pubertal dosed GH therapy led to rapid and complete resolution of hepatic steatosis, which we tracked using serial 1 H MRS. Pediatric patients with NASH cirrhosis secondary to panhypopituitarism can be good candidates for liver transplantation, but hormone deficiencies predispose to recurrence after transplant. High-dose GH replacement should be considered in pediatric patients with GH deficiency and recurrent disease. A multidisciplinary team approach is essential for successful outcomes. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Effects of pioglitazone on nonalcoholic steatohepatitis in a patient with anorexia nervosa: A case report.

    PubMed

    Ohno, Tomohiko; Nishigaki, Yoichi; Yamada, Tetsuya; Wakahara, Yuko; Sakai, Hiroyasu; Yoshimura, Kotaro; Shimizu, Masahito; Usui, Toshio; Saito, Masaya; Yasuda, Ichiro; Tsurumi, Hisashi; Tomita, Eiichi; Moriwaki, Hisataka

    2014-04-01

    Diseases associated with metabolic syndromes are of major concern in developed countries. Nonalcoholic steatohepatitis (NASH) is one of the manifestations of metabolic syndrome in the liver. Previous studies have shown that NASH is also caused by malnutrition. In the present study, a case of malnutrition-associated NASH in a 66-year-old female with anorexia nervosa is reported. The patient had a body mass index (BMI) of only 11.1 kg/m 2 and serum alanine aminotransferase levels of 1,495 IU/l. Steatohepatitis with fibrosis was confirmed by percutaneous liver needle biopsy. Total parenteral nutrition was conducted at first, followed by the administration of Stronger Neo-Minophagen C (a glycyrrhizin-containing preparation), ursodeoxycholic acid and prednisolone. The abnormal elevation of aminotransferase levels of the patient was prolonged and total bilirubin levels increased. Pioglitazone (15 mg/day), which has been identified to be effective for nonalcoholic steatohepatitis, was then administered. This resulted in marked reductions in aminotransferase and bilirubin levels within three months. Histological improvement of the liver was also confirmed by percutaneous liver needle biopsy after one year. The observations in the present case suggest that pioglitazone may be useful for the treatment of malnutrition-associated NASH.

  7. Non-alcoholic steatohepatitis: review of a growing medical problem.

    PubMed

    Te Sligte, K.; Bourass, I.; Sels, J.P.; Driessen, A.; Stockbrugger, R.W.; Koek, G.H.

    2004-02-01

    Non-alcoholic steatohepatitis (NASH) is a metabolic liver disorder that is seen in 2-6% of the general population. It manifests itself by elevated liver enzymes, frequently without symptoms. The histological findings include steatosis, inflammation, fibrosis, and cirrhosis. Three case reports are presented to illustrate features of NASH. A two-hit model has been proposed in the pathogenesis of NASH. The first hit is hepatic steatosis. A hypercaloric diet with high levels of carbohydrates and saturated fatty acids results in elevated plasma free fatty acids (FFA) and expands the adipose tissue. Insulin resistance develops and augments steatosis. Oxidation of FFA yields toxic free radicals, resulting in lipid peroxidation. They cause the second hits: increased oxidative stress on hepatocytes and induction of pro-inflammatory cytokines. When the antioxidant capacities of the liver are insufficient, mitochondrial dysfunction and tumor necrosis factor alpha (TNF-alpha) cause inflammation and fibrosis. Treatment consists of life style modifications, particularly weight loss and exercise. Many drugs have been tried in the treatment of NASH. The insulin-sensitizing drugs metformin, rosiglitazone, and pioglitazone, and the antioxidant vitamin E show promising results. Further investigation of therapeutic options is needed to direct the choice of therapy in the future.

  8. The Worst-Case Weighted Multi-Objective Game with an Application to Supply Chain Competitions.

    PubMed

    Qu, Shaojian; Ji, Ying

    2016-01-01

    In this paper, we propose a worst-case weighted approach to the multi-objective n-person non-zero sum game model where each player has more than one competing objective. Our "worst-case weighted multi-objective game" model supposes that each player has a set of weights to its objectives and wishes to minimize its maximum weighted sum objectives where the maximization is with respect to the set of weights. This new model gives rise to a new Pareto Nash equilibrium concept, which we call "robust-weighted Nash equilibrium". We prove that the robust-weighted Nash equilibria are guaranteed to exist even when the weight sets are unbounded. For the worst-case weighted multi-objective game with the weight sets of players all given as polytope, we show that a robust-weighted Nash equilibrium can be obtained by solving a mathematical program with equilibrium constraints (MPEC). For an application, we illustrate the usefulness of the worst-case weighted multi-objective game to a supply chain risk management problem under demand uncertainty. By the comparison with the existed weighted approach, we show that our method is more robust and can be more efficiently used for the real-world applications.

  9. On Nash Equilibria in Stochastic Games

    DTIC Science & Technology

    2003-10-01

    Traditionally automata theory and veri cation has considered zero sum or strictly competitive versions of stochastic games . In these games there are two players...zero- sum discrete-time stochastic dynamic games . SIAM J. Control and Optimization, 19(5):617{634, 1981. 18. R.J. Lipton, E . Markakis, and A. Mehta...Playing large games using simple strate- gies. In EC 03: Electronic Commerce, pages 36{41. ACM Press, 2003. 19. A. Maitra and W. Sudderth. Finitely

  10. Liver biopsy in type 2 diabetes mellitus: Steatohepatitis represents the sole feature of liver damage.

    PubMed

    Masarone, Mario; Rosato, Valerio; Aglitti, Andrea; Bucci, Tommaso; Caruso, Rosa; Salvatore, Teresa; Sasso, Ferdinando Carlo; Tripodi, Marie Francoise; Persico, Marcello

    2017-01-01

    Recent studies report a prevalence of non-alcoholic fatty liver disease (NAFLD) of between 70% and 80% in patients with metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Nevertheless, it is not possible to differentiate between simple steatosis and non-alcoholic steatohepatitis (NASH) with non-invasive tests. The aim of this study was to differentiate between simple steatosis and NASH by liver biopsy in patients with hypertransaminasemia and MS or T2DM. Two hundred and fifteen patients with increased ALT levels and MS, and 136 patients at their first diagnosis of T2DM regardless of ALT values were consecutively admitted to a tertiary hepatology center between January 2004 and November 2014. Exclusion criteria were other causes of liver disease/ALT increase. Each patient underwent a clinical, laboratory and ultrasound evaluation, and a liver biopsy. Gender distribution, age, and body mass index were similar in the two groups of patients, whereas cholesterol levels, glycemia and blood pressure were significantly different between the two groups. The prevalence of NAFLD was 94.82% in MS patients and 100% in T2DM patients. NASH was present in 58.52% of MS patients and 96.82% of T2DM. Consequently, this study reveals that, by using liver biopsy, almost all patients with T2DM or MS have NAFLD, which in patients with T2DM means NASH. Importantly, it suggests that NASH may be one of the early complications of T2DM due to its pathophysiological correlation with insulin resistance.

  11. Chemical shift magnetic resonance imaging is helpful in detecting hepatic steatosis but not fibrosis in patients with nonalcoholic fatty liver disease (NAFLD).

    PubMed

    Kalra, Naveen; Duseja, Ajay; Das, Ashim; Dhiman, Radha Krishan; Virmani, Vivek; Chawla, Yogesh; Singh, Paramjee; Khandelwal, Niranjan

    2009-01-01

    Imaging modalities have a role in the diagnosis of patients with nonalcoholic fatty liver disease. Aim of the present study was to evaluate the role of chemical shift magnetic resonance imaging in assessing hepatic steatosis and fibrosis in patients with nonalcoholic fatty liver disease. Chemical shift magnetic resonance imaging was done in 10 biopsy proven patients (7 females, mean age 41 +/- 9.2 years) with nonalcoholic fatty liver disease. Objective measurements of signal intensity (SI) were done and a ratio was calculated (SI out-of- phase liver/ SI out-of- phase kidney)/ (SI in- phase liver/ SI in-phase kidney). A lower ratio indicated a higher signal drop and hence higher fat content. The ratio was correlated with hepatic steatosis on histology (< 33% and > 33%). Patients were classified as having histological NASH or no NASH and MRI was assessed in diagnosing hepatic fibrosis as seen on liver histology. Six patients had > 33% hepatic steatosis on histology. Five patients (50%) had evidence of histological NASH. MRI was not helpful in differentiating patients with and without histological NASH. One patient amongst NASH patients did not have fibrosis, one had stage 1, 2 had stage 2 and one had stage 4 fibrosis. SI ratio ranged between 0.35-0.69 in 6 patients with steatosis > 33% and was in the range of 0.69-1.20 in four patients with steatosis < 33% on histology. Fibrotic changes seen in 4 patients on biopsy were not detected on MRI. Chemical shift MRI provides objective data on fat infiltration in patients with NAFLD without giving information about hepatic fibrosis.

  12. Shear wave velocity is a useful marker for managing nonalcoholic steatohepatitis

    PubMed Central

    Osaki, Akihiko; Kubota, Tomoyuki; Suda, Takeshi; Igarashi, Masato; Nagasaki, Keisuke; Tsuchiya, Atsunori; Yano, Masahiko; Tamura, Yasushi; Takamura, Masaaki; Kawai, Hirokazu; Yamagiwa, Satoshi; Kikuchi, Toru; Nomoto, Minoru; Aoyagi, Yutaka

    2010-01-01

    AIM: To investigate whether a noninvasive measurement of tissue strain has a potential usefulness for management of nonalcoholic steatohepatitis (NASH). METHODS: In total 26 patients, 23 NASHs and 3 normal controls were enrolled in this study. NASH was staged based on Brunt criterion. At a region of interest (ROI), a shear wave was evoked by implementing an acoustic radiation force impulse (ARFI), and the propagation velocity was quantified. RESULTS: Shear wave velocity (SWV) could be reproducibly quantified at all ROIs in all subjects except for 4 NASH cases, in which a reliable SWV value was not calculated at several ROIs. An average SWV of 1.34 ± 0.26 m/s in fibrous stage 0-1 was significantly slower than 2.20 ± 0.74 m/s and 2.90 ± 1.01 m/s in stages 3 and 4, respectively, but was not significantly different from 1.79 ± 0.78 m/s in stage 2. When a cutoff value was set at 1.47 m/s, receiver operating characteristic analysis showed significance to dissociate stages 3 and 4 from stage 0-1 (P = 0.0092) with sensitivity, specificity and area under curve of 100%, 75% and 94.2%, respectively. In addition, the correlation between SWV and hyaluronic acid was significant (P < 0.0001), while a tendency toward negative correlation was observed with serum albumin (P = 0.053). CONCLUSION: The clinical implementation of ARFI provides noninvasive repeated evaluations of liver stiffness at an arbitrary position, which has the potential to shed new light on NASH management. PMID:20556839

  13. Fibromyalgia Symptoms and Cirrhosis

    PubMed Central

    Bielefeldt, Klaus; Wasan, Ajay D.; Szigethy, Eva; Lotrich, Francis; DiMartini, Andrea F.

    2015-01-01

    Background An association between fibromyalgia and hepatitis C virus (HCV) has been previously described. However, the relationship between nonalcoholic steatohepatitis (NASH) and fibromyalgia symptoms has not been assessed, though they share several risk factors. Aim We aimed to assess the factors associated with fibromyalgia symptoms across etiologies of liver disease. Methods Patients with cirrhosis due to HCV, NASH, or alcohol were recruited from an outpatient hepatology clinic and administered the Hospital Anxiety and Depression Score, Pittsburgh Sleep Quality Index, and the modified 2010 American College of Rheumatology Diagnostic Criteria for Fibromyalgia. Serum inflammatory markers were measured with standard luminex assays. Results Of 193 participants, 53 (27 %) met criteria for fibromyalgia. Fibromyalgia symptoms were significantly associated with etiology of liver disease (HCV: 35 %, NASH: 30 %, alcohol-related liver disease: 12 %, p < 0.01). Using logistic regression, mood symptoms (OR 1.14, 95 % CI 1.06, 1.22), sleep disturbance (OR 1.32, 95 % CI 1.16, 1.52), and etiology of liver disease (NASH vs. HCV not different, alcohol vs. HCV OR 0.19, 95 % CI 0.05, 0.63) were associated with fibromyalgia symptoms. If abdominal pain was included in the model, etiology became nonsignificant, indicating that it may be central sensitization due to abdominal pain in patients with chronic liver disease that explains fibromyalgia symptoms rather than the etiology of liver disease or inflammation. Conclusions Fibromyalgia symptoms were significantly associated with HCV and NASH cirrhosis and with psychiatric symptoms. Future work should focus on the underlying pathophysiology and management of widespread pain in patients with cirrhosis. PMID:25433921

  14. Association of mRNA expression of iron metabolism-associated genes and progression of non-alcoholic steatohepatitis in rats.

    PubMed

    Higuchi, Teruhisa; Moriyama, Mitsuhiko; Fukushima, Akiko; Matsumura, Hiroshi; Matsuoka, Shunichi; Kanda, Tatsuo; Sugitani, Masahiko; Tsunemi, Akiko; Ueno, Takahiro; Fukuda, Noboru

    2018-05-25

    Excess iron is associated with non-alcoholic steatohepatitis (NASH). mRNA expression of duodenal cytochrome b, divalent metal transporter 1, ferroportin 1, hepcidin, hephaestin and transferrin receptor 1 in liver were higher in high fat, high cholesterol-containing diet (HFCD) group than in normal diet (ND) group. mRNA levels of divalent metal transporter 1 and transferrin receptor 1, which stimulate iron absorption and excretion, were enhanced in small intestine. Epithelial mucosa of small intestine in HFCD group was characterized by plasma cell and eosinophil infiltration and increased vacuoles. Iron absorption was enhanced in this NASH model in the context of chronic inflammation of small intestinal epithelial cells, consequences of intestinal epithelial cell impairment caused by HFCD. Iron is transported to hepatocytes via portal blood, and abnormalities in iron absorption and excretion occur in small intestine from changes in iron transporter expression, which also occurs in NASH liver. Knockdown of hepcidin antimicrobial peptide led to enhanced heavy chain of ferritin expression in human hepatocytes, indicating association between hepcidin production and iron storage in hepatocytes. Iron-related transporters in liver and lower/upper portions of small intestine play critical roles in NASH development. Expression of iron metabolism-related genes in liver and small intestine was analyzed in stroke-prone spontaneously hypertensive rats (SHR-SP), which develop NASH. Five-week-old SHR-SP fed ND or HFCD were examined. mRNA and protein levels of iron metabolism-related genes in liver and small intestine from 12- and 19-week-old rats were evaluated by real-time RT-PCR and immunohistochemistry or Western blot.

  15. Delta-9-Tetrahydrocannabinol Potentiates Fear Memory Salience Through Functional Modulation of Mesolimbic Dopaminergic Activity States.

    PubMed

    Fitoussi, Aurelie; Zunder, Jordan; Tan, Huibing; Laviolette, Steven R

    2018-05-18

    Chronic or acute exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, has been associated with numerous neuropsychiatric side-effects, including dysregulation of emotional processing and associative memory formation. Clinical and pre-clinical evidence suggests that the effects of THC are due to the ability to modulate mesolimbic dopamine (DA) activity states in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Nevertheless, the mechanisms by which THC modulates mesolimbic DA function and emotional processing are not well understood. Using an olfactory associative fear memory procedure combined with in vivo neuronal electrophysiology, we examined the effects of direct THC microinfusions targeting the shell region of the NAc (NASh) and examined how THC may modulate the processing of fear-related emotional memory and concomitant activity states of the mesolimbic DA system. We report that intra-NASh THC dose-dependently potentiates the emotional salience of normally sub-threshold fear-conditioning cues. These effects were dependent upon intra-VTA transmission through GABAergic receptor mechanisms and intra-NASh DAergic transmission. Furthermore, doses of intra-NASh THC that potentiated fear memory salience were found to modulate intra-VTA neuronal network activity by increasing the spontaneous firing and bursting frequency of DAergic neurons whilst decreasing the activity levels of a subpopulation of putative GABAergic VTA neurons. These findings demonstrate that THC can act directly in the NASh to modulate mesolimbic activity states and induce disturbances in emotional salience and memory formation through modulation of VTA DAergic transmission. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  16. A novel and comprehensive mouse model of human non-alcoholic steatohepatitis with the full range of dysmetabolic and histological abnormalities induced by gold thioglucose and a high-fat diet.

    PubMed

    Ogasawara, Mitsunari; Hirose, Akira; Ono, Masafumi; Aritake, Kosuke; Nozaki, Yasuko; Takahashi, Masaya; Okamoto, Nobuto; Sakamoto, Shuji; Iwasaki, Shinji; Asanuma, Taketoshi; Taniguchi, Taketoshi; Urade, Yoshihiro; Onishi, Saburo; Saibara, Toshiji; Oben, Jude A

    2011-04-01

    The search for effective treatments of non-alcoholic steatohepatitis (NASH), now the most common chronic liver disease in affluent countries, is hindered by a lack of animal models having the range of anthropometric and pathophysiological features as human NASH. To examine if mice treated with gold thioglucose (GTG) - known to induce lesions in the ventromedial hypothalamus, leading to hyperphagia and obesity - and then fed a high-fat diet (HF) had a comprehensive histological and dysmetabolic phenotype resembling human NASH. C57BL/6 mice were injected intraperitoneally with GTG and then fed HF for 12 weeks (GTG+HF). The extent of abdominal adiposity was assayed by CT scanning. A glucose tolerance test and an insulin tolerance test were performed to evaluate insulin resistance (IR). Histological, molecular and biochemical analyses were also performed. Gold thioglucose+HF induced dysmetabolism, with hyperphagia, obesity with increased abdominal adiposity, IR and consequent steatohepatitis, with hepatocyte ballooning, Mallory-Denk bodies, perivenular and pericellular fibrosis as seen in adult NASH, paralleled by an increased expression of the profibrogenic factors, transforming growth factor-β1 and TIMP-1. Plasma adiponectin and the expression of adiponectin receptor 1 and receptor 2 were decreased, while PPAR-γ and FAS were increased in the livers of GTG+HF mice. In addition, GTG+HF mice showed glucose intolerance and severe IR. Treatment with GTG and HF diet induce, in mice, a comprehensive model of human NASH, with the full range of dysmetabolic and histological abnormalities. © 2011 John Wiley & Sons A/S.

  17. Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis.

    PubMed

    Lee, Da Hyun; Han, Dai Hoon; Nam, Ki Taek; Park, Jeong Su; Kim, Soo Hyun; Lee, Milim; Kim, Gyuri; Min, Byung Soh; Cha, Bong-Soo; Lee, Yu Seol; Sung, Su Haeng; Jeong, Haengdueng; Ji, Hye Won; Lee, Moon Joo; Lee, Jae Sung; Lee, Hui-Young; Chun, Yoomi; Kim, Joungmok; Komatsu, Masaaki; Lee, Yong-Ho; Bae, Soo Han

    2016-10-01

    Oxidative stress is important for the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a chronic disease that ranges from hepatic steatosis to nonalcoholic steatohepatitis (NASH). The nuclear factor erythroid 2-related factor 2-Kelch-like ECH associated protein 1 (Nrf2-Keap1) pathway is essential for cytoprotection against oxidative stress. In this study, we found that oxidative stress or inflammatory biomarkers and TUNEL positive cells were markedly increased in NASH patients compared to normal or simple steatosis. In addition, we identified that the hepatic mRNA levels of Nrf2 target genes such as Nqo-1 and GSTA-1 were significantly increased in NASH patients. Ezetimibe, a drug approved by the Food and Drug Administration for the treatment of hypercholesterolemia, improves NAFLD and alleviates oxidative stress. However, the precise mechanism of its antioxidant function remains largely unknown. We now demonstrate that ezetimibe activates Nrf2-Keap1 pathway which was dependent of autophagy adaptor protein p62, without causing cytotoxicity. Ezetimibe activates AMP-activated protein kinase (AMPK), which in turn phosphorylates p62 (p-S351) via their direct interaction. Correspondingly, Ezetimibe protected liver cells from saturated fatty acid-induced apoptotic cell death through p62-dependent Nrf2 activation. Furthermore, its role as an Nrf2 activator was supported by methione- and choline- deficient (MCD) diet-induced NASH mouse model, showing that ezetimibe decreased the susceptibility of the liver to oxidative injury. These data demonstrate that the molecular mechanisms underlying ezetimibe's antioxidant role in the pathogenesis of NASH. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Mapping Physical Characteristics of the Columbia River Mouth Using Transmittered Diving Waterbirds

    DTIC Science & Technology

    2013-09-30

    Fisheries and Wildlife Oregon State University 104 Nash Hall Corvallis, OR 97331 Phone: 541-737-1955 Fax: 541-737-3590 Email: daniel.roby...oregonstate.edu Donald E. Lyons Oregon Cooperative Fish and Wildlife Research Unit Department of Fisheries and Wildlife Oregon State University 104...Fish and Wildlife Research Unit Department of Fisheries and Wildlife Oregon State University 104 Nash Hall Corvallis, OR 97331 Phone: 360-510-8904

  19. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis

    PubMed Central

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K.; Mukherjee, Rathin; Reddy, Duvvur N.; Rao, Padaki N.

    2015-01-01

    Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed. PMID:26155043

  20. Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis

    PubMed Central

    Pejnovic, Nada; Jeftic, Ilija; Jovicic, Nemanja; Arsenijevic, Nebojsa; Lukic, Miodrag L

    2016-01-01

    Immune reactivity and chronic low-grade inflammation (metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death. Experimental models of dietary-induced NAFLD/NASH in mice on different genetic backgrounds or knockout mice with different immune reactivity are used for elucidating the pathogenesis of NASH and liver fibrosis. Galectin-3 (Gal-3), a unique chimera-type β-galactoside-binding protein of the galectin family has a regulatory role in immunometabolism and fibrogenesis. Mice deficient in Gal-3 develop pronounced adiposity, hyperglycemia and hepatic steatosis, as well as attenuated liver inflammation and fibrosis when fed an obesogenic high-fat diet. Interleukin (IL)-33, a member of the IL-1 cytokine family, mediates its effects through the ST receptor, which is present on immune and nonimmune cells and participates in immunometabolic and fibrotic disorders. Recent evidence, including our own data, suggests a protective role for the IL-33/IL-33R (ST2) signaling pathway in obesity, adipose tissue inflammation and atherosclerosis, but a profibrotic role in NASH development. The link between Gal-3 and soluble ST2 in myocardial fibrosis and heart failure progression has been demonstrated and we have recently shown that Gal-3 and the IL-33/ST2 pathway interact and both have a profibrotic role in diet-induced NASH. This review discusses the current

  1. Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis

    PubMed Central

    Kawai, Hirokazu; Nomoto, Minoru; Suda, Takeshi; Kamimura, Kenya; Tsuchiya, Atsunori; Tamura, Yasushi; Yano, Masahiko; Takamura, Masaaki; Igarashi, Masato; Wakai, Toshifumi; Yamagiwa, Satoshi; Matsuda, Yasunobu; Ohkoshi, Shogo; Kurosaki, Isao; Shirai, Yoshio; Okada, Masahiko; Aoyagi, Yutaka

    2011-01-01

    AIM: To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis (NASH) focusing on multicentric occurrence (MO) of HCC. METHODS: We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background. The clinical features were implicated with reference to the literature available. RESULTS: MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC (2 males and 2 females). One patient had synchronous MO; an advanced HCC, two well-differentiated HCCs and a dysplastic nodule, followed by the development of metachronous MO of HCC. The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule. Of these three patients, one had synchronous MO, one had metachronous MO and the other had both synchronous and metachronous MO. There were no obvious differences between the patients with or without MO in terms of liver function tests, tumor markers and anatomical extent of HCC. On the other hand, all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity, type 2 diabetes mellitus (T2DM), hypertension and cirrhosis. Although these conditions were not limited to MO of HCC, all the conditions were met in only one of eight patients without MO of HCC. Thus, concurrence of these conditions may be a predisposing situation to synchronous MO of HCC. In particular, old age, T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature. CONCLUSION: The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study. Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic

  2. The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement.

    PubMed

    Athyros, Vasilios G; Alexandrides, Theodore K; Bilianou, Helen; Cholongitas, Evangelos; Doumas, Michael; Ganotakis, Emmanuel S; Goudevenos, John; Elisaf, Moses S; Germanidis, Georgios; Giouleme, Olga; Karagiannis, Asterios; Karvounis, Charalambos; Katsiki, Niki; Kotsis, Vasilios; Kountouras, Jannis; Liberopoulos, Evangelos; Pitsavos, Christos; Polyzos, Stergios; Rallidis, Loukianos S; Richter, Dimitrios; Tsapas, Apostolos G; Tselepis, Alexandros D; Tsioufis, Konstantinos; Tziomalos, Konstantinos; Tzotzas, Themistoklis; Vasiliadis, Themistoklis G; Vlachopoulos, Charalambos; Mikhailidis, Dimitri P; Mantzoros, Christos

    2017-06-01

    Non-alcoholic fatty liver disease (NAFLD), the most common liver disease, is characterized by accumulation of fat (>5% of the liver tissue), in the absence of alcohol abuse or other chronic liver diseases. It is closely related to the epidemic of obesity, metabolic syndrome or type 2 diabetes mellitus (T2DM). NAFLD can cause liver inflammation and progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular cancer (HCC). Nevertheless, cardiovascular disease (CVD) is the most common cause of death in NAFLD/NASH patients. Current guidelines suggest the use of pioglitazone both in patients with T2DM and in those without. The use of statins, though considered safe by the guidelines, have very limited use; only 10% in high CVD risk patients are on statins by tertiary centers in the US. There are data from several animal studies, 5 post hoc analyses of prospective long-term survival studies, and 5 rather small biopsy proven NASH studies, one at baseline and on at the end of the study. All these studies provide data for biochemical and histological improvement of NAFLD/NASH with statins and in the clinical studies large reductions in CVD events in comparison with those also on statins and normal liver. Ezetimibe was also reported to improve NAFLD. Drugs currently in clinical trials seem to have potential for slowing down the evolution of NAFLD and for reducing liver- and CVD-related morbidity and mortality, but it will take time before they are ready to be used in everyday clinical practice. The suggestion of this Expert Panel is that, pending forthcoming randomized clinical trials, physicians should consider using a PPARgamma agonist, such as pioglitazone, or, statin use in those with NAFLD/NASH at high CVD or HCC risk, alone and/or preferably in combination with each other or with ezetimibe, for the primary or secondary prevention of CVD, and the avoidance of cirrhosis, liver transplantation or HCC, bearing in mind that CVD is the main cause

  3. Role of aramchol in steatohepatitis and fibrosis in mice

    PubMed Central

    Iruarrizaga‐Lejarreta, Marta; Varela‐Rey, Marta; Fernández‐Ramos, David; Martínez‐Arranz, Ibon; Delgado, Teresa C; Simon, Jorge; Gutiérrez‐de Juan, Virginia; delaCruz‐Villar, Laura; Azkargorta, Mikel; Lavin, José L.; Mayo, Rebeca; Van Liempd, Sebastiaan M.; Aurrekoetxea, Igor; Buqué, Xabier; Delle Cave, Donatella; Peña, Arantza; Rodríguez‐Cuesta, Juan; Aransay, Ana M.; Elortza, Felix; Falcón‐Pérez, Juan M.; Aspichueta, Patricia; Hayardeny, Liat; Noureddin, Mazen; Sanyal, Arun J.; Alonso, Cristina; Anguita, Juan; Martínez‐Chantar, María Luz; Lu, Shelly C.

    2017-01-01

    Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits, including oxidative stress, mitochondrial dysfunction, inflammation, and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Arachidyl‐amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine‐ and choline‐deficient (MCD) diet model of NASH. We collected liver and serum from mice fed an MCD diet containing 0.1% methionine (0.1MCD) for 4 weeks; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were determined for both groups. The 0.1MCD‐fed mice were given Aramchol (5 mg/kg/day for the last 2 weeks), and liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD‐fed mice. Aramchol down‐regulated stearoyl‐coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β‐oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD‐fed mice and patients with NAFLD showed a substantial overlap. Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl‐coenyzme A desaturase 1 and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in

  4. Serum Levels of Oxidative Stress Markers in Patients with Type 2 Diabetes Mellitus and Non-alcoholic Steatohepatitis.

    PubMed

    Casoinic, F; Sampelean, D; Buzoianu, Anca D; Hancu, N; Baston, Dorina

    2016-12-01

    Oxidative stress is one of the key mechanisms responsible for disease progression in non-alcoholic fatty liver disease. The aim of this study was to evaluate the serum levels of oxidative stress markers in patients with type 2 diabetes mellitus (DMT2) and non-alcoholic steatohepatitis (NASH) and test their relationships with clinical and biochemical patient characteristics, compared to patients with DMT2 without non-alcoholic fatty liver disease (NAFLD), and controls. In all, 60 consecutive patients with DMT2 and NASH, 55 with DMT2 without NAFLD, and 50 age-and-gender-matched healthy subjects participated in the study. The serum levels of protein carbonyls and 8-isoprostane were determined by ELISA methods, while the serum levels of malondialdehyde (MDA) were detected by means of the spectrophotometric method. Clinical, demographic, and laboratory parameters were examined for all the subjects included in the study. Multivariate logistic regression was used to test the independent predictive factors in the relationships investigated here. Patients with DMT2 and NASH displayed significantly higher serum levels of protein carbonyls (1.112 ± 0.42 nmol/dL), MDA (6.181 ± 1.81 ng/mL), and 8-isoprostane (338.6 ± 98.5 pg/mL) compared to patients with DMT2 without NAFLD, and controls. Results of multivariate logistic regression analyses indicate that in patients with DMT2 and NASH, the serum levels of oxidative stress markers were independently and positively associated with: HbA1c, duration of diabetes, the UKPDS cardiovascular risk score (for protein carbonyls); age, LDL-cholesterol (for 8-isoprostane); and triglycerides serum levels (for MDA). Our findings indicate that the process of oxidative stress tends to increase in patients with DMT2 and NASH, compared to patients with DMT2 without NAFLD, and controls. This evidence suggests that an antioxidant therapy might prove useful in the treatment of patients with DMT2 and NASH.

  5. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome.

    PubMed

    Kargiotis, Konstantinos; Athyros, Vasilios G; Giouleme, Olga; Katsiki, Niki; Katsiki, Evangelia; Anagnostis, Panagiotis; Boutari, Chrysoula; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

    2015-07-07

    To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis (NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH. This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome (MetS) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients received lifestyle advice and were treated for a 12 mo period with rosuvastatin (10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid (SUA), high sensitivity C reactive protein (hsCRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values. The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20(th), which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3(rd) treatment month (ANOVA P < 0.001), while alkaline phosphatase activities by the 6(th) treatment month (ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced (P < 0.001). Lipid values were normalised by the 3(rd) treatment month. No patient had MetS by the 9(th) treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should

  6. Synthesis of Nanoscale CaO-Al2O3-SiO2-H2O and Na2O-Al2O3-SiO2-H2O Using the Hydrothermal Method and Their Characterization

    PubMed Central

    Yang, Jingbin; Li, Dongxu; Fang, Yuan

    2017-01-01

    C-A-S-H (CaO-Al2O3-SiO2-H2O) and N-A-S-H (Na2O-Al2O3-SiO2-H2O) have a wide range of chemical compositions and structures and are difficult to separate from alkali-activated materials. Therefore, it is difficult to analyze their microscopic properties directly. This paper reports research on the synthesis of C-A-S-H and N-A-S-H particles with an average particle size smaller than 300 nm by applying the hydrothermal method. The composition and microstructure of the products with different CaO(Na2O)/SiO2 ratios and curing conditions were characterized using XRD, the RIR method, FTIR, SEM, TEM, and laser particle size analysis. The results showed that the C-A-S-H system products with a low CaO/SiO2 ratio were mainly amorphous C-A-S-H gels. With an increase in the CaO/SiO2 ratio, an excess of Ca(OH)2 was observed at room temperature, while in a high-temperature reaction system, katoite, C4AcH11, and other crystallized products were observed. The katoite content was related to the curing temperature and the content of Ca(OH)2 and it tended to form at a high-temperature and high-calcium environment, and an increase in the temperature renders the C-A-S-H gels more compact. The main products of the N-A-S-H system at room temperature were amorphous N-A-S-H gels and a small amount of sodalite. An increase in the curing temperature promoted the formation of the crystalline products faujasite and zeolite-P. The crystallization products consisted of only zeolite-P in the high-temperature N-A-S-H system and its content were stable above 70%. An increase in the Na2O/SiO2 ratio resulted in more non-bridging oxygen and the TO4 was more isolated in the N-A-S-H structure. The composition and microstructure of the C-A-S-H and N-A-S-H system products synthesized by the hydrothermal method were closely related to the ratio of the raw materials and the curing conditions. The results of this study increase our understanding of the hydration products of alkali-activated materials. PMID

  7. Levels of metacaspase1 and chaperones related to protein quality control in alcoholic and nonalcoholic steatohepatitis.

    PubMed

    Mendoza, Alejandro S; Dorce, Jacques; Peng, Yue; French, Barbara A; Tillman, Brittany; Li, Jun; French, Samuel W

    2015-02-01

    Efficient management of misfolded or aggregated proteins in ASH and NASH is crucial for continued hepatic viability. Cellular protein quality control systems play an important role in the pathogenesis and progression of ASH and NASH. In a recent study, elevated Mca1 expression counteracted aggregation and accumulation of misfolded proteins and extended the life span of the yeast Saccharomyces cerevisiae (Hill et al, 2014). Mca1 may also associate with Ssa1 and Hsp104 in disaggregation and fragmentation of aggregated proteins and their subsequent degradation through the ER-associated degradation (ERAD) pathway. If degradation is not available, protection of the cellular environment from a misfolded protein is accomplished by its sequestration into two distinct inclusion bodies (Kaganovich et al., 2008) called the JUNQ (JUxta Nuclear Quality control compartment) and the IPOD (Insoluble Protein Deposit). Mca1, Hsp104, Hsp40, Ydj1, Ssa1, VCP/p97, and p62 all play important roles in protein quality control systems. This study aims to measure the expression of Mca1 and related chaperones involved in protein quality control in alcoholic steatohepatitis (ASH), and nonalcoholic steatohepatitis (NASH) compared with normal control liver biopsies. Mca1, Hsp104, Hsp40, Ydj1, Ssa1, VCP/p97, and p62 expressions were measured in three to six formalin-fixed paraffin embedded ASH and NASH liver biopsies and control normal liver specimens by immunofluorescence staining and quantified by immunofluorescence intensity. Mca1, Hsp104, Ydj1 and p62 were significantly upregulated compared to control (p<0.05) in ASH specimens. Hsp40 and VCP/p97 were also uptrending in ASH. In NASH, the only significant difference was the increased expression of Hsp104 compared to control (p<0.05). Ssa1 levels were uptrending in both ASH and NASH specimens. The upregulation of Mca1, Hsp104, Ydj1 and p62 in ASH may be elicited as a response to the chronic exposure of the hepatocytes to the toxicity of alcohol

  8. Dietary intervention, but not losartan, completely reverses non-alcoholic steatohepatitis in obese and insulin resistant mice.

    PubMed

    Verbeek, Jef; Spincemaille, Pieter; Vanhorebeek, Ilse; Van den Berghe, Greet; Vander Elst, Ingrid; Windmolders, Petra; van Pelt, Jos; van der Merwe, Schalk; Bedossa, Pierre; Nevens, Frederik; Cammue, Bruno; Thevissen, Karin; Cassiman, David

    2017-02-23

    Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment. However, histological evidence of its efficacy is limited and its impact on hepatic pathways involved in NASH is underreported. The efficacy of the angiotensin receptor type 1 blocker losartan is controversial because of varying results in a few animal and human studies. We evaluated the effect of dietary intervention versus losartan on NASH and associated systemic metabolic features in a representative mouse model. Male C57BL/6 J mice with high fat-high sucrose diet (HF-HSD) induced NASH, obesity, insulin resistance and hypercholesterolemia were subjected to dietary intervention (switch from HF-HSD to normal chow diet (NCD)) (n = 9), continuation HF-HSD together with losartan (30 mg/kg/day) (n = 9) or continuation HF-HSD only (n = 9) for 8 weeks. 9 mice received NCD during the entire experiment (20 weeks). We assessed the systemic metabolic effects and performed a detailed hepatic histological and molecular profiling. A P-value of < 0.05, using the group with continuation of HF-HSD only as control, was considered as statistically significant. Dietary intervention normalized obesity, insulin resistance, and hypercholesterolemia (for all P < 0.001), and remarkably, completely reversed all histological features of pre-existent NASH (for all P < 0.001), including fibrosis measured by quantification of collagen proportional area (P < 0.01). At the hepatic molecular level, dietary intervention targeted fibrogenesis with a normalization of collagen type I alpha 1, transforming growth factor β1, tissue inhibitor of metalloproteinase 1 mRNA levels (for all P < 0.01), lipid metabolism with a normalization of fatty acid translocase/CD36, fatty acid transport protein 5, fatty acid synthase mRNA levels (P < 0.05) and markers related to mitochondrial function with a normalization of hepatic ATP content (P < 0.05) together with sirtuin1 and

  9. Oily fish, coffee and walnuts: Dietary treatment for nonalcoholic fatty liver disease.

    PubMed

    Gupta, Vikas; Mah, Xian-Jun; Garcia, Maria Carmela; Antonypillai, Christina; van der Poorten, David

    2015-10-07

    Rates of non-alcoholic fatty liver disease (NAFLD) are increasing worldwide in tandem with the metabolic syndrome, with the progressive form of disease, non-alcoholic steatohepatitis (NASH) likely to become the most common cause of end stage liver disease in the not too distant future. Lifestyle modification and weight loss remain the main focus of management in NAFLD and NASH, however, there has been growing interest in the benefit of specific foods and dietary components on disease progression, with some foods showing protective properties. This article provides an overview of the foods that show the most promise and their potential benefits in NAFLD/NASH, specifically; oily fish/ fish oil, coffee, nuts, tea, red wine, avocado and olive oil. Furthermore, it summarises results from animal and human trials and highlights potential areas for future research.

  10. Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice.

    PubMed

    Xu, Bing; Jiang, Mingzuo; Chu, Yi; Wang, Weijie; Chen, Di; Li, Xiaowei; Zhang, Zhao; Zhang, Di; Fan, Daiming; Nie, Yongzhan; Shao, Feng; Wu, Kaichun; Liang, Jie

    2017-12-20

    Gasdermin D (GSDMD)-executed programmed necrosis is involved in inflammation and controls interleukin (IL)-1β release. However, the role of GSDMD in non-alcoholic steatohepatitis (NASH) remains unclear. We investigated the role of GSDMD in the pathogenesis of steatohepatitis. Human liver tissues from patients with non-alcoholic fatty liver disease (NAFLD) and control individuals were obtained to evaluate GSDMD expression. Gsdmd knockout (Gsdmd -/- ) mice, obese db/db mice and their wild-type (WT) littermates were fed with methionine-choline deficient (MCD) or control diet to induce steatohepatitis. The Gsdmd -/- and WT mice were also used in a high-fat diet (HFD)-induced NAFLD model. In addition, Alb-Cre mice were administered an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and were fed with either MCD or control diet for 10 days. GSDMD and its pyroptosis-inducing fragment GSDMD-N were upregulated in liver tissues of human NAFLD/NASH. Importantly, hepatic GSDMD-N protein levels were significantly higher in human NASH and correlated with the NAFLD activity score and fibrosis. GSDMD-N remained a potential biomarker for the diagnosis of NASH. MCD-fed Gsdmd -/- mice exhibit decreased severity of steatosis and inflammation compared with WT littermates. GSDMD was associated with the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and MCP-1 [CCL2]) and persistent activation of the NF-ĸB signaling pathway. Gsdmd -/- mice showed lower steatosis, mainly because of reduced expression of the lipogenic gene Srebp1c (Srebf1) and upregulated expression of lipolytic genes, including Pparα, Aco [Klk15], Lcad [Acadl], Cyp4a10 and Cyp4a14. Alb-Cre mice administered with AAV9-FLEX-GSDMD-N showed significantly aggravated steatohepatitis when fed with MCD diet. As an executor of pyroptosis, GSDMD plays a key role in the pathogenesis of steatohepatitis, by controlling cytokine secretion, NF-ĸB activation, and lipogenesis

  11. Liver-specific loss of Perilipin 2 alleviates diet-induced hepatic steatosis, inflammation, and fibrosis

    PubMed Central

    Najt, Charles P.; Senthivinayagam, Subramanian; Aljazi, Mohammad B.; Fader, Kelly A.; Olenic, Sandra D.; Brock, Julienne R. L.; Lydic, Todd A.; Jones, A. Daniel

    2016-01-01

    Hepatic inflammation and fibrosis are key elements in the pathogenesis of nonalcoholic steatohepatitis (NASH), a progressive liver disease initiated by excess hepatic lipid accumulation. Lipid droplet protein Perilipin 2 (Plin2) alleviates dietary-induced hepatic steatosis when globally ablated; however, its role in the progression of NASH remains unknown. To investigate this further, we challenged Plin2 liver-specific knockout mice (designated L-KO) and their respective wild-type (WT) controls with a methionine-choline-deficient (MCD) diet for 15 days to induce a NASH phenotype of increased hepatic triglyceride levels through impaired phosphatidylcholine (PC) synthesis and very-low-density lipoprotein (VLDL) secretion. Results on liver weights, body weights, fat tissue mass, and histology in WT and L-KO mice fed the MCD diet revealed signs of hepatic steatosis, fibrosis, and inflammation; however, these effects were blunted in L-KO mice. In addition, levels of PC and VLDL were unchanged, and hepatic steatosis was reduced in L-KO mice fed the MCD diet, due in part to an increase in remodeling of PE to PC via the enzyme phosphatidylethanolamine N-methyltransferase (PEMT). These mice also exhibited decreased hepatic expression of proinflammatory markers cyclooxygenase 2, IL-6, TNF-α, IL-1β, and reduced expression of endoplasmic reticulum (ER) stress proteins C/EBP homologous protein and cleaved caspase-1. Taken together, these results suggest that Plin2 liver-specific ablation alleviates diet-induced hepatic steatosis and inflammation via a PEMT-mediated mechanism that involves compensatory changes in proteins involved in phospholipid remodeling, inflammation, and ER stress that work to alleviate diet-induced NASH. Overall, these findings support a role for Plin2 as a target for NASH therapy. PMID:26968211

  12. Nitric oxide plays a crucial role in the development/progression of nonalcoholic steatohepatitis in the choline-deficient, l-amino acid-defined diet-fed rat model.

    PubMed

    Fujita, Koji; Nozaki, Yuichi; Yoneda, Masato; Wada, Koichiro; Takahashi, Hirokazu; Kirikoshi, Hiroyuki; Inamori, Masahiko; Saito, Satoru; Iwasaki, Tomoyuki; Terauchi, Yasuo; Maeyama, Shiro; Nakajima, Atsushi

    2010-02-01

    The pathogenesis of nonalcoholic steatohepatitis (NASH) is still unclear. Recently, the 2-hit hypothesis was proposed, in which nitric oxide production, representing oxidative stress, was proposed as a very important candidate for the second hit. The total study period was 10 weeks. A total of 20 rats were randomly divided into 2 groups. Group 1 was administered the Choline-Deficient, l-Amino Acid-Defined diet to produce a NASH model, and Group 2 as control received the Choline-Sufficient, l-Amino Acid-defined diet. The blood and tissue concentrations of nitrate + nitrite were measured using the Griess reagent and the expression levels of inducible nitric oxide synthase (iNOS) proteins and mRNA was determined by Western blotting. In regard to nitric oxide (NO) and NO metabolites, there were significant differences in the blood (especially portal venous blood) as well as tissue (liver and visceral fat) concentrations between the 2 animal groups; the amounts of NO metabolites in the tissues were much higher in the NASH models. The level of nitrotyrosine was much markedly higher in the NASH models than in the controls. In regard to the tissue expression of iNOS a significant difference between the 2 groups was found in the visceral fat, especially in the mesenterium. Based on these results, we hypothesize that the iNOS expression and NO levels in the visceral fat increase, with increased diffusion of NO and its metabolites into the liver, resulting in increased nitrotyrosine formation in the liver; this, in turn, induces inflammation, apoptosis, and fibrosis in the liver, which are one of the characteristic features of NASH.

  13. A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice.

    PubMed

    Abulizi, Abudukadier; Perry, Rachel J; Camporez, João Paulo G; Jurczak, Michael J; Petersen, Kitt Falk; Aspichueta, Patricia; Shulman, Gerald I

    2017-07-01

    Lipodystrophy is a rare disorder characterized by complete or partial loss of adipose tissue. Patients with lipodystrophy exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). Efforts to ameliorate NASH in lipodystrophies with pharmacologic agents have met with limited success. We examined whether a controlled-release mitochondrial protonophore (CRMP) that produces mild liver-targeted mitochondrial uncoupling could decrease hypertriglyceridemia and reverse NASH and diabetes in a mouse model (fatless AZIP/F-1 mice) of severe lipodystrophy and diabetes. After 4 wk of oral CRMP (2 mg/kg body weight per day) or vehicle treatment, mice underwent hyperinsulinemic-euglycemic clamps combined with radiolabeled glucose to assess liver and muscle insulin responsiveness and tissue lipid measurements. CRMP treatment reversed hypertriglyceridemia and insulin resistance in liver and skeletal muscle. Reversal of insulin resistance could be attributed to reductions in diacylglycerol content and reduced PKC-ε and PKC-θ activity in liver and muscle respectively. CRMP treatment also reversed NASH as reflected by reductions in plasma aspartate aminotransferase and alanine aminotransferase concentrations; hepatic steatosis; and hepatic expression of IL-1α, -β, -2, -4, -6, -10, -12, CD69, and caspase 3 and attenuated activation of the IRE-1α branch of the unfolded protein response. Taken together, these results provide proof of concept for the development of liver-targeted mitochondrial uncoupling agents as a potential novel therapy for lipodystrophy-associated hypertriglyceridemia, NASH and diabetes.-Abulizi, A., Perry, R. J., Camporez, J. P. G., Jurczak, M. J., Petersen, K. F., Aspichueta, P., Shulman, G. I. A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice. © FASEB.

  14. Emergence of scale-free characteristics in socio-ecological systems with bounded rationality

    PubMed Central

    Kasthurirathna, Dharshana; Piraveenan, Mahendra

    2015-01-01

    Socio–ecological systems are increasingly modelled by games played on complex networks. While the concept of Nash equilibrium assumes perfect rationality, in reality players display heterogeneous bounded rationality. Here we present a topological model of bounded rationality in socio-ecological systems, using the rationality parameter of the Quantal Response Equilibrium. We argue that system rationality could be measured by the average Kullback–-Leibler divergence between Nash and Quantal Response Equilibria, and that the convergence towards Nash equilibria on average corresponds to increased system rationality. Using this model, we show that when a randomly connected socio-ecological system is topologically optimised to converge towards Nash equilibria, scale-free and small world features emerge. Therefore, optimising system rationality is an evolutionary reason for the emergence of scale-free and small-world features in socio-ecological systems. Further, we show that in games where multiple equilibria are possible, the correlation between the scale-freeness of the system and the fraction of links with multiple equilibria goes through a rapid transition when the average system rationality increases. Our results explain the influence of the topological structure of socio–ecological systems in shaping their collective cognitive behaviour, and provide an explanation for the prevalence of scale-free and small-world characteristics in such systems. PMID:26065713

  15. Emergence of scale-free characteristics in socio-ecological systems with bounded rationality.

    PubMed

    Kasthurirathna, Dharshana; Piraveenan, Mahendra

    2015-06-11

    Socio-ecological systems are increasingly modelled by games played on complex networks. While the concept of Nash equilibrium assumes perfect rationality, in reality players display heterogeneous bounded rationality. Here we present a topological model of bounded rationality in socio-ecological systems, using the rationality parameter of the Quantal Response Equilibrium. We argue that system rationality could be measured by the average Kullback--Leibler divergence between Nash and Quantal Response Equilibria, and that the convergence towards Nash equilibria on average corresponds to increased system rationality. Using this model, we show that when a randomly connected socio-ecological system is topologically optimised to converge towards Nash equilibria, scale-free and small world features emerge. Therefore, optimising system rationality is an evolutionary reason for the emergence of scale-free and small-world features in socio-ecological systems. Further, we show that in games where multiple equilibria are possible, the correlation between the scale-freeness of the system and the fraction of links with multiple equilibria goes through a rapid transition when the average system rationality increases. Our results explain the influence of the topological structure of socio-ecological systems in shaping their collective cognitive behaviour, and provide an explanation for the prevalence of scale-free and small-world characteristics in such systems.

  16. Obeticholic Acid Improves Adipose Morphometry and Inflammation and Reduces Steatosis in Dietary but not Metabolic Obesity in Mice

    PubMed Central

    Haczeyni, Fahrettin; Poekes, Laurence; Wang, Hans; Mridha, Auvro R.; Barn, Vanessa; Haigh, W. Geoffrey; Ioannou, George N.; Yeh, Matthew M; Leclercq, Isabelle A.; Teoh, Narcissus C.; Farrell, Geoffrey C.

    2018-01-01

    Objective Non-alcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients, but for unknown reason does not resolve NASH pathology. We therefore investigated OCA effects in Wt mice which develop obesity with atherogenic dietary feeding, and appetite-dysregulated, Alms1 mutant foz/foz mice fed the same diet which develop metabolic obesity and diabetes. Methods OCA (1mg/kg) was administered orally to female foz/foz mice and Wt littermates from weaning until 28 weeks. We studied adipose indices, glucose tolerance and fatty liver pathology. Experiments were repeated with OCA 10mg/kg. Results OCA reduced body weight and hepatic lipids and improved glucose disposal only in Wt mice. OCA limited Wt adipose expansion, altered morphometry in favour of small adipocytes, enhanced expression of genes indicating adipose browning, and reduced crown-like structure (CLS) number in visceral adipose. foz/foz mice showed more CLSs in all compartments; OCA failed to alter adipose morphometry, browning, inflammation, or improve NASH severity, even at 10mg/kg. Conclusion OCA improves adipose indices, glucose tolerance and steatosis in milder metabolic phenotype, but fails to improve these factors in morbidly obese diabetic mice. These results help explain OCA’s limited efficacy to reverse human NASH. PMID:27804232

  17. High-salt in addition to high-fat diet may enhance inflammation and fibrosis in liver steatosis induced by oxidative stress and dyslipidemia in mice.

    PubMed

    Uetake, Yuzaburo; Ikeda, Hitoshi; Irie, Rie; Tejima, Kazuaki; Matsui, Hiromitsu; Ogura, Sayoko; Wang, Hong; Mu, ShengYu; Hirohama, Daigoro; Ando, Katsuyuki; Sawamura, Tatsuya; Yatomi, Yutaka; Fujita, Toshiro; Shimosawa, Tatsuo

    2015-02-13

    It is widely known that salt is an accelerating factor for the progression of metabolic syndrome and causes cardiovascular diseases, most likely due to its pro-oxidant properties. We hypothesized that excessive salt intake also facilitates the development of nonalcoholic steatohepatitis (NASH), which is frequently associated with metabolic syndrome. We examined the exacerbating effect of high-salt diet on high-fat diet-induced liver injury in a susceptible model to oxidative stress, apoE knockout and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transgenic mice. High-salt diet led to NASH in high-fat diet-fed LOX-1 transgenic/apoE knockout mice without affecting high-fat diet-induced dyslipidemia or hepatic triglyceride accumulation. Additionally, a high-salt and high-fat diet stimulated oxidative stress production and inflammatory reaction to a greater extent than did a high-fat diet in the liver of LOX-1 transgenic/apoE knockout mice. We demonstrated that high-salt diet exacerbated NASH in high-fat diet-fed LOX-1 transgenic /apoE knockout mice and that this effect was associated with the stimulation of oxidative and inflammatory processes; this is the first study to suggest the important role of excessive salt intake in the development of NASH.

  18. The Worst-Case Weighted Multi-Objective Game with an Application to Supply Chain Competitions

    PubMed Central

    Qu, Shaojian; Ji, Ying

    2016-01-01

    In this paper, we propose a worst-case weighted approach to the multi-objective n-person non-zero sum game model where each player has more than one competing objective. Our “worst-case weighted multi-objective game” model supposes that each player has a set of weights to its objectives and wishes to minimize its maximum weighted sum objectives where the maximization is with respect to the set of weights. This new model gives rise to a new Pareto Nash equilibrium concept, which we call “robust-weighted Nash equilibrium”. We prove that the robust-weighted Nash equilibria are guaranteed to exist even when the weight sets are unbounded. For the worst-case weighted multi-objective game with the weight sets of players all given as polytope, we show that a robust-weighted Nash equilibrium can be obtained by solving a mathematical program with equilibrium constraints (MPEC). For an application, we illustrate the usefulness of the worst-case weighted multi-objective game to a supply chain risk management problem under demand uncertainty. By the comparison with the existed weighted approach, we show that our method is more robust and can be more efficiently used for the real-world applications. PMID:26820512

  19. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

    PubMed Central

    Henao-Mejia, Jorge; Elinav, Eran; Jin, Cheng-Cheng; Hao, Liming; Mehal, Wajahat Z.; Strowig, Till; Thaiss, Christoph A.; Kau, Andrew L.; Eisenbarth, Stephanie C.; Jurczak, Michael J.; Camporez, Joao-Paulo; Shulman, Gerald I.; Gordon, Jeffrey I.; Hoffman, Hal M.; Flavell, Richard A.

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty percent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different animal models reveal that inflammasome deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic TNF-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient animals to wild type mice results in exacerbation of hepatic steatosis, glucose intolerance, and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders. PMID:22297845

  20. Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.

    PubMed

    Da Silva, Hannah E; Teterina, Anastasia; Comelli, Elena M; Taibi, Amel; Arendt, Bianca M; Fischer, Sandra E; Lou, Wendy; Allard, Johane P

    2018-01-23

    This study aimed to determine if there is an association between dysbiosis and nonalcoholic fatty liver disease (NAFLD) independent of obesity and insulin resistance (IR). This is a prospective cross-sectional study assessing the intestinal microbiome (IM) of 39 adults with biopsy-proven NAFLD (15 simple steatosis [SS]; 24 nonalcoholic steatohepatitis [NASH]) and 28 healthy controls (HC). IM composition (llumina MiSeq Platform) in NAFLD patients compared to HC were identified by two statistical methods (Metastats, Wilcoxon). Selected taxa was validated using quantitative PCR (qPCR). Metabolites in feces and serum were also analyzed. In NAFLD, 8 operational taxonomic units, 6 genera, 6 families and 2 phyla (Bacteroidetes, Firmicutes) were less abundant and; 1 genus (Lactobacillus) and 1 family (Lactobacillaceae) were more abundant compared to HC. Lower abundance in both NASH and SS patients compared to HC were confirmed by qPCR for Ruminococcus, Faecalibacterium prausnitzii and Coprococcus. No difference was found between NASH and SS. This lower abundance in NAFLD (NASH+SS) was independent of BMI and IR. NAFLD patients had higher concentrations of fecal propionate and isobutyric acid and serum 2-hydroxybutyrate and L-lactic acid. These findings suggest a potential role for a specific IM community and functional profile in the pathogenesis of NAFLD.

  1. Oily fish, coffee and walnuts: Dietary treatment for nonalcoholic fatty liver disease

    PubMed Central

    Gupta, Vikas; Mah, Xian-Jun; Garcia, Maria Carmela; Antonypillai, Christina; van der Poorten, David

    2015-01-01

    Rates of non-alcoholic fatty liver disease (NAFLD) are increasing worldwide in tandem with the metabolic syndrome, with the progressive form of disease, non-alcoholic steatohepatitis (NASH) likely to become the most common cause of end stage liver disease in the not too distant future. Lifestyle modification and weight loss remain the main focus of management in NAFLD and NASH, however, there has been growing interest in the benefit of specific foods and dietary components on disease progression, with some foods showing protective properties. This article provides an overview of the foods that show the most promise and their potential benefits in NAFLD/NASH, specifically; oily fish/ fish oil, coffee, nuts, tea, red wine, avocado and olive oil. Furthermore, it summarises results from animal and human trials and highlights potential areas for future research. PMID:26457022

  2. Historical and Architectural Study of Buildings and Artifacts Associated with the Bulltown Historic Area, Burnsville Lake Project, Braxton County, West Virginia,

    DTIC Science & Technology

    1979-09-01

    consider ways in which troops could be effectively, even humanely employed in light of such developments. The result was an appalling loss of human and...specified by Canonical law and stems from the belief in the sanctity of human remains which is in turn linked to the concept of bodily resurrection. The...Robert Nash 1978, pers. omm.) . Catholic cemeteries are subject to three types of onsecration (Father Robert Nash 1978, pers. cumin .). A Pontifical

  3. Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis

    PubMed Central

    de Campos Mazo, Daniel Ferraz; Mattar, Rejane; Stefano, José Tadeu; da Silva-Etto, Joyce Matie Kinoshita; Diniz, Márcio Augusto; Duarte, Sebastião Mauro Bezerra; Rabelo, Fabíola; Lima, Rodrigo Vieira Costa; de Campos, Priscila Brizolla; Carrilho, Flair José; Oliveira, Claudia P

    2016-01-01

    AIM To assess lactase gene (LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients in comparison with healthy controls. METHODS This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, São Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence (LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients (steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher’s exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed. RESULTS No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients (66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls (59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism (LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase non-persistence (low lactase activity or hypolactasia) phenotype was associated with higher insulin levels (23.47 ± 15.94 μU/mL vs 15.8 ± 8.33 μU/mL, P = 0.027) and a higher frequency of insulin resistance (91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes (P = 0

  4. Prevalence of Prediabetes and Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease.

    PubMed

    Newton, Kimberly P; Hou, Jiayi; Crimmins, Nancy A; Lavine, Joel E; Barlow, Sarah E; Xanthakos, Stavra A; Africa, Jonathan; Behling, Cynthia; Donithan, Michele; Clark, Jeanne M; Schwimmer, Jeffrey B

    2016-10-03

    Nonalcoholic fatty liver disease (NAFLD) is a major chronic liver disease in children in the United States and is associated with insulin resistance. In adults, NAFLD is also associated with type 2 diabetes. To our knowledge, the prevalence of type 2 diabetes in children with NAFLD is unknown. To determine the prevalence of type 2 diabetes and prediabetes in children with NAFLD and assess type 2 diabetes and prediabetes as risk factors for nonalcoholic steatohepatitis (NASH). This was a multicenter, cross-sectional study at 12 pediatric clinical centers across the United States participating in the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network. Children younger than 18 years with biopsy-confirmed NAFLD enrolled in the NASH Clinical Research Network. The presence of type 2 diabetes and prediabetes as determined by American Diabetes Association screening criteria using clinical history and fasting laboratory values. There were 675 children with NAFLD included in the study with a mean age of 12.6 years and mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 32.5. Most of the children were boys (480 of 675) and Hispanic (445 of 675).The estimated prevalence of prediabetes was 23.4% (95% CI, 20.2%-26.6%), and the estimated prevalence of type 2 diabetes was 6.5% (95% CI, 4.6%-8.4%). Girls with NAFLD had 1.6 (95% CI, 1.04-2.40) times greater odds of having prediabetes and 5.0 (95% CI, 2.49-9.98) times greater odds of having type 2 diabetes than boys with NAFLD. The prevalence of NASH was higher in those with type 2 diabetes (43.2%) compared with prediabetes (34.2%) or normal glucose (22%) (P < .001). The odds of having NASH were significantly higher in those with prediabetes (OR, 1.9; 95% CI, 1.21-2.9) or type 2 diabetes (OR, 3.1; 95% CI, 1.5-6.2) compared with those with normal glucose. In this study, nearly 30% of children with NAFLD also had type 2 diabetes or prediabetes

  5. Celecoxib Ameliorates Non-Alcoholic Steatohepatitis in Type 2 Diabetic Rats via Suppression of the Non-Canonical Wnt Signaling Pathway Expression

    PubMed Central

    Tian, Feng; Zhang, Ya Jie; Li, Yu; Xie, Ying

    2014-01-01

    Our aim was to test whether pharmacological inhibition of cycloxygenase-2 (COX-2) reverses non-alcoholic steatohepatitis (NASH) in type 2 diabetes mellitus (T2DM) rats via suppression of the non-canonical Wnt signaling pathway expression. Twenty-four male Sprague-Dawley rats were randomly distributed to two groups and were fed with a high fat and sucrose (HF-HS) diet or a normal chow diet, respectively. After four weeks, rats fed with a HF-HS diet were made diabetic with low-dose streptozotocin. At the 9th week the diabetic rats fed with a HF-HS diet or the non-diabetic rats fed with a normal chow diet were further divided into two subgroups treated with vehicle or celecoxib (a selective COX-2 inhibitor, 10 mg/Kg/day, gavage) for the last 4 weeks, respectively. At the end of the 12th week, rats were anesthetized. NASH was assessed by histology. Related cytokine expression was measured at both the protein and gene levels through immunohistochemistry (IHC), Western blot and real-time PCR. T2DM rats fed with a HF-HS diet developed steatohepatitis and insulin resistance associated with elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin levels and the non-alcoholic fatty liver disease (NAFLD) activity score (NAS). The expression of Wnt5a, JNK1, NF-κB p65, and COX-2 were all significantly increased in the T2DM-NASH group compared with the control and control-cele group. Hepatic injury was improved by celecoxib in T2DM-NASH-Cele group indicated by reduced serum ALT and AST levels and hepatic inflammation was reduced by celecoxib showed by histology and the NAFLD activity score (NAS). Serum related metabolic parameters, HOMA-IR and insulin sensitivity index were all improved by celecoxib. The expression of Wnt5a, JNK1, NF-κB p65, and COX-2 expression were all suppressed by celecoxib in T2DM-NASH-Cele group. The results of the present study indicated that celecoxib ameliorated NASH in T2DM rats via suppression of the non-canonical Wnt

  6. CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8 + T cells aid progression of environment-linked nonalcoholic steatohepatitis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Seth, Ratanesh Kumar; Das, Suvarthi; Kumar, Ashutosh

    2014-01-01

    Environmental toxins induce a novel CYP2E1/leptin signaling axis in liver. This in turn activates a poorly characterized innate immune response that contributes to nonalcoholic steatohepatitis (NASH) progression. To identify the relevant subsets of T-lymphocytes in CYP2E1-dependent, environment-linked NASH, we utilized a model of diet induced obese (DIO) mice that are chronically exposed to bromodichloromethane. Mice deficient in CYP2E1, leptin (ob/ob mice), or both T and B cells (Pfp/Rag2 double knockout (KO) mice) were used to delineate the role of each of these factors in metabolic oxidative stress-induced T cell activation. Results revealed that elevated levels of lipid peroxidation, tyrosyl radicalmore » formation, mitochondrial tyrosine nitration and hepatic leptin as a consequence of metabolic oxidative stress caused increased levels of hepatic CD57, a marker of peripheral blood lymphocytes including NKT cells. CD8 + CD57 + cytotoxic T cells but not CD4 + CD57 + cells were significantly decreased in mice lacking CYP2E1 and leptin. There was a significant increase in the levels of T cell cytokines IL-2, IL-1β, and IFN-γ in bromodichloromethane exposed DIO mice but not in mice that lacked CYP2E1, leptin or T and B cells. Apoptosis as evidenced by TUNEL assay and levels of cleaved caspase-3 was significantly lower in leptin and Pfp/Rag2 KO mice and highly correlated with protection from NASH. The results described above suggest that higher levels of oxidative stress-induced leptin mediated CD8 + CD57 + T cells play an important role in the development of NASH. It also provides a novel insight of immune dysregulation and may be a key biomarker in NASH. - Highlights: • Metabolic oxidative stress caused increased levels of hepatic CD57 expression. • CD8+ CD57+ cytotoxic T cells were decreased in mice lacking CYP2E1 and leptin. • There was a significant increase in T cell cytokines in toxin-treated mice. • Apoptosis was significantly lower in leptin and

  7. Non invasive evaluation of liver fibrosis in paediatric patients with nonalcoholic steatohepatitis.

    PubMed

    Iacobellis, Angelo; Marcellini, Matilde; Andriulli, Angelo; Perri, Francesco; Leandro, Gioacchino; Devito, Rita; Nobili, Valerio

    2006-12-28

    To identify the independent predictors of hepatic fibrosis in 69 children with nonalcoholic steatohepatitis (NASH) due to nonalcoholic fatty liver disease (NAFLD). All patients with clinically suspected NASH underwent liver biopsy as a confirmatory test. The following clinical and biochemical variables at baseline were examined as likely predictors of fibrosis at histology: age, body mass index (BMI), systolic blood pressure (SBP), dyastolic blood pressure (DBP), fasting glucose, fasting insulin, homeostatic model assessment for insulin resistence (HOMA-IR), cholesterol, tryglicerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, gamma glutamil transferase (GT), platelet count, prothrombin time (PT). At histology 28 (40.6%) patients had no fibrosis and 41 (59.4%) had mild to bridging fibrosis. At multivariate analysis, BMI > 26.3 was the only independent predictor of fibrosis (OR = 5.85, 95% CI = 1.6-21). BMI helps identify children with NASH who might have fibrotic deposition in the liver.

  8. Nonalcoholic Fatty Liver Disease and Fibrosis in Youth Taking Psychotropic Medications: Literature Review, Case Reports, and Management.

    PubMed

    Gracious, Barbara L; Bhatt, Ramona; Potter, Carol

    2015-10-01

    Nonalcoholic fatty liver disease (NAFLD) has become a worldwide epidemic because of the greater prevalence of obesity. Despite implications for youth with severe mental disorders, little has been published in the psychiatric literature about this increasingly common medical comorbidity. The goals of this article are to: 1) provide an overview of the epidemiology and pathophysiology of NAFLD, including progression to nonalcoholic steatohepatitis (NASH); 2) describe two clinical cases illustrating difficulties faced in management; and 3) review screening recommendations, differential diagnosis, and monitoring and intervention approaches. A literature review was conducted, including guidelines and recommendations, with case presentations including case and control liver histology biopsy photographs. NAFLD in childhood and adolescence, as a precursor to NASH, progresses to fibrosis in a small percentage of youth, leading to risk for early onset cirrhosis and the need for transplantation. The cases presented raise concern that youth with severe mental health disorders, already at greater risk for obesity and its sequelae, may be at higher risk for progression to NASH, potentially because of greater rates of weight gain on top of overweight or obese status, and to liver metabolism changes from psychotropic medications favoring fat deposition. Patients with rapid weight gain into the overweight or obese categories, or who develop elevated liver transaminases that persist across 3-6 months, should be screened or referred for screening by their psychotropic-providing clinicians for early detection, diagnosis, and co-management by a pediatric gastroenterologist, to decrease risk of progression to NASH, which is reversible if early and sufficient lifestyle change results in significant weight loss. There is urgent need for controlled research on the relationships among weight gain, psychotropic medications, ultrasound and biopsy findings, and rates of progression to NAFLD and

  9. Serum adipokine levels in chronic liver diseases: association of resistin levels with fibrosis severity.

    PubMed

    Tsochatzis, Emmanuel; Papatheodoridis, George V; Hadziyannis, Emilia; Georgiou, Anastasia; Kafiri, Georgia; Tiniakos, Dina G; Manesis, Emanuel K; Archimandritis, Athanasios J

    2008-01-01

    Leptin and adiponectin have been implicated in the pathogenesis and progression of non-alcoholic steatohepatitis (NASH) and chronic hepatitis C (CHC), but little is known about the role of resistin in chronic liver diseases. The objective of this study was to investigate serum levels of the above three adipokines in relation to the etiology of liver disease and to determine their associations with histological severity. We prospectively evaluated 146 patients (HBeAg-negative chronic hepatitis B (CHB): 52, CHC: 70, NASH: 24) who consecutively underwent liver biopsy. Detailed epidemiological, anthropometric and laboratory data were recorded. Histological lesions were evaluated blindly according to the Ishak and the Brunt classifications for CHB/CHC and NASH, respectively. Serum adipokine levels were similar between CHB and CHC patients, while CHB/CHC patients had significantly lower leptin levels compared with NASH patients (8.3+/-7.3 versus 17.6+/-16.6 ng/ml, p=0.012) and higher adiponectin (10.2+/-5.1 versus 7.5+/-4 microg/ml, p=0.018) and resistin levels (7.1+/-2.5 versus 5.7+/-2.8 ng/ml, p=0.016). In CHB/CHC, there was no significant association between steatosis or necroinflammation and levels of adipokines, while the presence of moderate/severe fibrosis (stages 4-6) was associated with higher leptin and adiponectin levels in male but not in female patients and with lower resistin levels irrespective of gender or other factors (adjusted odds ratio=0.788, p=0.035). Serum adipokine levels depend on the etiology of liver disease differing between chronic viral hepatitis and NASH, but not between CHB and CHC. In CHB/CHC, resistin levels are independently associated with fibrosis severity, whereas in the association of leptin and adiponectin levels with fibrosis, it seems to be a gender effect.

  10. Increased parenchymal damage and steatohepatitis in Caucasian non-alcoholic fatty liver disease patients with common IL1B and IL6 polymorphisms.

    PubMed

    Nelson, J E; Handa, P; Aouizerat, B; Wilson, L; Vemulakonda, L A; Yeh, M M; Kowdley, K V

    2016-12-01

    Non-alcoholic fatty liver disease (NAFLD) is a complex, multifactorial disease affected by diet, lifestyle and genetics. Proinflammatory cytokines like IL-1β and IL-6 have been shown to be elevated in non-alcoholic steatohepatitis (NASH). To investigate the relationship between IL1B and IL6 gene polymorphisms and histological features of NAFLD in the NASH CRN cohort. A total of 604 adult (≥18 years) non-Hispanic Caucasians with biopsy-proven NAFLD were genotyped for the following SNPs: IL1B, rs16944, rs1143634; IL6, rs1800795, rs10499563. Logistic regression was used to examine the relationship between genotype and a definitive diagnosis and advanced histological features of NASH after controlling for the following variables selected a priori: age, sex, diabetes, obesity and HOMA-IR level. The IL6 rs10499563 C allele was independently associated with the presence of definitive NASH, and increased ballooning and Mallory bodies. The IL1B rs1143634 TT genotype was associated with advanced fibrosis and increased Mallory bodies. The IL6 rs1800795 C allele was associated with not only increased risk for severe steatosis, >66% but also decreased risk for advanced fibrosis and lobular inflammation and Mallory body formation. These results suggest that common variants in the IL6 and IL1B genes may increase susceptibility for NASH and confer a higher risk of hepatic parenchymal damage including increased ballooning, increased Mallory bodies, and bridging fibrosis or cirrhosis. In contrast, the IL6 rs1800795 C allele may confer a higher risk for steatosis, but less parenchymal damage. Our findings support the development of therapeutics aimed at IL-1β and IL-6 suppression. © 2016 John Wiley & Sons Ltd.

  11. Disease-specific miR-34a as diagnostic marker of non-alcoholic steatohepatitis in a Chinese population

    PubMed Central

    Liu, Xiao-Lin; Pan, Qin; Zhang, Rui-Nan; Shen, Feng; Yan, Shi-Yan; Sun, Chao; Xu, Zheng-Jie; Chen, Yuan-Wen; Fan, Jian-Gao

    2016-01-01

    AIM To assess disease-specific circulating microRNAs (miRNAs) in non-alcoholic steatohepatitis (NASH) patients. METHODS A total of 111 biopsy-proven non-alcoholic fatty liver disease (NAFLD) or chronic hepatitis B (CHB) patients and healthy controls from mainland China were enrolled to measure their serum levels of miR-122, -125b, -146b, -16, -21, -192, -27b and -34a. The correlations between serum miRNAs and histological features of NAFLD were determined. The diagnostic value of miRNA in NASH and significant fibrosis was analyzed and compared with that of cytokeratin-18 (CK-18), fibrosis-4 (FIB-4), and aspartate aminotransferase to platelet ratio index (APRI), respectively. RESULTS Circulating miR-122, -16, -192 and -34a showed differential expression levels between NAFLD and CHB patients, and miR-34a had an approximately 2-fold increase in NAFLD samples compared with that of CHB samples (P < 0.01). Serum miR-122, -192 and -34a levels were correlated with steatosis (R = 0.302, 0.323 and 0.470, respectively, P < 0.05) and inflammatory activity (R = 0.445, 0.447 and 0.517, respectively, P < 0.01); only serum miR-16 levels were associated with fibrosis (R = 0.350, P < 0.05) in patients with NAFLD. The diagnostic value of miR-34a for NASH (area under the receiver operating characteristic, 0.811, 95%CI: 0.670-0.953) was superior to that of alanine aminotransferase, CK-18, FIB-4 and APRI in NAFLD, but miR-16 showed a limited performance in the diagnosis of significant fibrosis in NASH. CONCLUSION Circulating miR-34a may serve as a disease-specific noninvasive biomarker for the diagnosis of NASH. PMID:27956809

  12. Restoration of a healthy intestinal microbiota normalizes portal hypertension in a rat model of nonalcoholic steatohepatitis.

    PubMed

    García-Lezana, Teresa; Raurell, Imma; Bravo, Miren; Torres-Arauz, Manuel; Salcedo, María Teresa; Santiago, Alba; Schoenenberger, Andreu; Manichanh, Chaysavanh; Genescà, Joan; Martell, María; Augustin, Salvador

    2018-04-01

    Portal hypertension (PH) drives most of the clinical complications in chronic liver diseases. However, its progression in nonalcoholic steatohepatitis (NASH) and its association with the intestinal microbiota (IM) have been scarcely studied. Our aim was to investigate the role of the IM in the mechanisms leading to PH in early NASH. The experimental design was divided in two stages. In stage 1, Sprague-Dawley rats were fed for 8 weeks a high-fat, high-glucose/fructose diet (HFGFD) or a control diet/water (CD). Representative rats were selected as IM donors for stage 2. In stage 2, additional HFGFD and CD rats underwent intestinal decontamination, followed by IM transplantation with feces from opposite-diet donors (heterologous transplant) or autologous fecal transplant (as controls), generating four groups: CD-autotransplanted, CD-transplanted, HFGFD-autotransplanted, HFGFD-transplanted. After IM transplantation, the original diet was maintained for 12-14 days until death. HFGFD rats developed obesity, insulin resistance, NASH without fibrosis but with PH, intrahepatic endothelial dysfunction, and IM dysbiosis. In HFGFD rats, transplantation with feces from CD donors caused a significant reduction of PH to levels comparable to CD without significant changes in NASH histology. The reduction in PH was due to a 31% decrease of intrahepatic vascular resistance compared to the HFGFD-autotransplanted group (P < 0.05). This effect occurs through restoration of the sensitivity to insulin of the hepatic protein kinase B-dependent endothelial nitric oxide synthase signaling pathway. The IM exerts a direct influence in the development of PH in rats with diet-induced NASH and dysbiosis; PH, insulin resistance, and endothelial dysfunction revert when a healthy IM is restored. (Hepatology 2018;67:1485-1498). © 2017 by the American Association for the Study of Liver Diseases.

  13. The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

    PubMed Central

    Luccarini, Jean‐Michel; Poekes, Laurence; Faye, Patrick; Kupkowski, Francine; Adarbes, Vanessa; Defrêne, Evelyne; Estivalet, Céline; Gawronski, Xavier; Jantzen, Ingrid; Philippot, Alain; Tessier, Julien; Tuyaa‐Boustugue, Pascale; Oakley, Fiona; Mann, Derek A.; Leclercq, Isabelle; Francque, Sven; Konstantinova, Irena; Broqua, Pierre; Junien, Jean‐Louis

    2017-01-01

    IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists

  14. Hepatic gene expression of Caucasian and African-American patients with obesity-related non-alcoholic fatty liver disease.

    PubMed

    Stepanova, Maria; Hossain, Noreen; Afendy, Arian; Perry, Kellie; Goodman, Zachary D; Baranova, Ancha; Younossi, Zobair

    2010-05-01

    There is increasing data suggesting that African Americans with NAFLD tend to have less progressive liver disease. The aim of this study is to assess differences in the hepatic gene expression of African-American and Caucasian patients with NAFLD who had undergone bariatric surgery. A total of 94 patients (81 NAFLD and 13 weight-matched controls with normal liver biopsy) were included. Of the entire cohort, 73 were Caucasians and 21 were African Americans. All patients were undergoing bariatric surgery. Two liver biopsies were obtained at the time of surgery. One biopsy was snap-frozen for gene expression and the other biopsy was stained for pathologic assessment. Liver biopsy confirmed that 24 patients from our cohort had NASH while 57 had only simple steatosis. Snap-frozen liver biopsy specimens of these patients were then used for the RNA extraction. cDNA probes were hybridized with customized microarray gene chips containing 5,220 relevant genes. Gene expression profiles were compared between groups using significance analysis of microarrays algorithm. In comparison to all Caucasian patients, African-American patients had over-expression of EPB41L1, IGF2, FAH, ACSL4, FUT4, CYP3A (q values < 10(-4)). In comparison to Caucasian NAFLD patients, African-American NAFLD patients showed over-expression of EPB41L1 and ACSL4 genes. Finally, in comparison to Caucasian NASH patients, African-American NASH patients showed over-expression of GSTM 2, GSTM4 and GSTM5 as well as FH and ASCL4 genes. Some genes highlighted by this analysis, particularly cytochrome CYP3A and glutathione transferases GSTM2, 4, 5, were previously implicated in the pathogenesis of NASH. African-American patients with biopsy-proven obesity-related NAFLD and NASH have a specific hepatic gene expression pattern that may explain their differences from Caucasian patients with NAFLD in developing progressive liver disease.

  15. Omega-3 polyunsaturated fatty acids in treating non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled trial.

    PubMed

    Nogueira, Monize Aydar; Oliveira, Claudia Pinto; Ferreira Alves, Venâncio Avancini; Stefano, José Tadeu; Rodrigues, Lívia Samara Dos Reis; Torrinhas, Raquel Susana; Cogliati, Bruno; Barbeiro, Hermes; Carrilho, Flair José; Waitzberg, Dan Linetzky

    2016-06-01

    & aims: Few clinical trials have addressed the potential benefits of omega-3 polyunsaturated fatty acids (PUFAs) on non-alcoholic steatohepatitis (NASH). We evaluated the effects of supplementation with omega-3 PUFAs from flaxseed and fish oils in patients with biopsy-proven NASH. Patients received three capsules daily, each containing 0.315 g of omega-3 PUFAs (64% alpha-linolenic [ALA], 16% eicosapentaenoic [EPA], and 21% docosahexaenoic [DHA] acids; n-3 group, n = 27) or mineral oil (placebo group, n = 23). Liver biopsies were evaluated histopathologically by the NASH activity score (NAS). Plasma levels of omega-3 PUFAs were assessed as a marker of intake at baseline and after 6 months of treatment. Secondary endpoints included changes in plasma biochemical markers of lipid metabolism, inflammation, and liver function at baseline and after 3 and 6 months of treatment. At baseline, NAS was comparable between the groups (p = 0.98). After intervention with omega-3 PUFAs, plasma ALA and EPA levels increased (p ≤ 0.05). However in the placebo group, we also observed increased EPA and DHA (p ≤ 0.05), suggesting an off-protocol intake of PUFAs. NAS improvement/stabilization was correlated with increased ALA in the n-3 group (p = 0.02) and with increased EPA (p = 0.04) and DHA (p = 0.05) in the placebo group. Triglycerides were reduced after 3 months in the n-3 group compared to baseline (p = 0.01). In NASH patients, the supplementation of omega-3 PUFA from flaxseed and fish oils significantly impacts on plasma lipid profile of patients with NASH. Plasma increase of these PUFAs was associated with better liver histology. (ID 01992809). Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  16. Increased Parenchymal Damage and Steatohepatitis in Caucasian Nonalcoholic Fatty Liver Disease Patients with Common IL1B and IL6 Polymorphisms

    PubMed Central

    Nelson, James E.; Handa, Priya; Aouizerat, Bradley; Wilson, Laura; Vemulakonda, L Akhila; Yeh, Matthew M.; Kowdley, Kris V.

    2016-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) is a complex, multifactorial disease affected by diet, lifestyle and genetics. Proinflammatory cytokines like IL-1β and IL-6 have been shown to be elevated in nonalcoholic steatohepatitis (NASH). The goal of this study was to investigate the relationship between IL1B and IL6 gene polymorphisms and histologic features of NAFLD in the NASH CRN cohort. Methods 604 adult (≥18 yrs) non-Hispanic Caucasians with biopsy-proven NAFLD were genotyped for the following SNPs: IL1B, rs16944, rs1143634; IL6, rs1800795, rs10499563. Logistic regression was used to examine the relationship between genotype and a definitive diagnosis and advanced histological features of NASH after controlling for the following variables selected a priori: age, sex, diabetes, obesity and HOMA-IR level. Results The IL6 rs10499563 C allele was independently associated with the presence of definitive NASH, and increased ballooning and Mallory bodies. The IL1B rs1143634 TT genotype was associated with advanced fibrosis and increased Mallory bodies. The IL6 rs1800795 C allele was associated with increased risk for severe steatosis, >66% but also decreased risk for advanced fibrosis and lobular inflammation and Mallory body formation. Conclusions These results suggest that common variants in the IL6 and IL1B genes may increase susceptibility for NASH and confer a higher risk of hepatic parenchymal damage including increased ballooning, increased Mallory bodies, and bridging fibrosis or cirrhosis. In contrast, the IL6 rs1800795 C allele may confer a higher risk for steatosis, but less parenchymal damage. Our findings support the development of therapeutics aimed at IL-1β and IL-6 suppression. PMID:27730688

  17. Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice.

    PubMed

    Legry, Vanessa; Van Rooyen, Derrick M; Lambert, Barbara; Sempoux, Christine; Poekes, Laurence; Español-Suñer, Regina; Molendi-Coste, Olivier; Horsmans, Yves; Farrell, Geoffrey C; Leclercq, Isabelle A

    2014-10-01

    Non-alcoholic fatty liver (steatosis) and steatohepatitis [non-alcoholic steatohepatitis (NASH)] are hepatic complications of the metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin-resistant animals (such as ob/ob mice) with simple steatosis, but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to a high-fat diet (HFD) at several time points. We then evaluated the effect of treatment with an ER stress inducer tunicamycin, or conversely with the ER protectant tauroursodeoxycholic acid (TUDCA), on the metabolic and hepatic features. foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response [phospho-eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α) activity and spliced X-box-binding protein 1 (Xbp1)]. Activation of c-Jun N-terminal kinase (JNK) and up-regulation of activating transcription factor-4 (Atf4) and CCAAT/enhancer-binding protein-homologous protein (Chop) transcripts were however compatible with a 'pathological' response to ER stress. We tested this by using intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, the ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese diabetic mice with steatohepatitis.

  18. Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity

    PubMed Central

    Patterson, Rainey E.; Kalavalapalli, Srilaxmi; Williams, Caroline M.; Nautiyal, Manisha; Mathew, Justin T.; Martinez, Janie; Reinhard, Mary K.; McDougall, Danielle J.; Rocca, James R.; Yost, Richard A.; Cusi, Kenneth; Garrett, Timothy J.

    2016-01-01

    The hepatic tricarboxylic acid (TCA) cycle is central to integrating macronutrient metabolism and is closely coupled to cellular respiration, free radical generation, and inflammation. Oxidative flux through the TCA cycle is induced during hepatic insulin resistance, in mice and humans with simple steatosis, reflecting early compensatory remodeling of mitochondrial energetics. We hypothesized that progressive severity of hepatic insulin resistance and the onset of nonalcoholic steatohepatitis (NASH) would impair oxidative flux through the hepatic TCA cycle. Mice (C57/BL6) were fed a high-trans-fat high-fructose diet (TFD) for 8 wk to induce simple steatosis and NASH by 24 wk. In vivo fasting hepatic mitochondrial fluxes were determined by 13C-nuclear magnetic resonance (NMR)-based isotopomer analysis. Hepatic metabolic intermediates were quantified using mass spectrometry-based targeted metabolomics. Hepatic triglyceride accumulation and insulin resistance preceded alterations in mitochondrial metabolism, since TCA cycle fluxes remained normal during simple steatosis. However, mice with NASH had a twofold induction (P < 0.05) of mitochondrial fluxes (μmol/min) through the TCA cycle (2.6 ± 0.5 vs. 5.4 ± 0.6), anaplerosis (9.1 ± 1.2 vs. 16.9 ± 2.2), and pyruvate cycling (4.9 ± 1.0 vs. 11.1 ± 1.9) compared with their age-matched controls. Induction of the TCA cycle activity during NASH was concurrent with blunted ketogenesis and accumulation of hepatic diacylglycerols (DAGs), ceramides (Cer), and long-chain acylcarnitines, suggesting inefficient oxidation and disposal of excess free fatty acids (FFA). Sustained induction of mitochondrial TCA cycle failed to prevent accretion of “lipotoxic” metabolites in the liver and could hasten inflammation and the metabolic transition to NASH. PMID:26814015

  19. Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis.

    PubMed

    Dattaroy, Diptadip; Pourhoseini, Sahar; Das, Suvarthi; Alhasson, Firas; Seth, Ratanesh Kumar; Nagarkatti, Mitzi; Michelotti, Gregory A; Diehl, Anna Mae; Chatterjee, Saurabh

    2015-02-15

    Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) is the common pathophysiological process resulting from chronic liver inflammation and oxidative stress. Although significant research has been carried out on the role of leptin-induced NADPH oxidase in fibrogenesis, the molecular mechanisms that connect the leptin-NADPH oxidase axis in upregulation of transforming growth factor (TGF)-β signaling have been unclear. We aimed to investigate the role of leptin-mediated upregulation of NADPH oxidase and its subsequent induction of micro-RNA 21 (miR21) in fibrogenesis. Human NASH livers and a high-fat (60% kcal) diet-fed chronic mouse model, where hepatotoxin bromodichloromethane was used to induce NASH, were used for this study. To prove the role of the leptin-NADPH oxidase-miR21 axis, mice deficient in genes for leptin, p47phox, and miR21 were used. Results showed that wild-type mice and human livers with NASH had increased oxidative stress, increased p47phox expression, augmented NF-κB activation, and increased miR21 levels. These mice and human livers showed increased TGF-β, SMAD2/3-SMAD4 colocalizations in the nucleus, increased immunoreactivity against Col1α, and α-SMA with a concomitant decrease in protein levels of SMAD7. Mice that were deficient in leptin or p47phox had decreased activated NF-κB and miR21 levels, suggesting the role of leptin and NADPH oxidase in inducing NF-κB-mediated miR21 expression. Further miR21 knockout mice had decreased colocalization events of SMAD2/3-SMAD4 in the nucleus, increased SMAD7 levels, and decreased fibrogenesis. Taken together, the studies show the novel role of leptin-NADPH oxidase induction of miR21 as a key regulator of TGF-β signaling and fibrogenesis in experimental and human NASH. Copyright © 2015 the American Physiological Society.

  20. Deficient copper concentrations in dried-defatted hepatic tissue from ob/ob mice: A potential model for study of defective copper regulation in metabolic liver disease.

    PubMed

    Church, Stephanie J; Begley, Paul; Kureishy, Nina; McHarg, Selina; Bishop, Paul N; Bechtold, David A; Unwin, Richard D; Cooper, Garth J S

    2015-05-08

    Ob/ob mice provide an animal model for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) in patients with obesity and type-2 diabetes. Low liver copper has been linked to hepatic lipid build-up (steatosis) in animals with systemic copper deficiency caused by low-copper diets. However, hepatic copper status in patients with NAFLD or NASH is uncertain, and a validated animal model useful for the study of hepatic copper regulation in common forms of metabolic liver disease is lacking. Here, we report parallel measurements of essential metal levels in whole-liver tissue and defatted-dried liver tissue from ob/ob and non-obese control mice. Measurements in whole-liver tissue from ob/ob mice at an age when they have developed NAFLD/NASH, provide compelling evidence for factitious lowering of copper and all other essential metals by steatosis, and so cannot be used to study hepatic metal regulation in this model. By marked contrast, metal measurements in defatted-dried liver samples reveal that most essential metals were actually normal and indicate specific lowering of copper in ob/ob mice, consistent with hepatic copper deficiency. Thus ob/ob mice can provide a model useful for the study of copper regulation in NAFLD and NASH, provided levels are measured in defatted-dried liver tissue. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Bile acid receptors link nutrient sensing to metabolic regulation

    PubMed Central

    Li, Jibiao; Li, Tiangang

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common liver disease in Western populations. Non-alcoholic steatohepatitis (NASH) is a more debilitating form of NAFLD characterized by hepatocellular injury and inflammation, which significantly increase the risk of end-stage liver and cardiovascular diseases. Unfortunately, there are no available drug therapies for NASH. Bile acids are physiological detergent molecules that are synthesized from cholesterol exclusively in the hepatocytes. Bile acids circulate between the liver and intestine, where they are required for cholesterol solubilization in the bile and dietary fat emulsification in the gut. Bile acids also act as signaling molecules that regulate metabolic homeostasis and inflammatory processes. Many of these effects are mediated by the bile acid-activated nuclear receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. Nutrient signaling regulates hepatic bile acid synthesis and circulating plasma bile acid concentrations, which in turn control metabolic homeostasis. The FXR agonist obeticholic acid has had beneficial effects on NASH in recent clinical trials. Preclinical studies have suggested that the TGR5 agonist and the FXR/TGR5 dual agonist are also potential therapies for metabolic liver diseases. Extensive studies in the past few decades have significantly improved our understanding of the metabolic regulatory function of bile acids, which has provided the molecular basis for developing promising bile acid-based therapeutic agents for NASH treatment. PMID:29098111

  2. Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis.

    PubMed

    Van Rooyen, Derrick M; Larter, Claire Z; Haigh, W Geoffrey; Yeh, Matthew M; Ioannou, George; Kuver, Rahul; Lee, Sum P; Teoh, Narci C; Farrell, Geoffrey C

    2011-10-01

    Type 2 diabetes and nonalcoholic steatohepatitis (NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to the pathogenesis of NASH. Alms1 mutant (foz/foz) and wild-type NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. Hepatic cholesterol accumulation was attributed to up-regulation of low-density lipoprotein receptor via activation of sterol regulatory element binding protein 2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and low-density lipoprotein receptor and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol levels exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis to NASH. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  3. Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice.

    PubMed

    Haczeyni, Fahrettin; Poekes, Laurence; Wang, Hans; Mridha, Auvro R; Barn, Vanessa; Geoffrey Haigh, W; Ioannou, George N; Yeh, Matthew M; Leclercq, Isabelle A; Teoh, Narcissus C; Farrell, Geoffrey C

    2017-01-01

    Nonalcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients but for unknown reasons does not resolve NASH pathology. This study therefore investigated OCA effects in Wt mice, which develop obesity with atherogenic dietary feeding, and appetite-dysregulated, Alms1 mutant foz/foz mice fed the same diet, which develop metabolic obesity and diabetes. OCA (1 mg/kg) was administered orally to female foz/foz mice and Wt littermates from weaning until 28 weeks. Adipose indices, glucose tolerance, and fatty liver pathology were studied. Experiments were repeated with OCA 10 mg/kg. OCA reduced body weight and hepatic lipids and improved glucose disposal only in Wt mice. OCA limited Wt adipose expansion, altered morphometry in favor of small adipocytes, enhanced expression of genes indicating adipose browning, and reduced crown-like structure number in visceral adipose tissue. foz/foz mice showed more crown-like structures in all compartments; OCA failed to alter adipose morphometry, browning, inflammation, or improve NASH severity, even at 10 mg/kg. OCA improved adipose indices, glucose tolerance, and steatosis in a milder metabolic phenotype but failed to improve these factors in morbidly obese diabetic mice. These results help explain OCA's limited efficacy to reverse human NASH. © 2016 The Obesity Society.

  4. Hepatic Free Cholesterol Accumulates in Obese, Diabetic Mice and Causes Non-Alcoholic Steatohepatitis

    PubMed Central

    Van Rooyen, Derrick M; Larter, Claire Z; Haigh, W Geoffrey; Yeh, Matthew M; Ioannou, George; Kuver, Rahul; Lee, Sum P; Teoh, Narci C; Farrell, Geoffrey C

    2011-01-01

    Background & Aims Type-2 diabetes and non-alcoholic steatohepatitis (NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to pathogenesis of NASH. Methods Alms1 mutant (foz/foz) and wild-type (WT) NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. Results Hepatic cholesterol accumulation was attributed to up-regulation of low density lipoprotein receptor (LDLR) via activation of sterol regulatory element binding protein-2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and LDLR and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. Conclusions In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis to NASH. PMID:21703998

  5. Nonalcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis in Childhood: Endocrine-Metabolic “Mal-Programming”

    PubMed Central

    Manti, Sara; Romano, Claudio; Chirico, Valeria; Filippelli, Martina; Cuppari, Caterina; Loddo, Italia; Salpietro, Carmelo; Arrigo, Teresa

    2014-01-01

    Context: Nonalcoholic Fatty Liver Disease (NAFLD) is the major chronic liver disease in the pediatric population. NAFLD includes a broad spectrum of abnormalities (inflammation, fibrosis and cirrhosis), ranging from accumulation of fat (also known as steatosis) towards non-alcoholic steatohepatitis (NASH). The development of NAFLD in children is significantly increased. Evidence Acquisition: A literature search of electronic databases was undertaken for the major studies published from 1998 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the key words: "non-alcoholic fatty liver disease, children, non-alcoholic steatohepatitis and fatty liver". Results: NAFLD/NASH is probably promoted by “multiple parallel hits”: environmental and genetic factors, systemic immunological disorders (oxidative stress, persistent-low grade of inflammation) as well as obesity and metabolic alterations (insulin resistance and metabolic syndrome). However its exact cause still underdiagnosed and unknown. Conclusions: Pediatric NAFLD/NASH is emerging problem. Longitudinal follow-up studies, unfortunately still insufficient, are needed to better understand the natural history and outcome of NAFLD in children. This review focuses on the current knowledge regarding the epidemiology, pathogenesis, environmental, genetic and metabolic factors of disease. The review also highlights the importance of studying the underlying mechanisms of pediatric NAFLD and the need for complete and personalized approach in the management of NAFLD/NASH. PMID:24829591

  6. [Non-alcoholic fatty liver: 10 years' experience at the Insituto Nacional de la Nutrición Salvador Zubirán].

    PubMed

    de la Mora, G; Olivera, M; de la Cerda, R; Arista, J; Kershenobich, D; Uribe, M

    1994-01-01

    To describe the characteristics of non-alcoholic steatohepatitis (NASH) at the Instituto Nacional de la Nutricion Salvador Zubiran. We reviewed all liver biopsy reports from January 1982 to December 1991. From patient records we obtained the following data: clinical, biochemical, imaging studies and we reviewed the histological material. We correlated clinical, biochemical and histological data. From 2963 biopsies reviewed we obtained 16 cases of NASH. We found a 7:1 female/male ratio. Median age was 30 years and six patients were obese. Eleven patients had concomitant disease (diabetes in seven) and nine were using drugs. All had been studied for biochemical abnormalities and were asymptomatic. Ten patients had hepatomegaly and six splenomegaly. Ultrasound suggested the diagnosis in 50% of the cases. All had steatosis, inflammatory infiltrate, necrosis, fibrosis and Mallory bodies at different stages. One case had cirrhosis on initial biopsy and two developed cirrhosis on follow-up (one and eight years later). We did not find any correlation between clinical, biochemical or imaging characteristics and histological findings. When we compared these findings between obese and non obese patients and primary and secondary NASH we did not find any differences between groups. NASH is infrequent in our institution. The underlying pathogenesis seems to be multifactorial. There is no biochemical-histological correlation. Cirrhosis can develop in some cases.

  7. Bee's honey attenuates non-alcoholic steatohepatitis-induced hepatic injury through the regulation of thioredoxin-interacting protein-NLRP3 inflammasome pathway.

    PubMed

    Xiao, Jia; Liu, Yingxia; Xing, Feiyue; Leung, Tung Ming; Liong, Emily C; Tipoe, George L

    2016-06-01

    We aim to examine whether honey ameliorates hepatic injury in non-alcoholic steatohepatitis (NASH) animal and cell line steatosis models. NASH was induced in female Sprague-Dawley rat by 8-week feeding with a high-fat diet. During the experiment, 5 g/kg honey was intragastrically fed daily. Rat normal hepatocyte BRL-3A cell was treated with sodium palmitate (SP) to induce steatosis in the absence or presence of honey pre-treatment or specific siRNA/overexpress plasmid of thioredoxin-interacting protein (TXNIP) or antagonist/agonist of Nod-like receptor protein 3 (NLRP3). Honey significantly improved the high-fat-diet-induced hepatic injury, steatosis, fibrosis, oxidative stress, and inflammation in rats. Honey also inhibited the overexpression of TXNIP and the activation of NLRP3 inflammasome. These effects were replicated in BRL-3A cell line which showed that the down-regulation of TXNIP or inhibition of NLRP3 contributed to the suppression of NLRP3 inflammasome activation, inflammation, and re-balanced lipid metabolism. In contrast, overexpression of TXNIP or agonism of NLRP3 exacerbated the cellular damage induced by SP. Suppression of the TXNIP-NLRP3 inflammasome pathway may partly contribute to the amelioration of hepatic injury during the progression of NASH by honey. Targeting hepatic TXNIP-NLRP3 inflammasome pathway is a potential therapeutic way for the prevention and treatment of NASH.

  8. Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability.

    PubMed

    Clarke, John D; Cherrington, Nathan J

    2015-07-01

    There are numerous factors in individual variability that make the development and implementation of precision medicine a challenge in the clinic. One of the main goals of precision medicine is to identify the correct dose for each individual in order to maximize therapeutic effect and minimize the occurrence of adverse drug reactions. Many promising advances have been made in identifying and understanding how factors such as genetic polymorphisms can influence drug pharmacokinetics (PK) and contribute to variable drug response (VDR), but it is clear that there remain many unidentified variables. Underlying liver diseases such as nonalcoholic steatohepatitis (NASH) alter absorption, distribution, metabolism, and excretion (ADME) processes and must be considered in the implementation of precision medicine. There is still a profound need for clinical investigation into how NASH-associated changes in ADME mediators, such as metabolism enzymes and transporters, affect the pharmacokinetics of individual drugs known to rely on these pathways for elimination. This review summarizes the key PK factors in individual variability and VDR and highlights NASH as an essential underlying factor that must be considered as the development of precision medicine advances. A multifactorial approach to precision medicine that considers the combination of two or more risk factors (e.g. genetics and NASH) will be required in our effort to provide a new era of benefit for patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. On a numerical solving of random generated hexamatrix games

    NASA Astrophysics Data System (ADS)

    Orlov, Andrei; Strekalovskiy, Alexander

    2016-10-01

    In this paper, we develop a global search method for finding a Nash equilibrium in a hexamatrix game (polymatrix game of three players). The method, on the one hand, is based on the equivalence theorem of the problem of finding a Nash equilibrium in the game and a special mathematical optimization problem, and, on the other hand, on the usage of Global Search Theory for solving the latter problem. The efficiency of this approach is demonstrated by the results of computational testing.

  10. Quantum prisoners' dilemma under enhanced interrogation

    NASA Astrophysics Data System (ADS)

    Siopsis, George; Balu, Radhakrishnan; Solmeyer, Neal

    2018-06-01

    In the quantum version of prisoners' dilemma, each prisoner is equipped with a single qubit that the interrogator can entangle. We enlarge the available Hilbert space by introducing a third qubit that the interrogator can entangle with the other two. We discuss an enhanced interrogation technique based on tripartite entanglement and analyze Nash equilibria. We show that for tripartite entanglement approaching a W-state, we calculate the Nash equilibria numerically and show that they coincide with the Pareto-optimal choice where both prisoners cooperate. Upon continuous variation between a W-state and a pure bipartite entangled state, the game is shown to have a surprisingly rich structure. The role of bipartite and tripartite entanglement is explored to explain that structure. As an application, we consider an evolutionary game based on our quantum game with a network of agents on a square lattice with periodic boundary conditions and show that the strategy corresponding to Nash equilibrium completely dominates without placing any restrictions on the initial set of strategies.

  11. Purified anthocyanins from bilberry and black currant attenuate hepatic mitochondrial dysfunction and steatohepatitis in mice with methionine and choline deficiency.

    PubMed

    Tang, Xilan; Shen, Tianran; Jiang, Xinwei; Xia, Min; Sun, Xujia; Guo, Honghui; Ling, Wenhua

    2015-01-21

    The berries of bilberry and black currant are a rich source of anthocyanins, which are thought to have favorable effects on nonalcoholic steatohepatitis (NASH). This study was designed to examine whether purified anthocyanins from bilberry and black currant are able to limit the disorders related to NASH induced by a methionine-choline-deficient (MCD) diet in mice. The results showed that treatment with anthocyanins not only alleviated inflammation, oxidative stress, steatosis, and even fibrosis but also improved depletion of mitochondrial content and damage of mitochondrial biogenesis and electron transfer chain developed concomitantly in the liver of mice fed the MCD diet. Furthermore, anthocyanins treatment promoted activation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α). These data provide evidence that anthocyanins possess significant protective effects against NASH and mitochondrial defects in response to a MCD diet, with a mechanism maybe through affecting the AMPK/PGC-1α signaling pathways.

  12. Optimal vaccination strategies and rational behaviour in seasonal epidemics.

    PubMed

    Doutor, Paulo; Rodrigues, Paula; Soares, Maria do Céu; Chalub, Fabio A C C

    2016-12-01

    We consider a SIRS model with time dependent transmission rate. We assume time dependent vaccination which confers the same immunity as natural infection. We study two types of vaccination strategies: (i) optimal vaccination, in the sense that it minimizes the effort of vaccination in the set of vaccination strategies for which, for any sufficiently small perturbation of the disease free state, the number of infectious individuals is monotonically decreasing; (ii) Nash-equilibria strategies where all individuals simultaneously minimize the joint risk of vaccination versus the risk of the disease. The former case corresponds to an optimal solution for mandatory vaccinations, while the second corresponds to the equilibrium to be expected if vaccination is fully voluntary. We are able to show the existence of both optimal and Nash strategies in a general setting. In general, these strategies will not be functions but Radon measures. For specific forms of the transmission rate, we provide explicit formulas for the optimal and the Nash vaccination strategies.

  13. The Role of Intestinal Bacteria Overgrowth in Obesity-Related Nonalcoholic Fatty Liver Disease

    PubMed Central

    Ferolla, Silvia M.; Armiliato, Geyza N. A.; Couto, Cláudia A.; Ferrari, Teresa C. A.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. It is a progressive disorder involving a spectrum of conditions that include pure steatosis without inflammation, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. The key factor in the pathophysiology of NAFLD is insulin resistance that determines lipid accumulation in the hepatocytes, which may be followed by lipid peroxidation, production of reactive oxygen species and consequent inflammation. Recent studies suggest that the characteristics of the gut microbiota are altered in NAFLD, and also, that small intestinal bacterial overgrowth (SIBO) contributes to the pathogenesis of this condition. This review presents the chief findings from all the controlled studies that evaluated SIBO, gut permeability and endotoxemia in human NAFLD. We also discuss the possible mechanisms involving SIBO, lipid accumulation and development of NASH. The understanding of these mechanisms may allow the development of new targets for NASH treatment in the future. PMID:25479248

  14. Non invasive evaluation of liver fibrosis in paediatric patients with nonalcoholic steatohepatitis

    PubMed Central

    Iacobellis, Angelo; Marcellini, Matilde; Andriulli, Angelo; Perri, Francesco; Leandro, Gioacchino; Devito, Rita; Nobili, Valerio

    2006-01-01

    AIM: To identify the independent predictors of hepatic fibrosis in 69 children with nonalcoholic steatohepatitis (NASH) due to nonalcoholic fatty liver disease (NAFLD). METHODS: All patients with clinically suspected NASH underwent liver biopsy as a confirmatory test. The following clinical and biochemical variables at baseline were examined as likely predictors of fibrosis at histology: age, body mass index (BMI), systolic blood pressure (SBP), dyastolic blood pressure (DBP), fasting glucose, fasting insulin, homeostatic model assessment for insulin resistence (HOMA-IR), cholesterol, tryglicerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, gamma glutamil transferase (GT), platelet count, prothrombin time (PT). RESULTS: At histology 28 (40.6%) patients had no fibrosis and 41 (59.4%) had mild to bridging fibrosis. At multivariate analysis, BMI > 26.3 was the only independent predictor of fibrosis (OR = 5.85, 95% CI = 1.6-21). CONCLUSION: BMI helps identify children with NASH who might have fibrotic deposition in the liver. PMID:17203527

  15. How Do Doctors Treat NAFLD and NASH?

    MedlinePlus

    ... Process Research Training & Career Development Funded Grants & Grant History Research Resources Research at NIDDK Technology Advancement & Transfer Meetings & Workshops Health Information Diabetes Digestive ...

  16. Nonalcoholic Fatty Liver Disease Is Exacerbated in High-Fat Diet-Fed Gnotobiotic Mice by Colonization with the Gut Microbiota from Patients with Nonalcoholic Steatohepatitis

    PubMed Central

    Chiu, Chien-Chao; Ching, Yung-Hao; Li, Yen-Peng; Liu, Ju-Yun; Huang, Yen-Te; Huang, Yi-Wen; Yang, Sien-Sing; Huang, Wen-Ching

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a serious liver disorder associated with the accumulation of fat and inflammation. The objective of this study was to determine the gut microbiota composition that might influence the progression of NAFLD. Germ-free mice were inoculated with feces from patients with nonalcoholic steatohepatitis (NASH) or from healthy persons (HL) and then fed a standard diet (STD) or high-fat diet (HFD). We found that the epididymal fat weight, hepatic steatosis, multifocal necrosis, and inflammatory cell infiltration significantly increased in the NASH-HFD group. These findings were consistent with markedly elevated serum levels of alanine transaminase, aspartate transaminase, endotoxin, interleukin 6 (IL-6), monocyte chemotactic protein 1 (Mcp1), and hepatic triglycerides. In addition, the mRNA expression levels of Toll-like receptor 2 (Tlr2), Toll-like receptor 4 (Tlr4), tumor necrosis factor alpha (Tnf-α), Mcp1, and peroxisome proliferator-activated receptor gamma (Ppar-γ) significantly increased. Only abundant lipid accumulation and a few inflammatory reactions were observed in group HL-HFD. Relative abundance of Bacteroidetes and Firmicutes shifted in the HFD-fed mice. Furthermore, the relative abundance of Streptococcaceae was the highest in group NASH-HFD. Nevertheless, obesity-related Lactobacillaceae were significantly upregulated in HL-HFD mice. Our results revealed that the gut microbiota from NASH Patients aggravated hepatic steatosis and inflammation. These findings might partially explain the NAFLD progress distinctly was related to different compositions of gut microbiota. PMID:29113135

  17. HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis.

    PubMed

    Nelson, James E; Bhattacharya, Renuka; Lindor, Keith D; Chalasani, Naga; Raaka, Stuart; Heathcote, E Jenny; Miskovsky, Emil; Shaffer, Eldon; Rulyak, Stephen J; Kowdley, Kris V

    2007-09-01

    Previous studies examining the relationship between HFE mutations and severity of nonalcoholic steatohepatitis (NASH) have been limited by small sample size or ascertainment bias. The aim of this study was to examine the relationship between HFE mutations and histological severity in a large North American multicenter cohort with NASH. Data from 126 NASH patients were collected from 6 North American centers. Liver biopsy and genotyping for the C282Y and H63D HFE mutations were performed in all subjects. Serum transferrin-iron saturation and ferritin levels as well as hepatic iron content were recorded whenever available. Univariate and multivariate logistic regression analyses were performed to identify factors associated with advanced hepatic fibrosis. The prevalence of heterozygous C282Y and H63D HFE mutations was 14.3% and 21.4%, respectively, in the overall cohort. Among Caucasians, C282Y heterozygotes were more likely to have bridging fibrosis or cirrhosis (44% versus 21% [P = 0.05]) and stainable hepatic iron (50% versus 16% [P = 0.011]) compared with patients with other genotypes. Diabetes mellitus was the only independent predictor of advanced hepatic fibrosis (OR 4.37, 95% CI 1.41-13.54 [P = 0.010]) using multiple logistic regression analysis adjusting for age, sex, ethnicity, body mass index, and HFE genotype status. The HFE C282Y heterozygous mutation is associated with advanced fibrosis among Caucasians with NASH. Additional studies are warranted to examine the possible mechanisms for this relationship.

  18. The Expression of PNPLA3 Polymorphism could be the Key for Severe Liver Disease in NAFLD in Hispanic Population.

    PubMed

    Martínez, Leonardo A; Larrieta, Elena; Kershenobich, David; Torre, Aldo

    Nonalcoholic fatty liver disease (NAFLD) encompasses: fatty liver (SS), steatohepatitis (NASH) with or without fibrosis and cirrhosis. Patatine-like phosphatas in domain 3 (PNPLA3; adiponutrin; SNP rs738409 C/G, M148I) shows anabolic and catabolic activities on lipid metabolism and significant association to fatty liver content; however, I148M demographics and ethnics, as its role with NAFLD have not been fully elucidated. PNPLA3 genotyping from peripheral blood DNA by polymerase chain reaction (PCR) and direct sequencing, 211 patients diagnosed with NAFLD including SS, NASH and fibrosis spectrum. Eighty nine per cent showed the G risk allele [CC: 23 (10.5%), GC: 73 (34.7%), GG 115 (54.7%)], the allele frequency was 77%, NASH (71%), SS (80%) and fibrosis (73%). GG genotype carriers showed 3.8 times (CI 95%: 3.03 - 4.79) of increased risk of steatohepatitis and 2.3 times more (CI 95%: 1.77 ~ 3.23) risk of having liver fibrosis (CC). PNPLA3 (GC, GG) conditioned higher probability of low levels of HDL cholesterol (p < 0.010), SS even in normal weight (p < 0.007), insulin resistance by HOMA (p < 0.029), NAFLD fibrosis score showed > 0.675 (p < 0.001) and altered serum alanine aminotransferase (p < 0.05). PNPLA3 expression in Hispanics could be decisive in NAFLD pathogenesis, it's highly prevalent and it's a key to condition and determine the spectrum associated, SS, NASH and fibrosis.

  19. Analysis of global and absorption, distribution, metabolism, and elimination gene expression in the progressive stages of human nonalcoholic fatty liver disease.

    PubMed

    Lake, April D; Novak, Petr; Fisher, Craig D; Jackson, Jonathan P; Hardwick, Rhiannon N; Billheimer, D Dean; Klimecki, Walter T; Cherrington, Nathan J

    2011-10-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to nonalcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of human NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism, and elimination (ADME) of drugs. Differential gene expression between three clinically defined pathological groups-normal, steatosis, and NASH-was analyzed. Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChip Human 1.0ST arrays. A total of 11,633 genes exhibited altered expression out of 33,252 genes at a 5% false discovery rate. Most gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis revealed that hepatic disease status was the major determinant of differential ADME gene expression rather than age or sex of sample donors. Among the 515 drug transporters and 258 drug-metabolizing enzymes (DMEs) examined, uptake transporters but not efflux transporters or DMEs were significantly over-represented in the number of genes down-regulated. These results suggest that uptake transporter genes are coordinately targeted for down-regulation at the global level during the pathological development of NASH and that these patients may have decreased drug uptake capacity. This coordinated regulation of uptake transporter genes is indicative of a hepatoprotective mechanism acting to prevent accumulation of toxic intermediates in disease-compromised hepatocytes.

  20. Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science.

    PubMed

    Siddiqui, Mohammad Shadab; Harrison, Stephen A; Abdelmalek, Manal F; Anstee, Quentin M; Bedossa, Pierre; Castera, Laurent; Dimick-Santos, Lara; Friedman, Scott L; Greene, Katherine; Kleiner, David E; Megnien, Sophie; Neuschwander-Tetri, Brent A; Ratziu, Vlad; Schabel, Elmer; Miller, Veronica; Sanyal, Arun J

    2018-05-01

    Nonalcoholic steatohepatitis (NASH) is an important cause of liver-related morbidity and mortality. There are no approved therapies, and the results of clinical trials have been difficult to compare due to inconsistent definitions of relevant disease parameters in patients with NASH. The natural course of the disease has not been rigorously characterized, particularly with respect to the contributions of underlying obesity, type 2 diabetes, and other comorbidities and the treatments provided for these comorbidities. Efforts to perform analyses of pooled data are limited by heterogeneous case definitions used across studies to define disease states. There remains a major unmet need in the field to develop standardized definitions for populations for interventional trials. Such definitions are expected to impact how endpoints for clinical trials are constructed. The Liver Forum is a multistakeholder effort including US and European regulatory agencies, academic investigators, professional and patient representative organizations, and industry to catalyze therapeutic development for NASH by developing potential solutions to barriers to development. The Case Definitions Working Group was established by The Liver Forum to evaluate the validity of case definitions for populations to be included in clinical trials for NASH from a regulatory science perspective. Based on such analyses, specific recommendations are provided noting the strengths and weaknesses of the case definitions along with knowledge gaps that require additional study. (Hepatology 2018;67:2001-2012). © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.

  1. Sarcopenia in hiding: The risk and consequence of underestimating muscle dysfunction in nonalcoholic steatohepatitis.

    PubMed

    Bhanji, Rahima A; Narayanan, Praveena; Allen, Alina M; Malhi, Harmeet; Watt, Kymberly D

    2017-12-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Up to one third of individuals with NAFLD will develop nonalcoholic steatohepatitis (NASH), which is associated with progression to cirrhosis and is rapidly becoming the leading indication for liver transplantation. Sarcopenia is defined as a progressive and generalized loss of skeletal muscle mass, strength, and function. It is observed in up to 60% of patients with end-stage liver disease and portends a poor prognosis. Recent studies have shown that sarcopenia is a novel risk factor for developing NAFLD. Pathophysiological mechanisms relating sarcopenia and NASH may include insulin resistance (IR) and increased inflammation. IR leads to accumulation of triglycerides in both muscle tissue and the liver. It also exacerbates proteolysis and leads to muscle depletion. Chronic inflammation leads to liver injury and progression of fibrosis. The inflammatory milieu also stimulates protein catabolism. Viewing skeletal muscle as an endocrine organ that secretes various salutary myokines may help us understand its role in the development of steatosis. A better understanding of the pathophysiology will aid in developing physical and pharmacological therapeutic interventions. In this review, we will explore the complex inter-relationships between sarcopenia and NASH. We will discuss the impact of sarcopenia in patients with NASH and therapeutic options for the management of sarcopenia. (Hepatology 2017;66:2055-2065). © 2017 by the American Association for the Study of Liver Diseases.

  2. Prevalence of cirrhosis in patients with thrombocytopenia who receive bone marrow biopsy.

    PubMed

    Sheikh, Muhammad Y; Raoufi, Rahim; Atla, Pradeep R; Riaz, Muhammad; Oberer, Chad; Moffett, Michael J

    2012-01-01

    Thrombocytopenia is a common finding in patients with cirrhosis and may lead to unnecessary referral for bone marrow (BM) biopsy. To date, the prevalence of cirrhosis in patients with thrombocytopenia who receive BM biopsy is largely unknown. Between fiscal years 2006-2010, 744 patients (≥18 years) who underwent BM biopsies for thrombocytopenia at our hospital were identified retrospectively. 541 patients were excluded who had hematologic malignancies and received chemotherapy. Remaining 203 patients with predominant isolated thrombocytopenia were included in the study. Of 203 patients, 136 (67%) had a normal and 67 (33%) had an abnormal BM examination. Prevalence of cirrhosis in the study population was 35% (95% CI: 28.4-41.9). 51% patients with normal BM were found to have cirrhosis compared to 3% of patients with abnormal BM exam (P < 0.0001). Common causes of cirrhosis were nonalcoholic steatohepatitis (NASH) (47%), followed by alcohol and Hepatitis C virus infection. Idiopathic thrombocytopenia and myelodysplastic syndrome were most frequent causes of thrombocytopenia in patients without cirrhosis. Patients with NASH had higher body mass index (BMI) (33.4 vs. 25.8, P < 0.001) and lower MELD scores (11.1 vs. 16, P = 0.028) when compared to non-NASH patients with cirrhosis. Approximately, one third (35%) of patients with cirrhosis induced thrombocytopenia may undergo unwarranted BM biopsies. Clinical diagnosis of cirrhosis is still a challenge for many physicians, particularly with underlying NASH. We propose cirrhosis to be the prime cause of isolated thrombocytopenia.

  3. Quantum Prisoners' Dilemma in Fluctuating Massless Scalar Field

    NASA Astrophysics Data System (ADS)

    Huang, Zhiming

    2017-12-01

    Quantum systems are easily affected by external environment. In this paper, we investigate the influences of external massless scalar field to quantum Prisoners' Dilemma (QPD) game. We firstly derive the master equation that describes the system evolution with initial maximally entangled state. Then, we discuss the effects of a fluctuating massless scalar field on the game's properties such as payoff, Nash equilibrium, and symmetry. We find that for different game strategies, vacuum fluctuation has different effects on payoff. Nash equilibrium is broken but the symmetry of the game is not violated.

  4. Nonconvergence to Saddle Boundary Points under Perturbed Reinforcement Learning

    DTIC Science & Technology

    2012-12-07

    of the ODE (12). Note that for some games not all stationary points of the ODE (12) are Nash equilibria. For example, if you consider the Typewriter ...B A 4, 4 2, 2 B 2, 2 3, 3 Table 1: The Typewriter Game. On the other hand, any stationary point in the interior of the probability simplex will... Typewriter Game of Table 1. We observe that it is possible for the process to converge to a pure strategy profile which is not a Nash equilibrium when Ri(α

  5. Social dilemmas in multistrategy evolutionary potential games

    NASA Astrophysics Data System (ADS)

    Szabó, György; Bunth, Gergely

    2018-01-01

    The nature of social dilemmas is studied in n -strategy evolutionary potential games on a square lattice with nearest-neighbor interactions and the logit rule. For symmetric games with symmetric payoff matrices there are no dilemmas because of the coincidence of individual and common interests. The dilemmas are caused by the antisymmetric parts of the self- and cross-dependent payoff components if it modifies the preferred Nash equilibrium. The contentment of players and the emergence of dilemmas in the preferred Nash equilibria are illustrated on some two-dimensional cross sections of the parameter space.

  6. NOGAPS-ALPHA Simulations of the 2002 Southern Hemisphere Stratospheric Major Warming

    DTIC Science & Technology

    2006-01-01

    2003; We- ber et al. 2003; Harnik et al. 2005; Newman and Nash 2005; Scaife et al. 2005). The source of this wave energy flux may be related to...contributions from waves 1, 2, and 3 (Newman and Nash 2005; Krüger et al. 2005; Harnik et al. 2005). As shown by Allen et al. (2003), this heat flux was...superposition of eastward-propagating wave 2 and sta- tionary wave 1 was shown by Harnik et al. (2005) to play a key role in the forcing of this

  7. Analysis of the dynamics of multi-team Bertrand game with heterogeneous players

    NASA Astrophysics Data System (ADS)

    Ding, Zhanwen; Hang, Qinglan; Yang, Honglin

    2011-06-01

    In this article, we study the dynamics of a two-team Bertrand game with players having heterogeneous expectations. We study the equilibrium solutions and the conditions of their locally asymptotic stability. Numerical simulations are used to illustrate the complex behaviours of the proposed model of the Bertrand game. We demonstrate that some parameters of the model have great influence on the stability of Nash equilibrium and on the speed of convergence to Nash equilibrium. The chaotic behaviour of the model has been controlled by using feedback control method.

  8. Nonalcoholic fatty liver disease and hepatic cirrhosis: Comparison with viral hepatitis-associated steatosis.

    PubMed

    Haga, Yuki; Kanda, Tatsuo; Sasaki, Reina; Nakamura, Masato; Nakamoto, Shingo; Yokosuka, Osamu

    2015-12-14

    Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus (HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity, type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review, the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed.

  9. Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease.

    PubMed

    Koo, Bo Kyung; Joo, Sae Kyung; Kim, Donghee; Bae, Jeong Mo; Park, Jeong Hwan; Kim, Jung Ho; Kim, Won

    2017-11-29

    We investigated the effects of PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7-TMC4 rs641738 variants on metabolic phenotypes and their combined effects on the histological severity of non-alcoholic fatty liver disease (NAFLD). We genotyped rs738409, rs58542926, and rs641738 in biopsy-proven NAFLD patients (n = 416) and healthy controls (n = 109). Homeostasis model assessment of insulin resistance and adipose tissue insulin resistance were calculated. The rs738409 and rs58542926 variants, but not rs641738, were associated not only with non-alcoholic steatohepatitis (NASH) (odds ratio [OR], 2.00; 95% confidence interval [CI], 1.46-2.73 and OR, 1.91; 95% CI, 1.04-3.51) but also with significant fibrosis (≥ F2) (OR, 1.53; 95% CI, 1.11-2.11 and OR, 1.88; 95% CI, 1.02-3.46) in NAFLD, even after adjustment for metabolic risk factors. Of both variants, only rs738409 was associated with homeostasis model assessment of insulin resistance and adipose tissue insulin resistance even in healthy controls (P = 0.046 and 0.002, respectively) as well as in the entire study cohort (P = 0.016 and 0.048, respectively). PNPLA3 and TM6SF2 risk variants additively increased the risk of NASH and significant fibrosis (OR per risk allele, 2.03; 95% CI, 1.50-2.73 and 1.61; 95% CI, 1.19-2.17). Even in subjects with low insulin resistance, the risk of NASH or significant fibrosis increased as the number of risk alleles increased (P = 0.008 and 0.020, respectively). PNPLA3 and TM6SF2 determine the risk of NASH and significant fibrosis, even after adjustment for insulin resistance, and exert an additive effect on NASH and significant fibrosis. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  10. A Metabolomic Analysis of Omega-3 Fatty Acid-Mediated Attenuation of Western Diet-Induced Nonalcoholic Steatohepatitis in LDLR -/- Mice

    PubMed Central

    Depner, Christopher M.; Traber, Maret G.; Bobe, Gerd; Kensicki, Elizabeth; Bohren, Kurt M.; Milne, Ginger; Jump, Donald B.

    2013-01-01

    Background Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR-/- mice. Methods Using livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism. Results Livers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoyl-sphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress. Conclusion DHA regulation of

  11. Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible?

    PubMed Central

    Lytle, Kelli A.; Jump, Donald B.

    2016-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative. Methods We evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice. Results Mice fed WD for 22–24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7–8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 ≥ 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (PUFA) content. Conclusion These studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD

  12. Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease.

    PubMed

    Tang, Y; Bian, Z; Zhao, L; Liu, Y; Liang, S; Wang, Q; Han, X; Peng, Y; Chen, X; Shen, L; Qiu, D; Li, Z; Ma, X

    2011-11-01

    Mechanisms associated with the progression of simple steatosis to non-alcoholic fatty liver disease (NAFLD) remain undefined. Regulatory T cells (T(regs)) play a critical role in regulating inflammatory processes in non-alcoholic steatohepatitis (NASH) and because T helper type 17 (Th17) functionally oppose T(reg)-mediated responses, this study focused on characterizing the role of Th17 cells using a NAFLD mouse model. C57BL/6 mice were fed either a normal diet (ND) or high fat (HF) diet for 8 weeks. Mice in the HF group had a significantly higher frequency of liver Th17 cells compared to ND-fed mice. Neutralization of interleukin (IL)-17 in HF mice ameliorated lipopolysaccharide (LPS)-induced liver injury reflected by decreased serum alanine aminotransferase (ALT) levels and reduced inflammatory cell infiltrates in the liver. In vitro, HepG2 cells cultured in the presence of free fatty acids (FFA; oleic acid and palmitic acid) for 24 h and IL-17 developed steatosis via insulin-signalling pathway interference. IL-17 and FFAs synergized to induce IL-6 production by HepG2 cells and murine primary hepatocytes which, in combination with transforming growth factor (TGF-β), expanded Th17 cells. It is likely that a similar process occurs in NASH patients, as there were significant levels of IL-17(+) cell infiltrates in NASH patient livers. The hepatic expression of Th17 cell-related genes [retinoid-related orphan receptor gamma (ROR)γt, IL-17, IL-21 and IL-23] was also increased significantly in NASH patients compared to healthy controls. Th17 cells and IL-17 were associated with hepatic steatosis and proinflammatory response in NAFLD and facilitated the transition from simple steatosis to steatohepatitis. Strategies designed to alter the balance between Th17 cells and T(regs) should be explored as a means of preventing progression to NASH and advanced liver diseases in NAFLD patients. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for

  13. A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice.

    PubMed

    Depner, Christopher M; Traber, Maret G; Bobe, Gerd; Kensicki, Elizabeth; Bohren, Kurt M; Milne, Ginger; Jump, Donald B

    2013-01-01

    Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR(-/-) mice. Using livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism. Livers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoyl-sphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress. DHA regulation of hepatic SFA, MUFA, PUFA

  14. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis.

    PubMed

    Pirola, Carlos J; Fernández Gianotti, Tomas; Castaño, Gustavo O; Mallardi, Pablo; San Martino, Julio; Mora Gonzalez Lopez Ledesma, María; Flichman, Diego; Mirshahi, Faridodin; Sanyal, Arun J; Sookoian, Silvia

    2015-05-01

    We used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome. The study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls. Among 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.05) either in simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH vs controls and 3.1-fold change in NASH vs SS) and miR-192 (4.4-fold change in NASH vs controls); these results were replicated in the validation set. The majority of serum miR-122 circulate in argonaute2-free forms. Circulating miR-19a/b and miR-125b were correlated with biomarkers of atherosclerosis. Liver miR-122 expression was 10-fold (p<0.03) downregulated in NASH compared with SS and was preferentially expressed at the edge of lipid-laden hepatocytes. In vitro exploration showed that overexpression of miR-122 enhances alanine aminotransferase activity. miR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histological and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  15. Prognostic value of high sensitivity C-reaction protein in non-insulin dependent diabetes mellitus patients with non-alcoholic fatty liver disease.

    PubMed

    Bi, Yiliang; Min, Min; Shen, Wei; Deng, Pei; Du, Qiupeng; Dong, Mingjie; Liu, Yan

    2015-01-01

    High sensitivity C-reaction protein (hsCRP) has been used as a significant predictive factor of cardiovascular events in patients with non-insulin dependent diabetes mellitus (NIDDM). However, existing reports in regards to the significance of hsCRP in predicting the progression of hepatic complications in NIDDM patients are too sparse to deliver clear results. This study is aimed at investigating the prognostic value of hsCRP in NIDDM patients with non-alcoholic fatty liver disease (NAFLD). 1128 NIDDM patients with a definite diagnosis of NAFLD were enrolled and followed for one year. The baseline body mass index (BMI), waist-hip circumference ratio (WHR), serum aspartate aminotransferase (AST), presence of hypertension, alanine aminotransferase (ALT), serum hsCRP, total cholesterol (Tch), fasting blood glucose (FBG), triglycerine (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and hepatitis B surface antigen (HBsAg) were recorded to analyze the significance of hsCRP in predicting the short-term progression from NAFLD to non-alcoholic steatohepatitis (NASH). One year after baseline, 32% of the NAFLD patients suffered progression to NASH and the percentages of NASH were respectively 8.2%, 12.5%, 33.8% and 72.6% in 4 groups with quartered baseline serum level of hsCRP; there was significant difference among the 4 groups in percentage of NASH (P<0.001). With sex, age, WHR, BMI, hypertension, TG, TCH, HDL-C, LDL-C, FBG and HBsAg included, the calibrated regression model gave the OR values of 1.000, 1.669, 6.635 and 32.131 in in 4 quartered baseline serum levels of hsCRP. High serum level of hsCRP is an independent risk factor of short-term progression to NASH in patients with NIDDM and NAFLD. Those NIDDM patients with NAFLD that present with high serum level of hsCRP should be subjected to regular monitoring, lifestyle intervention and medication.

  16. Wheat-bran autolytic peptides containing a branched-chain amino acid attenuate non-alcoholic steatohepatitis via the suppression of oxidative stress and the upregulation of AMPK/ACC in high-fat diet-fed mice.

    PubMed

    Kawaguchi, Takumi; Ueno, Takato; Nogata, Yoichi; Hayakawa, Masako; Koga, Hironori; Torimura, Takuji

    2017-02-01

    Whole-wheat intake is known to reduce the risk of metabolic syndrome. However, the active component remains unclear. Recently, we identified bioactive peptides [leucine-arginine-proline (LRP) and leucine-glutamine‑proline (LQP)] from wheat bran autolytic hydrolysate. The present study aimed to investigate the effects of LRP and LQP on non-alcoholic steatohepatitis (NASH) in a mouse model. We also evaluated the effects of these peptides on oxidative stress and on the AMP-activated protein kinase (AMPK) signaling pathway, two major pathogenic factors of NASH. Seven‑week-old male C57BL/6 mice were fed a high-fat diet for 10 weeks and administered water supplemented with 0.05% LRP, 0.20% LRP, 0.05% LQP, or 0.20% LQP (each n=5) or distilled water (control; n=5) ad libitum. Oxidative stress was evaluated by measuring the serum levels of diacron reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP). Hepatic expression of phosphorylated AMPK and phosphorylated acetyl-CoA carboxylase (ACC) were evaluated by immunoblotting. The result showed that non‑alcoholic fatty liver disease activity score was significantly decreased in all types of treatment. Serum d-ROM levels were significantly decreased in the 0.20% LRP group, but not in the 0.05% LRP, 0.05% LQP, and 0.20% LQP groups. Serum BAP levels were significantly increased in the 0.05% LRP and 0.20% LRP groups, but not in the 0.05% LQP and 0.20% LQP groups. Immunoblotting analysis revealed that the expression of phospho-AMPK was increased whereas that of phospho-ACC was decreased in the 0.20% LQP group. In conclusion, we demonstrated that both LRP and LQP alleviated the severity of NASH in a high-fat diet-induced NASH mouse model. In addition, we showed that LRP and LQP modulated oxidative stress and upregulated AMPK/ACC, respectively. Thus, LRP and LQP may constitute clinically applicable therapeutic agents for NASH.

  17. A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice.

    PubMed

    Valdecantos, M Pilar; Pardo, Virginia; Ruiz, Laura; Castro-Sánchez, Luis; Lanzón, Borja; Fernández-Millán, Elisa; García-Monzón, Carmelo; Arroba, Ana I; González-Rodríguez, Águeda; Escrivá, Fernando; Álvarez, Carmen; Rupérez, Francisco J; Barbas, Coral; Konkar, Anish; Naylor, Jacqui; Hornigold, David; Santos, Ana Dos; Bednarek, Maria; Grimsby, Joseph; Rondinone, Cristina M; Valverde, Ángela M

    2017-03-01

    Because nonalcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the effects of G49, a dual glucagon-like peptide-1/glucagon receptor agonist, on NASH and hepatic regeneration. C57Bl/6 mice fed chow or a methionine and choline-deficient (MCD) diet for 1 week were divided into 4 groups: control (chow diet), MCD diet, chow diet plus G49, and M+G49 (MCD diet plus G49). Mice fed a high-fat diet (HFD) for 10 weeks were divided into groups: HFD and H+G49 (HFD plus G49). Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy (PH) was performed, and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration, and comprehensive genomic and metabolic profiling were conducted. NASH was ameliorated in the M+G49 group, manifested by reduced inflammation, steatosis, oxidative stress, and apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose use through the pentose phosphate cycle and oxidative metabolism. Following PH, G49 treatment increased survival, restored the cytokine-mediated priming phase, and enhanced the proliferative capacity and hepatic regeneration ratio in mice on the MCD diet. NASH markers remained decreased in M+G49 mice after PH, and glucose use was shifted to the pentose phosphate cycle and oxidative metabolism. G49 administered immediately after PH was also effective at alleviating the pathological changes induced by the MCD diet. Benefits in terms of liver regeneration were also found in mice fed HFD and treated with G49. Dual-acting glucagon-like peptide-1/glucagon receptor agonists such as G49 represent a novel therapeutic approach for patients with NASH and particularly those requiring PH. (Hepatology 2017;65:950-968). © 2016 by the American Association for the Study of Liver Diseases.

  18. Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis.

    PubMed

    Beraza, Naiara; Ofner-Ziegenfuss, Lisa; Ehedego, Haksier; Boekschoten, Mark; Bischoff, Stephan C; Mueller, Michael; Trauner, Michael; Trautwein, Christian

    2011-03-01

    Hepatocyte-specific NEMO/NF-κB deleted mice (NEMO(Δhepa)) develop spontaneous non-alcoholic steatohepatitis (NASH). Free fatty acids and bile acids promote DR5 expression. TRAIL/NK cell-mediated activation of TRAIL-R2/DR5 plays an important role during acute injury in NEMO(Δhepa) mice. To inhibit the progression of NASH in the absence of hepatocyte-NEMO/NF-kB signaling. NEMOf/f and NEMO(Δhepa) mice were fed with a low-fat diet, and with two anticholestatic diets; UDCA and NorUDCA. The impact of these treatments on the progression of NASH was evaluated. We show that high expression of DR5 in livers from NEMO(Δhepa) mice is accompanied by an abundant presence of bile acids (BAs), misregulation of BA transporters and significant alteration of lipid metabolism-related genes. Additionally, mice lacking NEMO in hepatocytes spontaneously showed ductular response at young age. Unexpectedly, feeding of NEMO(Δhepa) mice with low-fat diet failed to improve chronic liver injury. Conversely, anti-cholestatic treatment with nor-ursodeoxycholic acid (NorUDCA), but not with ursodeoxycholic acid (UDCA), led to a significant attenuation of liver damage in NEMO(Δhepa) mice. The strong therapeutic effect of NorUDCA relied on a significant downregulation of LXR-dependent lipogenesis and the normalisation of BA metabolism through mechanisms involving cross-talk between Cyp7a1 and SHP. This was associated with the significant improvement of liver histology, NEMO(Δhepa)/NorUDCA-treated mice showed lower apoptosis and reduced CyclinD1 expression, indicating attenuation of the compensatory proliferative response to hepatocellular damage. Finally, fibrosis and ductular reaction markers were significantly reduced in NorUDCA-treated NEMO(Δhepa) mice. Overall, our work demonstrates the contribution of bile acids metabolism to the progression of NASH in the absence of hepatocyte-NF-kB through mechanisms involving DR5-apoptosis, inflammation and fibrosis. Our work suggests a potential

  19. Ezetimibe for the Treatment of Nonalcoholic Steatohepatitis: Assessment by Novel Magnetic Resonance Imaging and Magnetic Resonance Elastography in a Randomized Trial (MOZART Trial)

    PubMed Central

    Loomba, Rohit; Sirlin, Claude B; Ang, Brandon; Bettencourt, Ricki; Jain, Rashmi; Salotti, Joanie; Soaft, Linda; Hooker, Jonathan; Kono, Yuko; Bhatt, Archana; Hernandez, Laura; Nguyen, Phirum; Noureddin, Mazen; Haufe, William; Hooker, Catherine; Yin, Meng; Ehman, Richard; Lin, Grace Y; Valasek, Mark A; Brenner, David A; Richards, Lisa

    2015-01-01

    Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) and liver histology in patients with biopsy-proven NASH. In this randomized, double-blind, placebo-controlled trial, 50 patients with biopsy-proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF (mean difference between the ezetimibe and placebo arms -1.3%, P = 0.4). Compared to baseline, however, end-of-treatment MRI-PDFF was significantly lower in the ezetimibe arm (15%-11.6%, P < 0.016) but not in the placebo arm (18.5%-16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI-PDFF (-4.35 ± 4.9% versus -0.30 ± 4.1%, P < 0.019). Conclusions: Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess

  20. Diabetes mellitus and non-alcoholic fatty liver disease: the thread of Ariadne.

    PubMed

    Kosmidou, Maria; Milionis, Haralampos

    2017-06-01

    Non alcoholic fatty liver disease (NAFLD, the hepatic fat accumulation) and non alcoholic steatohepatitis (NASH, the aggressive form of liver steatosis plus inflammation and hepatocyte necrosis) are reaching epidemic dimensions in subjects with diabetes mellitus (DM). Taking into account that the incidence of DM increases worldwide, these entities represent major health problems. There is accumulating evidence that diabetic subjects with NASH are at increased risk not only for cardiovascular disease compications but also for cirrhosis and hepatocellular cancer. On the other hand, the presence of NAFLD correlates with an increased risk for the development of DM. The most-widely accepted pathophysiological mechanisms relating DM and NAFLD include central obesity and insulin resistanc, but new insights are under scrutiny. Therapeutic modalities used for the management of diabetes have been studied for their impact on NAFLD/NASH and both neutral and beneficial effects have been reported. In this review, we discuss issues regarding the epidemiology, the pathophysiological pathways relating NAFLD with DM and consider strategies that may be useful in the management of NAFLD in the diabetic population.

  1. Imagine-Self Perspective-Taking and Rational Self-Interested Behavior in a Simple Experimental Normal-Form Game.

    PubMed

    Karbowski, Adam; Ramsza, Michał

    2017-01-01

    The purpose of this study is to explore the link between imagine-self perspective-taking and rational self-interested behavior in experimental normal-form games. Drawing on the concept of sympathy developed by Adam Smith and further literature on perspective-taking in games, we hypothesize that introduction of imagine-self perspective-taking by decision-makers promotes rational self-interested behavior in a simple experimental normal-form game. In our study, we examined behavior of 404 undergraduate students in the two-person game, in which the participant can suffer a monetary loss only if she plays her Nash equilibrium strategy and the opponent plays her dominated strategy. Results suggest that the threat of suffering monetary losses effectively discourages the participants from choosing Nash equilibrium strategy. In general, players may take into account that opponents choose dominated strategies due to specific not self-interested motivations or errors. However, adopting imagine-self perspective by the participants leads to more Nash equilibrium choices, perhaps by alleviating participants' attributions of susceptibility to errors or non-self-interested motivation to the opponents.

  2. Imagine-Self Perspective-Taking and Rational Self-Interested Behavior in a Simple Experimental Normal-Form Game

    PubMed Central

    Karbowski, Adam; Ramsza, Michał

    2017-01-01

    The purpose of this study is to explore the link between imagine-self perspective-taking and rational self-interested behavior in experimental normal-form games. Drawing on the concept of sympathy developed by Adam Smith and further literature on perspective-taking in games, we hypothesize that introduction of imagine-self perspective-taking by decision-makers promotes rational self-interested behavior in a simple experimental normal-form game. In our study, we examined behavior of 404 undergraduate students in the two-person game, in which the participant can suffer a monetary loss only if she plays her Nash equilibrium strategy and the opponent plays her dominated strategy. Results suggest that the threat of suffering monetary losses effectively discourages the participants from choosing Nash equilibrium strategy. In general, players may take into account that opponents choose dominated strategies due to specific not self-interested motivations or errors. However, adopting imagine-self perspective by the participants leads to more Nash equilibrium choices, perhaps by alleviating participants’ attributions of susceptibility to errors or non-self-interested motivation to the opponents. PMID:28955276

  3. Biomarkers of NAFLD progression: a lipidomics approach to an epidemic.

    PubMed

    Gorden, D Lee; Myers, David S; Ivanova, Pavlina T; Fahy, Eoin; Maurya, Mano R; Gupta, Shakti; Min, Jun; Spann, Nathanael J; McDonald, Jeffrey G; Kelly, Samuel L; Duan, Jingjing; Sullards, M Cameron; Leiker, Thomas J; Barkley, Robert M; Quehenberger, Oswald; Armando, Aaron M; Milne, Stephen B; Mathews, Thomas P; Armstrong, Michelle D; Li, Chijun; Melvin, Willie V; Clements, Ronald H; Washington, M Kay; Mendonsa, Alisha M; Witztum, Joseph L; Guan, Ziqiang; Glass, Christopher K; Murphy, Robert C; Dennis, Edward A; Merrill, Alfred H; Russell, David W; Subramaniam, Shankar; Brown, H Alex

    2015-03-01

    The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. Recognition and timely diagnosis of these different stages, particularly NASH, is important for both potential reversibility and limitation of complications. Liver biopsy remains the clinical standard for definitive diagnosis. Diagnostic tools minimizing the need for invasive procedures or that add information to histologic data are important in novel management strategies for the growing epidemic of NAFLD. We describe an "omics" approach to detecting a reproducible signature of lipid metabolites, aqueous intracellular metabolites, SNPs, and mRNA transcripts in a double-blinded study of patients with different stages of NAFLD that involves profiling liver biopsies, plasma, and urine samples. Using linear discriminant analysis, a panel of 20 plasma metabolites that includes glycerophospholipids, sphingolipids, sterols, and various aqueous small molecular weight components involved in cellular metabolic pathways, can be used to differentiate between NASH and steatosis. This identification of differential biomolecular signatures has the potential to improve clinical diagnosis and facilitate therapeutic intervention of NAFLD. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

  4. Deficiency of eNOS exacerbates early-stage NAFLD pathogenesis by changing the fat distribution.

    PubMed

    Nozaki, Yuichi; Fujita, Koji; Wada, Koichiro; Yoneda, Masato; Shinohara, Yoshiyasu; Imajo, Kento; Ogawa, Yuji; Kessoku, Takaomi; Nakamuta, Makoto; Saito, Satoru; Masaki, Naohiko; Nagashima, Yoji; Terauchi, Yasuo; Nakajima, Atsushi

    2015-12-17

    Although many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We therefore investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet. eNOS-knockout and wild-type mice were fed a basal diet or a high-fat diet for 12 weeks. Lipid accumulation and inflammation were evaluated in the liver, and various factors that are closely associated with NAFLD/NASH and hepatic tissue blood flow were analyzed. Lipid accumulation and inflammation were more extensive in the liver and lipid accumulation was less extensive in the visceral fat tissue in eNOS-knockout mice, compared with wild-type mice, after 12 weeks of being fed a high-fat diet. While systemic insulin resistance was comparable between the eNOS-knockout and wild-type mice fed a high-fat diet, hepatic tissue blood flow was significantly suppressed in the eNOS-knockout mice, compared with the wild-type mice, in mice fed a high-fat diet. The microsomal triglyceride transfer protein activity was down-regulated in eNOS-knockout mice, compared with wild-type mice, in mice fed a high-fat diet. A deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.

  5. Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies

    PubMed Central

    Takeuchi, Masayoshi; Takino, Jun-ichi; Sakasai-Sakai, Akiko; Takata, Takanobu; Ueda, Tadashi; Tsutsumi, Mikihiro; Hyogo, Hideyuki; Yamagishi, Sho-ichi

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease around the world. It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, liver failure, and/or hepatocellular carcinoma. NAFLD is also associated with other medical conditions such as obesity, diabetes mellitus (DM), metabolic syndrome, hypertension, insulin resistance, hyperlipidemia, and cardiovascular disease (CVD). In diabetes, chronic hyperglycemia contributes to the development of both macro- and microvascular conditions through a variety of metabolic pathways. Thus, it can cause a variety of metabolic and hemodynamic conditions, including upregulated advanced glycation end-products (AGEs) synthesis. In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs, were found to make a significant contribution to the pathogenesis of DM-induced angiopathy. Furthermore, accumulating evidence suggests that the binding of TAGE with their receptor (RAGE) induces oxidative damage, promotes inflammation, and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells. All of these effects could facilitate the pathogenesis of hypertension, cancer, diabetic vascular complications, CVD, dementia, and NASH. Thus, inhibiting TAGE synthesis, preventing TAGE from binding to RAGE, and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH. Here, we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH. PMID:25544875

  6. Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis.

    PubMed

    Okura, Yasushi; Namisaki, Tadashi; Moriya, Kei; Kitade, Mitsuteru; Takeda, Kosuke; Kaji, Kosuke; Noguchi, Ryuichi; Nishimura, Norihisa; Seki, Kenichiro; Kawaratani, Hideto; Takaya, Hiroaki; Sato, Shinya; Sawada, Yasuhiko; Shimozato, Naotaka; Furukawa, Masanori; Nakanishi, Keisuke; Saikawa, Soichiro; Kubo, Takuya; Asada, Kiyoshi; Yoshiji, Hitoshi

    2017-11-01

    Dipeptidyl peptidase-4 (DPP4) inhibitors (DPP4-I) are oral glucose-lowering drugs for type 2 diabetes mellitus. Previously, we reported that DPP4-I (sitagliptin) exerted suppressive effects on experimental liver fibrosis in rats. Blockade of the renin-angiotensin system by angiotensin-II type 1 receptor blocker (losartan), commonly used in the management of hypertension, has been shown to significantly alleviate hepatic fibrogenesis and carcinogenesis. We aimed to elucidate the effects and possible mechanisms of a sitagliptin + losartan combination on the progression of non-diabetic non-alcoholic steatohepatitis (NASH) in a rat model. To induce NASH, Fischer 344 rats were fed a choline-deficient L-amino acid-defined diet for 12 weeks. We elucidated the chemopreventive effects of sitagliptin + losartan, especially in conjunction with hepatic stellate cell (HSC) activation, angiogenesis, and oxidative stress, all known to play important roles in the progression of NASH. Sitagliptin + losartan suppressed choline-deficient L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. The combination treatment exerted a greater inhibitory effect than monotherapy. These inhibitory effects occurred almost concurrently with the suppression of HSC activation, neovascularization, and oxidative stress. In vitro studies showed that sitagliptin + losartan inhibited angiotensin II-induced proliferation and expression of transforming growth factor-β1 and α1 (I)-procollagen mRNA of activated HSC and in vitro angiogenesis, in parallel with the suppression observed in in vivo studies. The widely and safely used sitagliptin + losartan combination treatment in clinical practice could be an effective strategy against NASH. © 2016 The Japan Society of Hepatology.

  7. Vismodegib Suppresses TRAIL-mediated Liver Injury in a Mouse Model of Nonalcoholic Steatohepatitis

    PubMed Central

    Hirsova, Petra; Ibrahim, Samar H.; Bronk, Steven F.; Yagita, Hideo; Gores, Gregory J.

    2013-01-01

    Hedgehog signaling pathway activation has been implicated in the pathogenesis of NASH. Despite this concept, hedgehog pathway inhibitors have not been explored. Thus, we examined the effect of vismodegib, a hedgehog signaling pathway inhibitor, in a diet-induced model of NASH. C57BL/6 mice were placed on 3-month chow or FFC (high saturated fats, fructose, and cholesterol) diet. One week prior to sacrifice, mice were treated with vismodegib or vehicle. Mice fed the FFC diet developed significant steatosis, which was unchanged by vismodegib therapy. In contrast, vismodegib significantly attenuated FFC-induced liver injury as manifested by reduced serum ALT and hepatic TUNEL-positive cells. In line with the decreased apoptosis, vismodegib prevented FFC-induced strong upregulation of death receptor DR5 and its ligand TRAIL. In addition, FFC-fed mice, but not chow-fed animals, underwent significant liver injury and apoptosis following treatment with a DR5 agonist; however, this injury was prevented by pre-treatment with vismodegib. Consistent with a reduction in liver injury, vismodegib normalized FFC-induced markers of inflammation including mRNA for TNF-α, IL-1β, IL-6, monocyte chemotactic protein-1 and a variety of macrophage markers. Furthermore, vismodegib in FFC-fed mice abrogated indices of hepatic fibrogenesis. In conclusion, inhibition of hedgehog signaling with vismodegib appears to reduce TRAIL-mediated liver injury in a nutrient excess model of NASH, thereby attenuating hepatic inflammation and fibrosis. We speculate that hedgehog signaling inhibition may be salutary in human NASH. PMID:23894677

  8. Prevalence of Cirrhosis in Patients with Thrombocytopenia Who Receive Bone Marrow Biopsy

    PubMed Central

    Sheikh, Muhammad Y.; Raoufi, Rahim; Atla, Pradeep R.; Riaz, Muhammad; Oberer, Chad; Moffett, Michael J.

    2012-01-01

    Background/Aim: Thrombocytopenia is a common finding in patients with cirrhosis and may lead to unnecessary referral for bone marrow (BM) biopsy. To date, the prevalence of cirrhosis in patients with thrombocytopenia who receive BM biopsy is largely unknown. Materials and Methods: Between fiscal years 2006-2010, 744 patients (≥18 years) who underwent BM biopsies for thrombocytopenia at our hospital were identified retrospectively. 541 patients were excluded who had hematologic malignancies and received chemotherapy. Remaining 203 patients with predominant isolated thrombocytopenia were included in the study. Results: Of 203 patients, 136 (67%) had a normal and 67 (33%) had an abnormal BM examination. Prevalence of cirrhosis in the study population was 35% (95% CI: 28.4-41.9). 51% patients with normal BM were found to have cirrhosis compared to 3% of patients with abnormal BM exam (P < 0.0001). Common causes of cirrhosis were nonalcoholic steatohepatitis (NASH) (47%), followed by alcohol and Hepatitis C virus infection. Idiopathic thrombocytopenia and myelodysplastic syndrome were most frequent causes of thrombocytopenia in patients without cirrhosis. Patients with NASH had higher body mass index (BMI) (33.4 vs. 25.8, P < 0.001) and lower MELD scores (11.1 vs. 16, P = 0.028) when compared to non-NASH patients with cirrhosis. Conclusion: Approximately, one third (35%) of patients with cirrhosis induced thrombocytopenia may undergo unwarranted BM biopsies. Clinical diagnosis of cirrhosis is still a challenge for many physicians, particularly with underlying NASH. We propose cirrhosis to be the prime cause of isolated thrombocytopenia. PMID:22824769

  9. A research on service quality decision-making of Chinese communications industry based on quantum game

    NASA Astrophysics Data System (ADS)

    Zhang, Cuihua; Xing, Peng

    2015-08-01

    In recent years, Chinese service industry is developing rapidly. Compared with developed countries, service quality should be the bottleneck for Chinese service industry. On the background of three major telecommunications service providers in China, the functions of customer perceived utilities are established. With the goal of consumer's perceived utility maximization, the classic Nash equilibrium solution and quantum equilibrium solution are obtained. Then a numerical example is studied and the changing trend of service quality and customer perceived utility is further analyzed by the influence of the entanglement operator. Finally, it is proved that quantum game solution is better than Nash equilibrium solution.

  10. Usefulness of Magnetic Resonance Imaging for the Diagnosis of Hemochromatosis with Severe Hepatic Steatosis in Nonalcoholic Fatty Liver Disease.

    PubMed

    Nozaki, Yuichi; Sato, Noriko; Tajima, Tsuyoshi; Hasuo, Kanehiro; Kojima, Yasushi; Umemoto, Kumiko; Mishima, Saori; Mikami, Shintaro; Nakayama, Tomohiro; Igari, Toru; Akiyama, Junichi; Imamura, Masatoshi; Masaki, Naohiko; Yanase, Mikio

    2016-01-01

    The ratio of the number of patients with non-alcoholic steatohepatitis (NASH) to the total number of patients with liver dysfunction has increased in many countries around the world. Liver dysfunction is also caused by multiple blood transfusions in patients with leukemia and other hematological diseases, with liver dysfunction often accompanied by secondary hemochromatosis. This study describes a 25-year-old man with secondary hemochromatosis combined with NASH. Magnetic resonance imaging was useful for visualizing the distributions of both iron and fat in the liver of this patient in order to make a differential diagnosis and to evaluate the effect of treatment.

  11. Quantum Approach to Cournot-type Competition

    NASA Astrophysics Data System (ADS)

    Frąckiewicz, Piotr

    2018-02-01

    The aim of this paper is to investigate Cournot-type competition in the quantum domain with the use of the Li-Du-Massar scheme for continuous-variable quantum games. We derive a formula which, in a simple way, determines a unique Nash equilibrium. The result concerns a large class of Cournot duopoly problems including the competition, where the demand and cost functions are not necessary linear. Further, we show that the Nash equilibrium converges to a Pareto-optimal strategy profile as the quantum correlation increases. In addition to illustrating how the formula works, we provide the readers with two examples.

  12. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial.

    PubMed

    Cusi, Kenneth; Orsak, Beverly; Bril, Fernando; Lomonaco, Romina; Hecht, Joan; Ortiz-Lopez, Carolina; Tio, Fermin; Hardies, Jean; Darland, Celia; Musi, Nicolas; Webb, Amy; Portillo-Sanchez, Paola

    2016-09-06

    The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited. To determine the efficacy and safety of long-term pioglitazone treatment in patients with NASH and prediabetes or T2DM. Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682). University hospital. Patients (n = 101) with prediabetes or T2DM and biopsy-proven NASH were recruited from the general population and outpatient clinics. All patients were prescribed a hypocaloric diet (500-kcal/d deficit from weight-maintaining caloric intake) and then randomly assigned to pioglitazone, 45 mg/d, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment. The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Secondary outcomes included other histologic outcomes, hepatic triglyceride content measured by magnetic resonance and proton spectroscopy, and metabolic parameters. Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, -0.5 [CI, -0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, -7 percentage points [CI, -10 to -4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of

  13. Effects of ursodeoxycholic acid and/or low-calorie diet on steatohepatitis in rats with obesity and hyperlipidemia

    PubMed Central

    Fan, Jian-Gao; Zhong, Lan; Tia, Li-Yan; Xu, Zheng-Jie; Li, Min-Sheng; Wang, Guo-Liang

    2005-01-01

    AIM: To evaluate the effects of ursodeoxycholic acid (UDCA) and/or low-calorie diet (LCD) on a rat model of nonalcoholic steatohepatitis (NASH). METHODS: Fifty-five Sprague-Dawley rats were divided into five groups. The control group (n = 9) was fed with standard rat diet for 12 wk, NASH group (n = 10) was fed with high-fat diet consisted of normal diet, 10% lard oil and 2% cholesterol for 12 wk, UDCA group (n = 10) was fed with high-fat diet supplemented with UDCA at a dose of 25 mg/(kg·d) in drinking water for 12 wk, LCD group (n = 10) was fed with high-fat diet for 10 wk and then LCD for 2 wk, and UDCA+LCD group (n = 15) was fed with high-fat diet for 10 wk, followed by LCD+UDCA for 2 wk. At the end of the experiment, body weight, serum biochemical index, and hepatopathologic changes were examined. RESULTS: Compared with the control group, rats in the NASH group had significantly increased body weight, liver weight, and serum lipid and aminotransferase levels. All rats in the NASH group developed steatohepatitis, as determined by their liver histology. Compared with the NASH group, there were no significant changes in body weight, liver weight, blood biochemical index, the degree of hepatic steatosis, and histological activity index (HAI) score in the UDCA group; however, body and liver weights were significantly decreased, and the degree of steatosis was markedly improved in rats of both the LCD group and the UDCA+LCD group, but significant improvement with regard to serum lipid variables and hepatic inflammatory changes were seen only in rats of the UDCA+LCD group, and not in the LCD group. CONCLUSION: LCD might play a role in the treatment of obesity and hepatic steatosis in rats, but it exerts no significant effect on both serum lipid disorders and hepatic inflammatory changes. UDCA may enhance the therapeutic effects of LCD on steatohepatitis accompanied by obesity and hyperl-ipidemia. However, UDCA alone is not effective in the prevention of

  14. Oral Supplementation of Glutamine Attenuates the Progression of Nonalcoholic Steatohepatitis in C57BL/6J Mice.

    PubMed

    Sellmann, Cathrin; Baumann, Anja; Brandt, Annette; Jin, Cheng Jun; Nier, Anika; Bergheim, Ina

    2017-11-01

    Background: Universally accepted therapeutic strategies for the treatment of nonalcoholic steatohepatitis (NASH) are still lacking. Studies suggest a preventive effect of oral Gln supplementation on the development of NASH; however, whether Gln also has therapeutic potential for pre-existing NASH has not yet been clarified. Objective: The aim of the present study was to determine whether Gln prevents the progression of diet-induced NASH in mice. Methods: For 8 wk, female C57BL/6J mice (6-8 wk old) were pair-fed a liquid Western-style diet [WSD, 25% of energy from fat, 50% wt:wt fructose, 0.16% wt:wt cholesterol] or control diet (C diet) to induce liver damage. From week 8 to 13, they were pair-fed the C diet or WSD alone or supplemented with l-Gln to provide 2.1 g/kg body weight (C diet + Gln or WSD + Gln). Energy intake was adjusted to the group with the lowest energy intake. Indexes of liver damage and inflammation, intestinal barrier function, and toll-like receptor 4 ( Tlr4 ) signaling in the liver were determined. Results: The liver histology scores significantly increased from 8 to 13 wk (+31%) in WSD-fed mice and were significantly higher than in controls ( P ≤ 0.05 for both time comparisons), whereas scores did not differ between C diet-fed and WSD + Gln-fed mice after 13 wk of feeding. The occludin protein concentrations in the small intestinal tissue were similarly reduced in both WSD-fed groups when compared with controls [WSD compared with C diet (-53%) and C diet + Gln (-42%), P ≤ 0.05; WSD + Gln compared with C diet + Gln (-34%), P ≤ 0.05] after 13 wk, whereas the expression of myeloid differentiation primary response gene 88 mRNA and concentration of inducible nitric oxide synthase and 4-hydroxynonenal protein adducts were significantly higher only in livers of WSD-fed mice ( P ≤ 0.05 for the WSD group compared with all other groups; WSD + Gln group compared with the C diet groups: NS). Conclusion: Taken together, our data suggest that oral

  15. Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease.

    PubMed

    Liu, Yan; Chen, Hongen; Wang, Jingjing; Zhou, Wenjing; Sun, Ruifang; Xia, Min

    2015-07-01

    Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor α (RXRα) in the liver were analyzed in subjects with different degrees of hepatic steatosis. Serum RA concentrations in patients with NAFLD (1.42 ± 0.47 ng/mL) and NASH (1.14 ± 0.26 ng/mL) were significantly lower than those in control subjects (2.70 ± 0.52 ng/mL) (P < 0.01). Furthermore, serum RA concentrations were significantly different between subjects with normal glucose tolerance and those with type 2 diabetes in control [2.87 ± 0.52 (n = 28) vs. 2.32 ± 0.44 ng/mL (n = 13)], NAFLD [1.61 ± 0.37 (n = 29) vs. 1.28 ± 0.41 ng/mL (n = 16)], and NASH [1.35 ± 0.34 (n = 24) vs. 1.07 ± 0.29 ng/mL (n = 14)] groups. In human liver tissue, RXRα mRNA expression was inversely correlated with the exacerbation of hepatic steatosis. Both serum RA concentrations and RXRα mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P < 0.001, and r = -0.611, P = 0.002, respectively). Compared with grade 0 severity, the concentration of RXRα protein was lower in more severe grades in patients with NAFLD. These results show that circulating RA concentrations were lower in subjects with NAFLD and were associated with hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263. © 2015

  16. Vitamin D Deficiency Is Associated With Increased Risk of Non-alcoholic Steatohepatitis in Adults With Non-alcoholic Fatty Liver Disease: Possible Role for MAPK and NF-κB?

    PubMed

    Nelson, James E; Roth, Christian L; Wilson, Laura A; Yates, Katherine P; Aouizerat, Bradley; Morgan-Stevenson, Vicki; Whalen, Elizabeth; Hoofnagle, Andrew; Mason, Michael; Gersuk, Vivian; Yeh, Matthew M; Kowdley, Kris V

    2016-06-01

    The objective of this study was to determine the relationship of serum vitamin D deficiency (VDD) to histologic features of non-alcoholic fatty liver disease (NAFLD), and associated demographic, clinical, laboratory, and transcriptomic data in the well-characterized Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN) cohort. Serum vitamin D 25(OH)D (VD) was quantified by liquid chromatography-tandem mass spectrometry in 190 adults (>18 years) with biopsy-proven NAFLD. Subjects were categorized according to their level of VD as either sufficient (>30 ng/ml), insufficient (≥20≤30 ng/ml), or deficient (VDD; <20 ng/ml). Multivariable logistic regression was used to investigate the association of VDD and the presence of definite NASH and individual histological features of NAFLD after adjusting for age, sex, race, body mass index, alanine aminotransferase, and diabetes status. Hepatic transcriptomic data was compared between VDD and non-VDD subjects. VDD was present in 55% of subjects and was independently associated with definitive NASH (odds ratio (OR) 3.15, 95% confidence interval (CI), 1.62-6.15, P=0.001), increased lobular inflammation (OR=1.98, 95% CI, 1.08-3.61, P=0.026), more ballooning (OR=2.38, 95% CI, 1.32-4.30, P=0.004), and the presence of fibrosis (OR=2.32, 95% CI, 1.13-4.77, P=0.022). There was a significant inverse relationship between lower levels of serum resistin and increased VD level category (P=0.013). The KRT10, SEMA3B, SNORD3C, ARSD, and IGKV4-1 genes were differentially expressed (false discovery rate <0.05) between VDD and non-VDD subjects. Gene ontology and pathway analysis suggest activation of the mitogen-activated protein kinase and nuclear factor-κB pathways in VDD NAFLD subjects. VDD is prevalent among US adult NAFLD patients and is independently associated with a definitive diagnosis of NASH and increased histological severity. Novel associations in proinflammatory pathways were identified, which suggest the

  17. Oral Administration of CardioAid and Lunasin Alleviates Liver Damage in a High-Fat Diet Nonalcoholic Steatohepatitis Model.

    PubMed

    Drori, Ariel; Rotnemer-Golinkin, Dvorah; Zolotarov, Lidya; Ilan, Yaron

    2017-01-01

    Several of the drugs in development for treatment of nonalcoholic steatohepatitis (NASH) target liver fibrosis or have side effects that prohibit their long-term use in patients with mild to moderate disease. Lunasin is a soy-derived peptide with anti-inflammatory properties. ADM's CardioAid™ is a plant sterol extract that exerts cholesterol- and triacylglycerol-lowering effects. To determine the immunomodulatory effects of CardioAid and lunasin in a high-fat diet (HFD) animal model of NASH. C57BL/6 mice on an HFD were orally administered CardioAid or lunasin for 25 weeks. The effects on the immune system, liver function, insulin resistance and lipid profile were studied. Treatment with CardioAid and lunasin was associated with a significant decrease in the CD4/CD8 ratio and an increase in CD4+CD25+ lymphocytes. A decrease in interleukin 1-alpha serum levels and an increase in transforming growth factor beta serum levels were noted. These were associated with alleviation of liver damage as indicated by a significant decrease in liver enzymes and improvement in the histological nonalcoholic fatty liver disease activity score (NAS). Decreases in both serum triglyceride and serum glucose levels were observed in treated mice. A decrease in total body fat measured by EchoMRI was also observed in treated mice. CardioAid and lunasin exerted hepatoprotective and glucose-protective effects in an HFD NASH model. These data and the high-safety profiles of CardioAid and Lunasin support their use in patients in the early stages of NASH to prevent deterioration due to the disease. © 2017 S. Karger AG, Basel.

  18. Non-Alcoholic Fatty Liver Disease.

    PubMed

    Engin, Atilla

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is in parallel with the obesity epidemic and it is the most common cause of liver diseases. The development of hepatic steatosis in majority of patients is linked to dietary fat ingestion. NAFLD is characterized by excess accumulation of triglyceride in the hepatocyte due to both increased inflow of free fatty acids and de novo hepatic lipogenesis. Insulin resistance with the deficiency of insulin receptor substrate-2 (IRS-2)-associated phosphatidylinositol 3-kinase (PI3K) activity causes an increase in intracellular fatty acid-derived metabolites such as diacylglycerol, fatty acyl CoA or ceramides. Lipotoxicity-related mechanism of NAFLD could be explained still best by the "double-hit" hypothesis. Insulin resistance is the major mechanism in the development and progression of NAFLD/Non-alcoholic steatohepatitis (NASH). Metabolic oxidative stress, autophagy, and inflammation induce NASH progression. In the "first hit" the hepatic concentrations of diacylglycerol increase with rising saturated liver fat content in human NAFLD. Activities of mitochondrial respiratory chain complexes are decreased in liver tissue of patients with NASH. Furthermore, hepatocyte lipoapoptosis is a critical feature of NASH. In "second hit" reduced glutathione levels due to oxidative stress lead to overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling that induces cell death in the steatotic liver. Accumulation of toxic levels of reactive oxygen species (ROS) is caused by the ineffectual cycling of the endoplasmic reticulum (ER) oxidoreductin (Ero1)-protein disulfide isomerase oxidation cycle through the downstream of the inner membrane mitochondrial oxidative metabolism and Kelch like-ECH-associated protein 1 (Keap1)- Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.

  19. Transgenic expression of human neutrophil peptide-1 enhances hepatic fibrosis in mice fed a choline-deficient, L-amino acid-defined diet.

    PubMed

    Ibusuki, Rie; Uto, Hirofumi; Arima, Shiho; Mawatari, Seiichi; Setoguchi, Yoshiko; Iwashita, Yuji; Hashimoto, Shinichi; Maeda, Takuro; Tanoue, Shiro; Kanmura, Shuji; Oketani, Makoto; Ido, Akio; Tsubouchi, Hirohito

    2013-11-01

    Neutrophils infiltrate the livers of patients with nonalcoholic steatohepatitis (NASH). Human neutrophil peptides (HNPs) induce cytokine and chemokine production under inflammatory conditions, which may contribute to the progression of NASH. In this study, we focused on the effects of HNP-1 on hepatic steatosis and fibrosis in a mouse model of NASH induced by a choline-deficient, L-amino acid-defined (CDAA) diet. We generated transgenic mice expressing HNP-1 under the control of a β-actin-based promoter. HNP-1 transgenic and wild-type C57BL/6N mice were fed a CDAA diet for 16 weeks to induce hepatic steatosis and fibrosis. Serological and histological features were examined, and the effects of HNP-1 on hepatic stellate cell lines were assessed. HNP-1 transgenic and wild-type mice fed the CDAA diet showed no significant differences in serum alanine aminotransferase levels or the degree of hepatic steatosis based on Oil red O staining and hepatic triglyceride content. In contrast, Sirius Red and Azan staining showed significantly more severe hepatic fibrosis in HNP-1 transgenic mice compared with wild-type mice. In addition, significantly more α-smooth muscle actin-positive hepatic stellate cells were observed in the transgenic mice than in the wild-type mice. Finally, the proliferation of the LI90 hepatic stellate cell line increased in response to HNP-1. Our data indicate that HNP-1 enhances hepatic fibrosis in fatty liver by inducing hepatic stellate cell proliferation. Thus, neutrophil-derived HNP-1 may contribute to the progression of NASH. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Salicornia Extract Ameliorates Salt-Induced Aggravation of Nonalcoholic Fatty Liver Disease in Obese Mice Fed a High-Fat Diet.

    PubMed

    Kim, Jae Hwan; Suk, Sujin; Jang, Woo Jung; Lee, Chang Hyung; Kim, Jong-Eun; Park, Jin-Kyu; Kweon, Mee-Hyang; Kim, Jong Hun; Lee, Ki Won

    2017-07-01

    High-fat and high-salt intakes are among the major risks of chronic diseases including obesity, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Salicornia is a halophytic plant known to exert antioxidant, antidiabetic, and hypolipidemic effects, and Salicornia-extracted salt (SS) has been used as a salt substitute. In this study, the effects of SS and purified salt (PS) on the aggravation of NAFLD/NASH were compared. C57BL/6J male mice (8-wk-old) were fed a high-fat diet (HFD) for 6 mo and divided into 3 dietary groups, which were additionally fed HFD, HFD + SS, and HFD + PS for 13 wk. PS induced aggravation of NAFLD/NASH in HFD-fed mice. Although the actual salt intake was same between the PS and SS groups as 1% of the diet (extrapolated from the World Health Organization [WHO] guideline), SS induced less liver injury and hepatic steatosis compared to PS. The hepatic mRNA expressions of inflammatory cytokines and fibrosis marker were significantly lower in the SS group than the PS group. Oxidative stress is one of the major causes of inflammation in NAFLD/NASH. Results of the component analysis showed that the major polyphenols that exhibited antioxidant activity in the Salicornia water extract were ferulic acid, caffeic acid, and isorhamnetin. These results suggest that even the level of salt intake recommended by WHO can accelerate the progression of liver disease in obese individuals consuming HFD. It is proposed that SS can be a salt substitute for obese individuals who consume HFD. © 2017 Institute of Food Technologists®.

  1. Nonalcoholic fatty liver disease is an independent risk factor for atherosclerosis in young adult men.

    PubMed

    Ozturk, Kadir; Uygun, Ahmet; Guler, Ahmet Kerem; Demirci, Hakan; Ozdemir, Cafer; Cakir, Mehmet; Sakin, Yusuf Serdar; Turker, Turker; Sari, Sebahattin; Demirbas, Seref; Karslıoğlu, Yıldırım; Saglam, Mutlu

    2015-06-01

    The possible cause of accelerated atherosclerosis in NAFLD may be the relationship with the MetS and its components. Our primary goal was to evaluate the relationship between NAFLD and subclinical atherosclerosis in adult male patients between 20 and 40 years of age. Moreover, we aimed to investigate the changes in this association according to the presence or absence of MetS. Sixty-one male patients with biopsy-proven NAFLD and 41 healthy male volunteers were enrolled. In order to exclude any interference of confounding factors, we studied a specifically selected group with no additional cardiovascular risk. PWV, CIMT and FMD levels were measured in all patients and controls. The levels of cf-PWV were significantly higher in SS and NASH patients compared to the control group (P < 0.001); no significant difference was found between SS and NASH patients (P > 0.05). We found significantly decreased FMD levels in patients with SS and NASH compared with control subjects (P < 0.001). Subjects with NASH had significantly greater CIMT measurements than the SS and controls (P = 0.026, P < 0.001, respectively). Although, NAFLD patients with MetS had increased cf-PWV and CIMT and reduced FMD compared to healthy subjects (P < 0.05), no significant difference existed between NAFLD with Mets and NAFLD without MetS in terms of cf-PWV, CIMT and FMD (P > 0.05) CONCLUSION: The present study showed that the presence of NAFLD leads to increased risk of endothelial dysfunction and atherosclerosis in adult male patients, independent of MetS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Saturated fat and cholesterol are critical to inducing murine metabolic syndrome with robust nonalcoholic steatohepatitis.

    PubMed

    Mells, Jamie E; Fu, Ping P; Kumar, Pradeep; Smith, Tekla; Karpen, Saul J; Anania, Frank A

    2015-03-01

    Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS). Up to a third of NAFLD subjects are at risk for developing nonalcoholic steatohepatitis (NASH). Many rodent models fail to replicate both MetS and NASH. The purpose of this study was to develop a reliable mouse model of NASH and MetS using a diet containing cholesterol, saturated fat and carbohydrate that is reflective of Western diets of North Americans. We used adult male C57BL/6 J 4- to 5-week-old mice and administered a solid diet containing 0.2% cholesterol, 45% of its calories from fat, with 30% of the fat in the form of partially hydrogenated vegetable oil. We also provided carbohydrate largely as high-fructose corn syrup equivalent in water. In a separate cohort, we gave the identical diet in the absence of cholesterol. Glucose and insulin tolerance testing was conducted throughout the feeding period. The feeding was conducted for 16 weeks, and the mice were sacrificed for histological analysis, markers of MetS, liver inflammation, circulating lipids, as well as liver staining for fibrosis and alpha smooth muscle actin (α-SMA). We found that cholesterol significantly increased serum leptin, interleukin-6, liver weight and liver weight/body weight ratio, fibrosis and liver α-SMA. Mice administered a diet accurately reflecting patterns associated with humans afflicted with MetS can reliably replicate features of MetS, NASH and significant liver fibrosis. The model we describe significantly reduces the time by several months for development of stage 3 hepatic fibrosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System

    PubMed Central

    Norris, Christopher; Loureiro, Michael; Kramar, Cecilia; Zunder, Jordan; Renard, Justine; Rushlow, Walter; Laviolette, Steven R

    2016-01-01

    Emerging evidence suggests that the largest phytochemical component of cannabis, cannabidiol (CBD), may possess pharmacotherapeutic properties in the treatment of neuropsychiatric disorders. CBD has been reported to functionally interact with both the mesolimbic dopamine (DA) and serotonergic (5-HT) receptor systems. However, the underlying mechanisms by which CBD may modulate emotional processing are not currently understood. Using a combination of in vivo electrophysiological recording and fear conditioning in rats, the present study aimed to characterize the behavioral, neuroanatomical, and pharmacological effects of CBD within the mesolimbic pathway, and its possible functional interactions with 5-HT and DAergic transmission. Using targeted microinfusions of CBD into the shell region of the mesolimbic nucleus accumbens (NASh), we report that intra-NASh CBD potently blocks the formation of conditioned freezing behaviors. These effects were challenged with DAergic, cannabinoid CB1 receptor, and serotonergic (5-HT1A) transmission blockade, but only 5-HT1A blockade restored associative conditioned freezing behaviors. In vivo intra-ventral tegmental area (VTA) electrophysiological recordings revealed that behaviorally effective doses of intra-NASh CBD elicited a predominant decrease in spontaneous DAergic neuronal frequency and bursting activity. These neuronal effects were reversed by simultaneous blockade of 5-HT1A receptor transmission. Finally, using a functional contralateral disconnection procedure, we demonstrated that the ability of intra-NASh CBD to block the formation of conditioned freezing behaviors was dependent on intra-VTA GABAergic transmission substrates. Our findings demonstrate a novel NAc→VTA circuit responsible for the behavioral and neuronal effects of CBD within the mesolimbic system via functional interactions with serotonergic 5-HT1A receptor signaling. PMID:27296152

  4. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent.

    PubMed

    Tetri, Laura H; Basaranoglu, Metin; Brunt, Elizabeth M; Yerian, Lisa M; Neuschwander-Tetri, Brent A

    2008-11-01

    The aims of this study were to determine whether combining features of a western lifestyle in mice with trans fats in a high-fat diet, high-fructose corn syrup in the water, and interventions designed to promote sedentary behavior would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH). Male C57BL/6 mice fed ad libitum high-fat chow containing trans fats (partially hydrogenated vegetable oil) and relevant amounts of a high-fructose corn syrup (HFCS) equivalent for 1-16 wk were compared with mice fed standard chow or mice with trans fats or HFCS omitted. Cage racks were removed from western diet mice to promote sedentary behavior. By 16 wk, trans fat-fed mice became obese and developed severe hepatic steatosis with associated necroinflammatory changes. Plasma alanine aminotransferase levels increased, as did liver TNF-alpha and procollagen mRNA, indicating an inflammatory and profibrogenic response to injury. Glucose intolerance and impaired fasting glucose developed within 2 and 4 wk, respectively. Plasma insulin, resistin, and leptin levels increased in a profile similar to that seen in patients with NASH. The individual components of this diet contributed to the phenotype independently; isocaloric replacement of trans fats with lard established that trans fats played a major role in promoting hepatic steatosis and injury, whereas inclusion of HFCS promoted food consumption, obesity, and impaired insulin sensitivity. Combining risk factors for the metabolic syndrome by feeding mice trans fats and HFCS induced histological features of NASH in the context of a metabolic profile similar to patients with this disease. Because dietary trans fats promoted liver steatosis and injury, their role in the epidemic of NASH needs further evaluation.

  5. Dietary modification dampens liver inflammation and fibrosis in obesity-related fatty liver disease.

    PubMed

    Larter, Claire Z; Yeh, Matthew M; Haigh, W Geoffrey; Van Rooyen, Derrick M; Brooling, John; Heydet, Deborah; Nolan, Christopher J; Teoh, Narci C; Farrell, Geoffrey C

    2013-06-01

    Alms1 mutant (foz/foz) mice develop hyperphagic obesity, diabetes, metabolic syndrome, and fatty liver (steatosis). High-fat (HF) feeding converts pathology from bland steatosis to nonalcoholic steatohepatitis (NASH) with fibrosis, which leads to cirrhosis in humans. We sought to establish how dietary composition contributes to NASH pathogenesis. foz/foz mice were fed HF diet or chow 24 weeks, or switched HF to chow after 12 weeks. Serum ALT, NAFLD activity score (NAS), fibrosis severity, neutrophil, macrophage and apoptosis immunohistochemistry, uncoupling protein (UCP)2, ATP, NF-κB activation/expression of chemokines/adhesion molecules/fibrogenic pathways were determined. HF intake upregulated liver fatty acid and cholesterol transporter, CD36. Dietary switch expanded adipose tissue and decreased hepatomegaly by lowering triglyceride, cholesterol ester, free cholesterol and diacylglyceride content of liver. There was no change in lipogenesis or fatty acid oxidation pathways; instead, CD36 was suppressed. These diet-induced changes in hepatic lipids improved NAS, reduced neutrophil infiltration, normalized UCP2 and increased ATP; this facilitated apoptosis with a change in macrophage phenotype favoring M2 cells. Dietary switch also abrogated NF-κB activation and chemokine/adhesion molecule expression, and arrested fibrosis by dampening stellate cell activation. Reversion to a physiological dietary composition after HF feeding in foz/foz mice alters body weight distribution but not obesity. This attenuates NASH severity and fibrotic progression by suppressing NF-κB activation and reducing neutrophil and macrophage activation. However, adipose inflammation persists and is associated with continuing apoptosis in the residual fatty liver disease. Taken together, these findings indicate that other measures, such as weight reduction, may be required to fully reverse obesity-related NASH. Copyright © 2013 The Obesity Society.

  6. Circulating microRNA 122 in the methionine and choline-deficient mouse model of non-alcoholic steatohepatitis.

    PubMed

    Clarke, John D; Sharapova, Tatiana; Lake, April D; Blomme, Eric; Maher, Jonathan; Cherrington, Nathan J

    2014-06-01

    Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) and is a major cause of liver cirrhosis and hepatic failure. The methionine choline-deficient diet (MCD) is a frequently used hepatotoxicity animal model of NASH that induces hepatic transaminase (ALT, AST) elevations and hepatobiliary histological changes similar to those observed in human NASH. Liver-specific microRNA-122 (miR-122) has been shown as a key regulator of cholesterol and fatty acid metabolism in adult liver, and has recently been proposed as a sensitive and specific circulating biomarker of hepatic injury. The purpose of this study was to assess miR-122 serum levels in mice receiving an MCD diet for 0, 3, 7, 14, 28 and 56 days and compare the performance vs. routine clinical chemistry when benchmarked against the histopathological liver findings. MiR-122 levels were quantified in serum using RT-qPCR. Both miR-122 and ALT/AST levels were significantly elevated in serum at all timepoints. MiR-122 levels increased on average by 40-fold after 3 days of initiating the MCD diet, whereas ALT and AST changes were 4.8- and 3.3-fold, respectively. In general, miR-122 levels remained elevated across all time points, whereas the ALT/AST increases were less robust but correlated with the progressive severity of NASH as assessed by histopathology. In conclusion, serum levels of miR-122 can potentially be used as a sensitive biomarker for the early detection of hepatotoxicity and can aid in monitoring the extent of NAFLD-associated liver injury in mouse efficacy models. Copyright © 2013 John Wiley & Sons, Ltd.

  7. Raloxifene Ameliorates Liver Fibrosis of Nonalcoholic Steatohepatitis Induced by Choline-Deficient High-Fat Diet in Ovariectomized Mice.

    PubMed

    Luo, Fangqiong; Ishigami, Masatoshi; Achiwa, Koichi; Ishizu, Yoji; Kuzuya, Teiji; Honda, Takashi; Hayashi, Kazuhiko; Ishikawa, Tetsuya; Katano, Yoshiaki; Goto, Hidemi

    2015-09-01

    The prevalence of nonalcoholic fatty liver disease (NAFLD) is higher in men than in women, but according to some epidemiological studies, this gender difference disappears after menopause. Estrogen therapy protects against NAFLD and nonalcoholic steatohepatitis (NASH) after menopause. We investigated the therapeutic effect of raloxifene, a second-generation selective estrogen-receptor modulator, on NASH induced by a choline-deficient high-fat (CDHF) diet in female ovariectomized (OVX) mice. Seven-week-old female C57BL/6J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + raloxifene (intraperitoneal injection, 3 mg/kg body weight/day; OVX + RLX group). These three groups of mice were fed a CDHF diet for 8 weeks; choline-sufficient high-fat (CSHF) diet was used as control diet. Serum biochemical indicators of hepatic function and liver histological changes were evaluated. Compared with CSHF diet, ovariectomy enhances liver injury and fibrosis in CDHF diet-fed mice. Serum alanine aminotransferase (ALT) levels were significantly lower in the OVX + RLX group than in the OVX group. The OVX group developed extensive steatosis with inflammation and fibrosis. Lobular inflammatory scores and fibrosis staging in the OVX + RLX group were significantly lower than in the OVX group. Furthermore, the OVX + RLX group exhibited significantly higher expression of hepatic estrogen receptor-α, which was significantly lower in the OVX group than in the SHAM group. Raloxifene may ameliorate progression of liver fibrosis of NASH induced by CDHF diet in ovariectomized female mice, and up-regulation of estrogen receptor-α may play an important role in the beneficial effects of raloxifene on NASH.

  8. What are the symptoms of NAFLD and NASH?

    MedlinePlus

    ... Process Research Training & Career Development Funded Grants & Grant History Research Resources Research at NIDDK Technology Advancement & Transfer Meetings & Workshops Health Information Diabetes Digestive ...

  9. Games of age-dependent prevention of chronic infections by social distancing.

    PubMed

    Reluga, Timothy C; Li, Jing

    2013-06-01

    Epidemiological games combine epidemic modelling with game theory to assess strategic choices in response to risks from infectious diseases. In most epidemiological games studied thus-far, the strategies of an individual are represented with a single choice parameter. There are many natural situations where strategies can not be represented by a single dimension, including situations where individuals can change their behavior as they age. To better understand how age-dependent variations in behavior can help individuals deal with infection risks, we study an epidemiological game in an SI model with two life-history stages where social distancing behaviors that reduce exposure rates are age-dependent. When considering a special case of the general model, we show that there is a unique Nash equilibrium when the infection pressure is a monotone function of aggregate exposure rates, but non-monotone effects can appear even in our special case. The non-monotone effects sometimes result in three Nash equilibria, two of which have local invasion potential simultaneously. Returning to a general case, we also describe a game with continuous age-structure using partial-differential equations, numerically identify some Nash equilibria, and conjecture about uniqueness.

  10. Function of inhibitor of Bruton's tyrosine kinase isoform α (IBTKα) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response.

    PubMed

    Willy, Jeffrey A; Young, Sara K; Mosley, Amber L; Gawrieh, Samer; Stevens, James L; Masuoka, Howard C; Wek, Ronald C

    2017-08-25

    Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify the α isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Joint decision of pricing and order quantity by considering product substitution in dual channel supply chain

    NASA Astrophysics Data System (ADS)

    Widodo, Erwin

    2017-11-01

    Dual channel supply chain (DCSC) has been attracting many researchers' attention. Their contributions mainly are in two folds, namely pricing problem and inventory policy. However, research to address both pricing and inventory problems simultaneously are still scarce. Meanwhile in recent competitive market, product substitution is an unavoidable practice in fulfilling customer demand when the main product is unavailable. Thus how to decide price and order quantity by considering product substitution under DCSC setting is an interesting topic to address. In this paper, corresponding mathematical model incorporating such problem is proposed. This model consists of objective function measuring sales revenue and inventory cost, and some constraints to assure positive profit margin, interplaying price between online and offline channel, and positive demand. Two pricing schemes, namely Vertical Nash and Stackelberg Leadership are evaluated. The result shows that in any situation of substitution level, Vertical Nash solution provides higher financial performance than that under Stackelberg Leadership. In addition, this work's results have also revealed that there exist some threshold values differentiating when it is better off to apply Vertical Nash scenario an, when Stackelberg Leadership scenario is preferable.

  12. Epigenetic Mechanisms Underlying the Link between Non-Alcoholic Fatty Liver Diseases and Nutrition

    PubMed Central

    Lee, Joo Ho; Friso, Simonetta; Choi, Sang-Woon

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is defined as a pathologic accumulation of fat in the form of triglycerides (TG) in the liver (steatosis) that is not caused by alcohol. A subgroup of NAFLD patients shows liver cell injury and inflammation coupled with the excessive fat accumulation (steatohepatitis), which is referred to as non-alcoholic steatohepatitis (NASH). Patients with NASH may develop cirrhosis and hepatocellular carcinoma (HCC). NAFLD shares the key features of metabolic syndrome including obesity, hyperlipidemia, hypertension, and insulin resistance. The pathogenesis of NAFLD is multi-factorial, however the oxidative stress seems to plays a major role in the development and progression of the disease. The emerging field of epigenetics provides a new perspective on the pathogenesis of NAFLD. Epigenetics is an inheritable but reversible phenomenon that affects gene expression without altering the DNA sequence and refers to DNA methylation, histone modifications and microRNAs. Epigenetic manipulation through metabolic pathways such as one-carbon metabolism has been proposed as a promising approach to retard the progression of NAFLD. Investigating the epigenetic modifiers in NAFLD may also lead to the development of preventive or therapeutic strategies for NASH-associated complications. PMID:25195642

  13. Roux-En Y Gastric Bypass Results in Long-Term Remission of Hepatocyte Apoptosis and Hepatic Histological Features of Non-alcoholic Steatohepatitis.

    PubMed

    Schneck, Anne-Sophie; Anty, Rodolphe; Patouraux, Stéphanie; Bonnafous, Stéphanie; Rousseau, Déborah; Lebeaupin, Cynthia; Bailly-Maitre, Beatrice; Sans, Arnaud; Tran, Albert; Gugenheim, Jean; Iannelli, Antonio; Gual, Philippe

    2016-01-01

    The long-term effects of bariatric surgery on non-alcoholic steatohepatitis (NASH), focusing on liver injury and hepatocyte apoptosis, are not well-established. We here performed a longitudinal study with paired liver biopsies of nine morbidly obese women (median BMI: 42 [38.7; 45.1] kg/m(2)) with NASH with a median follow-up of 55 [44; 75] months after laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. LRYGB surgery was associated with significant weight loss (median BMI loss -13.7 [-16.4; -9.5] kg/m(2)), improved hepatic steatosis in all patients (55.5% with total resolution), and resolution of hepatic inflammation and hepatocyte ballooning in 100 and 88.8% of cases, respectively. Alanine aminotransferase levels dropped to normal values while hepatic activated cleaved caspase-3 levels strongly decreased after a median follow-up of 55 months. Hepatocyte apoptosis, as evaluated by serum caspase-generated keratin-18 fragment, improved within the first year following LRYGB and these improvements persisted for at least 55 months. LRYGB in morbidly obese patients with NASH is thus associated with a long-lasting beneficial impact on hepatic steatohepatitis and hepatocyte death.

  14. Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

    PubMed

    Suzuki-Kemuriyama, Noriko; Matsuzaka, Takashi; Kuba, Motoko; Ohno, Hiroshi; Han, Song-Iee; Takeuchi, Yoshinori; Isaka, Masaaki; Kobayashi, Kazuto; Iwasaki, Hitoshi; Yatoh, Shigeru; Suzuki, Hiroaki; Miyajima, Katsuhiro; Nakae, Dai; Yahagi, Naoya; Nakagawa, Yoshimi; Sone, Hirohito; Yamada, Nobuhiro; Shimano, Hitoshi

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

  15. Second Harmonic Generation Reveals Subtle Fibrosis Differences in Adult and Pediatric Nonalcoholic Fatty Liver Disease.

    PubMed

    Liu, Feng; Zhao, Jing-Min; Rao, Hui-Ying; Yu, Wei-Miao; Zhang, Wei; Theise, Neil D; Wee, Aileen; Wei, Lai

    2017-11-20

    Investigate subtle fibrosis similarities and differences in adult and pediatric nonalcoholic fatty liver disease (NAFLD) using second harmonic generation (SHG). SHG/two-photon excitation fluorescence imaging quantified 100 collagen parameters and determined qFibrosis values by using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system in 62 adult and 36 pediatric NAFLD liver specimens. Six distinct parameters identified differences among the NASH CRN stages with high accuracy (area under the curve, 0835-0.982 vs 0.885-0.981, adult and pediatric). All portal region parameters showed similar changes across early stages 0, 1C, and 2, in both groups. Parameter values decreased in adults with progression from stage 1A/B to 2 in the central vein region. In children, aggregated collagen parameters decreased, but nearly all distributed collagen parameters increased from stage 1A/B to 2. SHG analysis accurately reproduces NASH CRN staging in NAFLD, as well as reveals differences and similarities between adult and pediatric collagen deposition not captured by currently available quantitative methods. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  16. On 2- and 3-person games on polyhedral sets

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Belenky, A.S.

    1994-12-31

    Special classes of 3 person games are considered where the sets of players` allowable strategies are polyhedral and the payoff functions are defined as maxima, on a polyhedral set, of certain kind of sums of linear and bilinear functions. Necessary and sufficient conditions, which are easy to verify, for a Nash point in these games are established, and a finite method, based on these conditions, for calculating Nash points is proposed. It is shown that the game serves as a generalization of a model for a problem of waste products evacuation from a territory. The method makes it possible tomore » reduce calculation of a Nash point to solving some linear and quadratic programming problems formulated on the basis of the original 3-person game. A class of 2-person games on connected polyhedral sets is considered, with the payoff function being a sum of two linear functions and one bilinear function. Necessary and sufficient conditions are established for the min-max, the max-min, and for a certain equilibrium. It is shown that the corresponding points can be calculated from auxiliary linear programming problems formulated on the basis of the master game.« less

  17. Mild Hypothermia and Acute Kidney Injury in Liver Transplantation

    ClinicalTrials.gov

    2018-06-18

    Cirrhosis; End Stage Liver Disease; Acute Kidney Injury; Liver Transplant; Complications; Chronic Kidney Diseases; Hepatitis c; Hepatitis B; NASH - Nonalcoholic Steatohepatitis; Alcoholic Cirrhosis; Hepatocellular Carcinoma

  18. Predictors of fibrosis in Asian patients with non-alcoholic steatohepatitis.

    PubMed

    Tsang, Steven Woon Choy; Ng, Wing Fung; Wu, Brian Ping Ying; Chow, David Alan; Li, Eric Ting Ho; Wong, Tak Cheung

    2006-01-01

    Non-alcoholic steatohepatitis (NASH) is increasingly recognized as an important cause of chronic liver disease. However, data on Asians with NASH is lacking in the literature. The aim of the present study was to describe the clinical, biochemical and histological characteristics of NASH in Asians and to determine the predictors for septal fibrosis. Sixty consecutive patients aged over 18 years with elevated serum alanine transferase, sonographic evidence of steatosis, and consent for liver biopsy were included. Patients with chronic hepatitis B or C, alcoholic, autoimmune, genetic, or drug-induced liver disease were excluded. Clinical, biochemical and histological variables were tested for association with septal liver fibrosis (F2/3). Median age of the cohort was 45.5 years (range 21-75 years) and 63% were male. Ninety percent of patients were obese (body mass index [BMI]>or= 25), 70% had hypertriglyceridemia, 68% had hypercholesterolemia, 58% had metabolic syndrome, 53% had hypertension, 47% had diabetes mellitus (DM), and 18% had obstructive sleep apnea. Sixty-eight percent had gamma-glutamyl transferase (GGT) >or= 2 x upper limit of normal (ULN), 55% had alanine aminotransferase (ALT) >or= 2 x ULN, and 23% had aspartate aminotransferase (AST) >or= 2 x ULN. Of the 40 non-diabetic patients undergoing oral glucose tolerance testing, 45% had normal tests, 30% had impaired glucose tolerance, 23% DM, and 2% impaired fasting glucose. Eighteen patients (30%) had septal fibrosis (F2/3), but none had cirrhosis. Necroinflammatory grade >or= 2 (odds ratio [OR] 13), AST >or= 2 x ULN (OR 5.3) and DM (OR 5) were significantly and independently correlated with septal fibrosis. Septal fibrosis is common in Asians with NASH. Necroinflammatory grade >or= 2, AST >or= 2 x ULN and DM are independent predictors for septal fibrosis.

  19. High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels.

    PubMed

    Portillo-Sanchez, Paola; Bril, Fernando; Maximos, Maryann; Lomonaco, Romina; Biernacki, Diane; Orsak, Beverly; Subbarayan, Sreevidya; Webb, Amy; Hecht, Joan; Cusi, Kenneth

    2015-06-01

    Nonalcoholic fatty liver disease (NAFLD) and its more severe form with steatohepatitis (NASH) are common in patients with type 2 diabetes mellitus (T2DM). However, they are usually believed to largely affect those with elevated aminotransferases. The aim of this study was to determine the prevalence of NAFLD by the gold standard, liver magnetic resonance spectroscopy ((1)H-MRS) in patients with T2DM and normal aminotransferases, and to characterize their metabolic profile. We recruited 103 patients with T2DM and normal plasma aminotransferases (age, 60 ± 8 y; body mass index [BMI], 33 ± 5 kg/m(2); glycated hemoglobin [A1c], 7.6 ± 1.3%). We measured the following: 1) liver triglyceride content by (1)H-MRS; 2) systemic insulin sensitivity (homeostasis model assessment-insulin resistance); and 3) adipose tissue insulin resistance, both fasting (as the adipose tissue insulin resistance index: fasting plasma free fatty acids [FFA] × insulin) and during an oral glucose tolerance test (as the suppression of FFA). The prevalence of NAFLD and NASH were much higher than expected (50% and 56% of NAFLD patients, respectively). The prevalence of NAFLD was higher in obese compared with nonobese patients as well as with increasing BMI (P = .001 for trend). Higher plasma A1c was associated with a greater prevalence of NAFLD and worse liver triglyceride accumulation (P = .01). Compared with nonobese patients without NAFLD, patients with NAFLD had severe systemic (liver/muscle) and, particularly, adipose tissue (fasting/postprandial) insulin resistance (all P < .01). The prevalence of NAFLD is much higher than previously believed in overweight/obese patients with T2DM and normal aminotransferases. Moreover, many are at increased risk of NASH. Physicians should have a lower threshold for screening patients with T2DM for NAFLD/NASH.

  20. Lipid Metabolism, Oxidative Stress and Cell Death Are Regulated by PKC Delta in a Dietary Model of Nonalcoholic Steatohepatitis

    PubMed Central

    Greene, Michael W.; Burrington, Christine M.; Lynch, Darin T.; Davenport, Samantha K.; Johnson, Andrew K.; Horsman, Melissa J.; Chowdhry, Saleem; Zhang, Jian; Sparks, Janet D.; Tirrell, Paul C.

    2014-01-01

    Steatosis, oxidative stress, and apoptosis underlie the development of nonalcoholic steatohepatitis (NASH). Protein kinase C delta (PKCδ) has been implicated in fatty liver disease and is activated in the methionine and choline-deficient (MCD) diet model of NASH, yet its pathophysiological importance towards steatohepatitis progression is uncertain. We therefore addressed the role of PKCδ in the development of steatosis, inflammation, oxidative stress, apoptosis, and fibrosis in an animal model of NASH. We fed PKCδ−/− mice and wildtype littermates a control or MCD diet. PKCδ−/− primary hepatocytes were used to evaluate the direct effects of fatty acids on hepatocyte lipid metabolism gene expression. A reduction in hepatic steatosis and triglyceride levels were observed between wildtype and PKCδ−/− mice fed the MCD diet. The hepatic expression of key regulators of β-oxidation and plasma triglyceride metabolism was significantly reduced in PKCδ−/− mice and changes in serum triglyceride were blocked in PKCδ−/− mice. MCD diet-induced hepatic oxidative stress and hepatocyte apoptosis were reduced in PKCδ−/− mice. MCD diet-induced NADPH oxidase activity and p47phox membrane translocation were blunted and blocked, respectively, in PKCδ−/− mice. Expression of pro-apoptotic genes and caspase 3 and 9 cleavage in the liver of MCD diet fed PKCδ−/− mice were blunted and blocked, respectively. Surprisingly, no differences in MCD diet-induced fibrosis or pro-fibrotic gene expression were observed in 8 week MCD diet fed PKCδ−/− mice. Our results suggest that PKCδ plays a role in key pathological features of fatty liver disease but not ultimately in fibrosis in the MCD diet model of NASH. PMID:24454937

  1. Effect of Colesevelam on Liver Fat Quantified by Magnetic Resonance in Nonalcoholic Steatohepatitis: A Randomized Controlled Trial

    PubMed Central

    Le, Thuy-Anh; Chen, Joshua; Changchien, Christopher; Peterson, Michael R; Kono, Yuko; Patton, Heather; Cohen, Benjamin L; Brenner, David; Sirlin, Claude; Loomba, Rohit

    2012-01-01

    Bile acid sequestrants (BAS) lower plasma low density lipoprotein levels and improve glycemic control. Colestimide, a BAS, has been claimed by computed tomography to reduce liver fat. Therefore, we examined the efficacy of colesevelam, a potent BAS, to decrease liver fat in patients with biopsy-proven nonalcoholic steatohepatitis (NASH). Liver fat was measured by a novel magnetic resonance imaging (MRI) technique, the proton-density-fat-fraction (PDFF), as well as by conventional MR spectroscopy (MRS). Fifty patients with biopsy-proven NASH were randomly assigned to either colesevelam 3.75 g/day orally or placebo for 24 weeks. The primary outcome was change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Compared with placebo, colesevelam increased liver fat by MRI-PDFF in all nine segments of the liver with a mean difference of 5.6% (P = 0.002). We cross-validated the MRI-PDFF-determined fat content with that assessed by colocalized MRS; the latter showed a mean difference of 4.9% (P = 0.014) in liver fat between the colesevelam and the placebo arms. MRI-PDFF correlated strongly with MRS-determined hepatic fat content (r2 = 0.96, P < 0.0001). Liver biopsy assessment of steatosis, cellular injury, and lobular inflammation did not detect any effect of treatment. Conclusion: Colesevelam increases liver fat in patients with NASH as assessed by MRI as well as MRS without significant changes seen on histology. Thus, MRI and MRS may be better than histology to detect longitudinal changes in hepatic fat in NASH. Underlying mechanisms and whether the small MR-detected increase in liver fat has clinical consequences is not known. (Hepatology 2012;56:922–932) PMID:22431131

  2. Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet

    PubMed Central

    Honda, Masao; Takegoshi, Kai; Yamashita, Taro; Nakamura, Mikiko; Shirasaki, Takayoshi; Sakai, Yoshio; Shimakami, Tetsuro; Nagata, Naoto; Takamura, Toshinari; Tanaka, Takuji; Kaneko, Shuichi

    2017-01-01

    The pathogenesis of non-alcoholic steatohepatitis (NASH) is still unclear and the prevention of the development of hepatocellular carcinoma (HCC) has not been established. We established an atherogenic and high-fat diet mouse model that develops hepatic steatosis, inflammation, fibrosis, and liver tumors at a high frequency. Using two NASH-HCC mouse models, we showed that peretinoin, an acyclic retinoid, significantly improved liver histology and reduced the incidence of liver tumors. Interestingly, we found that peretinoin induced autophagy in the liver of mice, which was characterized by the increased co-localized expression of microtubule-associated protein light chain 3B-II and lysosome-associated membrane protein 2, and increased autophagosome formation and autophagy flux in the liver. These findings were confirmed using primary mouse hepatocytes. Among representative autophagy pathways, the autophagy related (Atg) 5-Atg12-Atg16L1 pathway was impaired; especially, Atg16L1 was repressed at both the mRNA and protein level. Decreased Atg16L1 mRNA expression was also found in the liver of patients with NASH according to disease progression. Promoter analysis revealed that peretinoin activated the promoter of Atg16L1 by increasing the expression of CCAAT/enhancer-binding-protein-alpha. Interestingly, Atg16L1 overexpression in HepG2 cells inhibited palmitate-induced NF-kB activation and interleukin-6-induced STAT3 activation. We showed that Atg16L1 induced the de-phosphorylation of Gp130, a receptor subunit of interleukin-6 family cytokines, which subsequently repressed phosphorylated-STAT3 (Tyr705) levels, and this process might be independent of autophagy function. Thus, peretinoin prevents the progression of NASH and the development of HCC through activating the autophagy pathway by increased Atg16L1 expression, which is an essential regulator of autophagy and anti-inflammatory proteins. PMID:28591717

  3. Risk factors for biopsy-proven advanced non-alcoholic fatty liver disease in the Veterans Health Administration.

    PubMed

    Patel, Y A; Gifford, E J; Glass, L M; McNeil, R; Turner, M J; Han, B; Provenzale, D; Choi, S S; Moylan, C A; Hunt, C M

    2018-01-01

    With its increasing incidence, nonalcoholic fatty liver disease (NAFLD) is of particular concern in the Veterans Health Administration (VHA). To evaluate risk factors for advanced fibrosis in biopsy-proven NAFLD in the VHA, to identify patients at risk for adverse outcomes. In randomly selected cases from VHA databases (2005-2015), we performed a retrospective case-control study in adults with biopsy-defined NAFLD or normal liver. Of 2091 patients reviewed, 399 met inclusion criteria. Normal controls (n = 65) had normal liver function. The four NAFLD cohorts included: NAFL steatosis (n = 76), nonalcoholic steatohepatitis (NASH) without fibrosis (n = 68), NAFLD/NASH stage 1-3 fibrosis (n = 82), and NAFLD/NASH cirrhosis (n = 70). NAFLD with hepatocellular carcinoma (HCC) was separately identified (n = 38). Most patients were older White men. NAFLD patients with any fibrosis were on average severely obese (BMI>35 kg/m 2 ). Diabetes (54.4%-79.6%) and hypertension (85.8%-100%) were more common in NAFLD with fibrosis or HCC. Across NAFLD, 12.3%-19.5% were enrolled in diet/exercise programs and 0%-2.6% had bariatric surgery. Hispanics exhibited higher rates of NASH (20.6%), while Blacks had low NAFLD rates (1.4%-11.8%), particularly NAFLD cirrhosis and HCC (1.4%-2.6%). Diabetes (OR 11.8, P < .001) and BMI (OR 1.4, P < .001) were the most significant predictors of advanced fibrosis. In the VHA, diabetes and severe obesity increased risk for advanced fibrosis in NAFLD. Of these patients, only a small proportion (~20%) had enrolled in diet/exercise programs or had bariatric surgery (~2%). These results suggest that providers should focus/tailor interventions to improve outcomes, particularly in those with diabetes and severe obesity. © 2017 John Wiley & Sons Ltd.

  4. "Non alcoholic fatty liver disease and eNOS dysfunction in humans".

    PubMed

    Persico, Marcello; Masarone, Mario; Damato, Antonio; Ambrosio, Mariateresa; Federico, Alessandro; Rosato, Valerio; Bucci, Tommaso; Carrizzo, Albino; Vecchione, Carmine

    2017-03-07

    NAFLD is associated to Insulin Resistance (IR). IR is responsible for Endothelial Dysfunction (ED) through the impairment of eNOS function. Although eNOS derangement has been demonstrated in experimental models, no studies have directly shown that eNOS dysfunction is associated with NAFLD in humans. The aim of this study is to investigate eNOS function in NAFLD patients. Fifty-four NAFLD patients were consecutively enrolled. All patients underwent clinical and laboratory evaluation and liver biopsy. Patients were divided into two groups by the presence of NAFL or NASH. We measured vascular reactivity induced by patients' platelets on isolated mice aorta rings. Immunoblot assays for platelet-derived phosphorylated-eNOS (p-eNOS) and immunohistochemistry for hepatic p-eNOS have been performed to evaluate eNOS function in platelets and liver specimens. Flow-mediated-dilation (FMD) was also performed. Data were compared with healthy controls. Twenty-one (38, 8%) patients had NAFL and 33 (61, 7%) NASH. No differences were found between groups and controls except for HOMA and insulin (p < 0.0001). Vascular reactivity demonstrated a reduced function induced from NAFLD platelets as compared with controls (p < 0.001), associated with an impaired p-eNOS in both platelets and liver (p < 0.001). NAFL showed a higher impairment of eNOS phosphorylation in comparison to NASH (p < 0.01). In contrast with what observed in vitro, the vascular response by FMD was worse in NASH as compared with NAFL. Our data showed, for the first time in humans, that NAFLD patients show a marked eNOS dysfunction, which may contribute to a higher CV risk. eNOS dysfunction observed in platelets and liver tissue didn't match with FMD.

  5. Diagnosis of different liver fibrosis characteristics by blood tests in non-alcoholic fatty liver disease.

    PubMed

    Calès, Paul; Boursier, Jérôme; Chaigneau, Julien; Lainé, Fabrice; Sandrini, Jeremy; Michalak, Sophie; Hubert, Isabelle; Dib, Nina; Oberti, Frédéric; Bertrais, Sandrine; Hunault, Gilles; Cavaro-Ménard, Christine; Gallois, Yves; Deugnier, Yves; Rousselet, Marie C

    2010-10-01

    Our aim was to develop an accurate, non-invasive, blood-test-based method for identifying the main characteristics of liver fibrosis in non-alcoholic fatty liver disease (NAFLD). Fibrosis was staged according to NASH-CRN and Metavir systems in 226 patients with NAFLD. A fully automated algorithm measured the fractal dimension (FD) and the area of fibrosis (AOF). Independent predictors of diagnostic targets were determined using bootstrap methods. (i) Development. Significant fibrosis defined by NASH-CRN F ≥2 was diagnosed by weight, glycaemia, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and prothrombin index [area under the receiver operating characteristic (AUROC)=0.867]; significant fibrosis defined by Metavir F ≥2 was diagnosed by weight, age, glycaemia, AST, ALT, ferritin and platelets (FibroMeter AUROC=0.941, P<0.005). AOF was estimated by the combination of hyaluronic acid, glycaemia, AST, ALT, platelets and prothrombin index ((a) R(2) =0.530), while FD was estimated by hyaluronic acid, glycaemia, AST/ALT, weight and platelets ((a) R(2) =0.529). (ii) Evaluation. Although NASH-CRN was a better system for fibrosis staging, Metavir staging was a better reference for blood test. Thus, the patient rate with predictive values ≥90% by tests was 97.3% with Metavir reference vs. 66.5% with NASH-CRN reference (P<10(-3)). FibroMeter showed a significantly higher AUROC than the NAFLD fibrosis score for significant fibrosis, but not for severe fibrosis or cirrhosis, with both staging systems. Relationships between fibrosis lesions were well reflected by blood tests, e.g., the correlation between histological area and FD of fibrosis (r(s) =0.971, P<10(-3)) was well reflected by the relationship between respective blood tests (r(s) =0.852, P<10(-3)). Different characteristics of fibrosis in NAFLD can be diagnosed and quantified by blood tests with excellent accuracy. © 2010 John Wiley & Sons A/S.

  6. Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice

    PubMed Central

    Kim, Ja Kyung; Lee, Kwan Sik; Lee, Dong Ki; Lee, Su Yeon; Chang, Hye Young; Choi, Junjeong; Lee, Jung Il

    2014-01-01

    Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen α1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor α showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH. PMID:25523099

  7. Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats.

    PubMed

    Wang, Yan; Seitz, Helmut K; Wang, Xiang-Dong

    2010-03-01

    Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition. Sprague-Dawley rats were first fed ad libitum with Lieber-DeCarli high-fat diet (71% energy from fat) for 6 weeks to induce NASH, as demonstrated previously. Afterwards, these rats were continuously fed with high-fat diet (HFD, 55% total energy from fat) or high fat plus alcohol diet (HFA, 55% energy from fat and 16% energy from alcohol) for an additional 4 weeks. Pathological lesions including fat accumulation and inflammatory foci in liver were examined and graded. Lipid peroxidation and apoptotic hepatocytes in the liver were assessed. The mRNA expressions of tumor necrosis factor-alpha (TNFalpha) and TNF receptor 1 (TNF-R1), Fas death receptor (Fas) and Fas ligant (FasL), IL-1beta and IL-12 were determined by real-time PCR. Protein levels of total and cleaved caspase-3, CYP2E1, Bax, and Bcl-2 were measured by western blotting. The number of hepatic inflammatory foci and apoptotic hepatocytes were significantly increased in rats fed with HFA as compared with those in HFD-fed rats. The aggravated inflammatory response and cellular apoptosis mediated by HFA were associated with elevated mRNA expression of Fas/FasL and cleaved caspase-3 protein. Although no significant differences were observed between HFD and HFA groups, the levels of lipid peroxidation, Bax and Bcl-2 protein concentration, and mRNA levels of other inflammatory cytokines were significantly higher in these 2 groups than those in the control group. These data suggest that even moderate alcohol consumption can cause more hepatic inflammation and cellular apoptosis in a pre-existing NASH condition.

  8. Lipid-induced Signaling Causes Release of Inflammatory Extracellular Vesicles from Hepatocytes

    PubMed Central

    Hirsova, Petra; Ibrahim, Samar H.; Krishnan, Anuradha; Verma, Vikas K.; Bronk, Steven F.; Werneburg, Nathan W.; Charlton, Michael R.; Shah, Vijay H.; Malhi, Harmeet; Gores, Gregory J.

    2016-01-01

    BACKGROUND & AIMS Hepatocyte cellular dysfunction and death induced by lipids, and macrophage-associated inflammation are characteristics of nonalcoholic steatohepatitis (NASH). The fatty acid palmitate can activate death receptor 5 (DR5) on hepatocytes, leading to their death, but little is known about how this process contributes to macrophage-associated inflammation. We investigated whether lipid-induced DR5 signaling results in release of extracellular vesicles (EV) from hepatocytes, and whether these can induce an inflammatory macrophage phenotype. METHODS Primary mouse and human hepatocytes and Huh7 cells were incubated with palmitate, its metabolite lysophosphatidylcholine, or diluent (control). The released EV were isolated, characterized, quantified, and applied to macrophages. C57BL/6 mice were placed on chow or a diet high in fat, fructose, and cholesterol to induce NASH. Some mice were also given the ROCK1 inhibitor fasudil; 2 weeks later, serum EVs were isolated and characterized by immunoblot and nanoparticle-tracking analyses. Livers were collected and analyzed by histology, immunohistochemistry, and quantitative PCR. RESULTS Incubation of primary hepatocytes and Huh7 cells with palmitate or lysophosphatidylcholine increased their release of EV, compared with control cells. This release was reduced by inactivating mediators of the DR5 signaling pathway or ROCK1 inhibition. Hepatocyte-derived EV contained TRAIL and induced expression of interleukin-1, beta (Il1b) and Il6 mRNAs in mouse bone marrow-derived macrophages. Activation of macrophages required DR5 and RIP1. Administration of the ROCK1 inhibitor fasudil to mice with NASH reduced serum levels of EV; this reduction was associated with decreased liver injury, inflammation, and fibrosis. CONCLUSIONS Lipids, which stimulate DR5, induce release of hepatocyte EV, which activate an inflammatory phenotype in macrophages. Strategies to inhibit ROCK1-dependent release of EV by hepatocytes might be

  9. Treatment with geraniol ameliorates methionine-choline-deficient diet-induced non-alcoholic steatohepatitis in rats.

    PubMed

    Chen, Jun; Fan, Xiaoxia; Zhou, Lin; Gao, Xiaogang

    2016-07-01

    Non-alcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease and is considered to be a causative factor of cryptogenic cirrhosis and hepatocellular carcinoma. The aim of this work was to investigate whether treatment with geraniol (a monoterpene) attenuated NASH induced by methionine-choline-deficient (MCD) diet in rats. Rats were fed with MCD diet to induce NASH and treated with geraniol (200 mg/kg/day) for 10 weeks. Treatment with geraniol reduced histological scores, fibrosis, and apoptosis in livers, lowered activities of alanine aminotransferase and aspartate aminotransferase in serum, and attenuated hepatic fat accumulation in rats fed with MCD diet. Treatment with geraniol preserved hepatic mitochondrial function, evidenced by reduced mitochondrial reactive oxygen species formation, enhanced adenosine triphosphate formation and membrane integrity, restored mitochondrial electron transport chain enzyme activity, and increased mitochondrial DNA content in rats fed with MCD diet. Treatment with geraniol reduced uncoupling protein 2 protein expression, and enhanced protein expression of prohibitin, mRNA expression of peroxisome proliferator-activated receptor α, and activity of mitochondrial carnitine palmitoyl transferase-I in livers of rats fed with MCD diet. Treatment with geraniol abated oxidative stress, evidenced by reduced malondialdehyde and 3-nitrotyrosine formation, enhanced activity of glutathione S-epoxide transferase, and down-regulated expression of inducible nitric oxide synthase and cytochrome P450 2E1 in livers of rats fed with MCD diet. Treatment with geraniol reduced myeloperoxidase activity and protein expression of tumor necrosis factor alpha and IL-6 in livers of rats fed with MCD diet. Treatment with geraniol attenuated MCD-induced NASH in rats. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  10. New Pharmacologic Agents That Target Inflammation and Fibrosis in Nonalcoholic Steatohepatitis-Related Kidney Disease.

    PubMed

    Musso, Giovanni; De Michieli, Franco; Bongiovanni, Daria; Parente, Renato; Framarin, Luciana; Leone, Nicola; Berrutti, Mara; Gambino, Roberto; Cassader, Maurizio; Cohney, Solomon; Paschetta, Elena

    2017-07-01

    Epidemiologic data show an association between the prevalence and severity of nonalcoholic fatty liver disease and the incidence and stage of chronic kidney disease (CKD); furthermore, nonalcoholic steatohepatitis (NASH)-related cirrhosis has a higher risk of renal failure, a greater necessity for simultaneous liver-kidney transplantation, and a poorer renal outcome than cirrhosis of other etiologies even after simultaneous liver-kidney transplantation. These data suggest that NASH and CKD share common proinflammatory and profibrotic mechanisms of progression, which are targeted incompletely by current treatments. We reviewed therapeutic approaches to late preclinical/early clinical stage of development in NASH and/or CKD, focusing on anti-inflammatory and antifibrotic treatments, which could slow the progression of both disease conditions. Renin inhibitors and angiotensin-converting enzyme-2 activators are new renin-angiotensin axis modulators that showed incremental advantages over angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers in preclinical models. Novel, potent, and selective agonists of peroxisome proliferator-activated receptors and of farnesoid X receptor, designed to overcome limitations of older compounds, showed promising results in clinical trials. Epigenetics, heat stress response, and common effectors of redox regulation also were subjected to intensive research, and the gut was targeted by several approaches, including synbiotics, antilipopolysaccharide antibodies, Toll-like receptor-4 antagonists, incretin mimetics, and fibroblast growth factor 19 analogs. Promising anti-inflammatory therapies include inhibitors of NOD-like receptor family, pyrin domain containing 3 inflammasome, of nuclear factor-κB, and of vascular adhesion protein-1, chemokine antagonists, and solithromycin, and approaches targeting common profibrogenic pathways operating in the liver and the kidney include galectin-3 antagonists, and inhibitors of rho

  11. Assessment of treatment response in nonalcoholic steatohepatitis using advanced magnetic resonance imaging measures

    PubMed Central

    Lin, Steven C.; Heba, Elhamy; Bettencourt, Ricki; Lin, Grace Y.; Valasek, Mark A.; Lunde, Ottar; Hamilton, Gavin; Sirlin, Claude B.; Loomba, Rohit

    2017-01-01

    Background Magnetic resonance imaging derived measures of liver fat and volume are emerging as accurate, non-invasive imaging biomarkers in non-alcoholic steatohepatitis (NASH). Little is known about these measures in relation to histology longitudinally. Aims This study examines this relationship between MRI-derived proton-density fat-fraction (PDFF), total liver volume (TLV), total liver fat index (TLFI), vs. histology in a NASH trial. Methods This is a secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial of 50 patients with biopsy-proven NASH randomized to oral ezetimibe 10mg daily (n=25) vs. placebo (n=25). Baseline and post-treatment anthropometrics, biochemical profiling, MRI, and biopsies were obtained. Results Baseline mean PDFF correlated strongly with TLFI (Spearman’s ρ=0.94, n=45, P<0.0001) and had good correlation with TLV (ρ=0.57, n=45, P<0.0001). Mean TLV correlated strongly with TLFI (ρ=0.78, n=45, P<0.0001). After 24 weeks, PDFF remained strongly correlated with TLFI (ρ=0.94, n=45, P<0.0001), maintaining good correlation with TLV (ρ=0.51, n=45, P=0.0004). TLV remained strongly correlated with TLFI (ρ=0.74, n=45, P<0.0001). Patients with Grade 1 vs. 3 steatosis had lower PDFF, TLV, and TLFI (P<0.0001, P=0.0003, P<0.0001, respectively). Regression analysis of changes in MRI-PDFF vs. TLV indicates that 10% reduction in MRI-PDFF predicts 257 mL reduction in TLV. Conclusions MRI-PDFF and TLV strongly correlated with TLFI. Decreases in steatosis were associated with an improvement in hepatomegaly. Lower values of these measures reflect lower histologic-steatosis grades. MRI-derived measures of liver fat and volume may be used as dynamic and more responsive imaging biomarkers in a NASH trial than histology. ClinicalTrials.gov number, NCT01766713. PMID:28116801

  12. A randomized, placebo‐controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis

    PubMed Central

    Ratziu, Vlad; Harrison, Stephen A.; Abdelmalek, Manal F.; Aithal, Guruprasad P.; Caballeria, Juan; Francque, Sven; Farrell, Geoffrey; Kowdley, Kris V.; Craxi, Antonio; Simon, Krzysztof; Fischer, Laurent; Melchor‐Khan, Liza; Vest, Jeffrey; Wiens, Brian L.; Vig, Pamela; Seyedkazemi, Star; Goodman, Zachary; Wong, Vincent Wai‐Sun; Loomba, Rohit; Tacke, Frank; Sanyal, Arun; Lefebvre, Eric

    2018-01-01

    The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of C—C chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A randomized, double‐blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) ≥4, and LF (stages 1‐3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2‐point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis (SH) and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of SH. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary endpoint of NAS improvement in the intent‐to‐treat population and resolution of SH was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19%, P = 0.52 and 8% vs. 6%, P = 0.49, respectively). However, the fibrosis endpoint was met in significantly more subjects on CVC than placebo (20% vs. 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo. Conclusion: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of SH compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. (Hepatology 2018;67:1754‐1767). PMID:28833331

  13. Prevalence of Hypothyroidism in Nonalcoholic Fatty Liver disease

    PubMed Central

    Pagadala, Mangesh R.; Zein, Claudia O.; Dasarathy, Srinivasan; Yerian, Lisa; Lopez, Rocio; McCullough, Arthur J.

    2014-01-01

    Background A possible association between nonalcoholic fatty liver disease (NAFLD) and hypothyroidism has been suggested. Possible explanations for this association are the recognized links between hypothyroidism and various elements of the metabolic syndrome which is often present in NAFLD. To further explore this association, we determined the prevalence of hypothyroidism in a cohort of patients with NAFLD and analyzed the potential factors associated with hypothyroidism in this patient population. Methods Two hundred and forty six patients with biopsy proven NAFLD attending hepatology clinics at the Cleveland Clinic between October 2006 to June 2009 and 430 age, gender, race and BMI matched control subjects seen in the general internal medicine clinic were included. Patients with a clinical diagnosis of hypothyroidism who were on thyroid replacement therapy were considered to be hypothyroid. Results Hypothyroidism was more frequent among patients with NAFLD (21%vs 9.5%.; P<0.01) compared to controls and was higher in NASH patients than NAFLD patients without NASH (25% vs 12.8%, P=0.03). Subjects with hypothyroidism were 2.1 (95% CI: 1.1, 3.9,P=0.02)) and 3.8 (95% CI:2,6.9, P<0.001) times more likely to have NAFLD and NASH respectively. By Multivariate analysis, female gender (P<0.001) and increased BMI (P=.03) were associated with hypothyroidism. NAFLD subjects who reported mild alcohol consumption were less likely to have hypothyroidism compared to those who reported complete abstinence (OR 0.37, P=0.008). Conclusions A higher prevalence of hypothyroidism was demonstrated in patients with NAFLD compared to controls. Patients with hypothyroidism were more likely to have NASH. Among subjects with NALFD, female gender, increased BMI and history of abstinence from alcohol were associated with hypothyroidism. Further studies are needed in order to confirm and better characterized these findings as well as the described associations and their pathogenesis. PMID

  14. Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice.

    PubMed

    Bijnen, Mitchell; Josefs, Tatjana; Cuijpers, Ilona; Maalsen, Constantijn J; van de Gaar, José; Vroomen, Maria; Wijnands, Erwin; Rensen, Sander S; Greve, Jan Willem M; Hofker, Marten H; Biessen, Erik A L; Stehouwer, Coen D A; Schalkwijk, Casper G; Wouters, Kristiaan

    2017-10-26

    Obesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c + proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development. vAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr -/- acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH. Transplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c + and CD11c - macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c + ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes. ATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise

  15. Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice.

    PubMed

    Kim, Ja Kyung; Lee, Kwan Sik; Lee, Dong Ki; Lee, Su Yeon; Chang, Hye Young; Choi, Junjeong; Lee, Jung Il

    2014-12-19

    Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen α1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor α showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH.

  16. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent

    PubMed Central

    Tetri, Laura H.; Basaranoglu, Metin; Brunt, Elizabeth M.; Yerian, Lisa M.; Neuschwander-Tetri, Brent A.

    2008-01-01

    The aims of this study were to determine whether combining features of a western lifestyle in mice with trans fats in a high-fat diet, high-fructose corn syrup in the water, and interventions designed to promote sedentary behavior would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH). Male C57BL/6 mice fed ad libitum high-fat chow containing trans fats (partially hydrogenated vegetable oil) and relevant amounts of a high-fructose corn syrup (HFCS) equivalent for 1–16 wk were compared with mice fed standard chow or mice with trans fats or HFCS omitted. Cage racks were removed from western diet mice to promote sedentary behavior. By 16 wk, trans fat-fed mice became obese and developed severe hepatic steatosis with associated necroinflammatory changes. Plasma alanine aminotransferase levels increased, as did liver TNF-α and procollagen mRNA, indicating an inflammatory and profibrogenic response to injury. Glucose intolerance and impaired fasting glucose developed within 2 and 4 wk, respectively. Plasma insulin, resistin, and leptin levels increased in a profile similar to that seen in patients with NASH. The individual components of this diet contributed to the phenotype independently; isocaloric replacement of trans fats with lard established that trans fats played a major role in promoting hepatic steatosis and injury, whereas inclusion of HFCS promoted food consumption, obesity, and impaired insulin sensitivity. Combining risk factors for the metabolic syndrome by feeding mice trans fats and HFCS induced histological features of NASH in the context of a metabolic profile similar to patients with this disease. Because dietary trans fats promoted liver steatosis and injury, their role in the epidemic of NASH needs further evaluation. PMID:18772365

  17. Replicator dynamics with turnover of players

    NASA Astrophysics Data System (ADS)

    Juul, Jeppe; Kianercy, Ardeshir; Bernhardsson, Sebastian; Pigolotti, Simone

    2013-08-01

    We study adaptive dynamics in games where players abandon the population at a given rate and are replaced by naive players characterized by a prior distribution over the admitted strategies. We demonstrate how such a process leads macroscopically to a variant of the replicator equation, with an additional term accounting for player turnover. We study how Nash equilibria and the dynamics of the system are modified by this additional term for prototypical examples such as the rock-paper-scissors game and different classes of two-action games played between two distinct populations. We conclude by showing how player turnover can account for nontrivial departures from Nash equilibria observed in data from lowest unique bid auctions.

  18. Sida rhomboidea.Roxb extract alleviates pathophysiological changes in experimental in vivo and in vitro models of high fat diet/fatty acid induced non-alcoholic steatohepatitis.

    PubMed

    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Dandekar, Deven S; Devkar, Ranjitsinh V; Ramachandran, A V

    2012-03-01

    The present study was aim to evaluate protective role of Sida rhomboidea.Roxb (SR) extract against high fat diet/fatty acid induced pathophysiological alterations in experimental model of non-alcoholic steatohepatitis (NASH). Effect of SR extract on plasma levels of markers of hepatic damage, plasma and hepatic lipids, mitochondrial oxidative stress, status of enzymatic and non-enzymatic antioxidants and histopathological changes in liver tissue were evaluated in high fat diet fed C57BL/6J mice. Also, the effect of SR supplementation on lipid accumulation, lipid peroxidation, cytotoxicity and cell viability were evaluated in oleic acid treated HepG2 cells. Supplementation of NASH mice with SR extract prevented high fat diet induced elevation in plasma marker enzymes of liver damage, plasma and hepatic lipids, mitochondrial oxidative stress and compromised enzymatic and non-enzymatic antioxidant status. Further, addition of SR extract to in vitro HepG2 cells minimized oleic acid induced lipid accumulation, higher lipid peroxidation, cytotoxicity and reduced cell viability. These in vivo and in vitro studies suggest that SR extract has the potential of preventing high fat/fatty acid induced NASH mainly due to its hypolipidemic and antioxidant activities. Copyright © 2010 Elsevier GmbH. All rights reserved.

  19. Dynamics, morphogenesis and convergence of evolutionary quantum Prisoner's Dilemma games on networks

    PubMed Central

    Yong, Xi

    2016-01-01

    The authors proposed a quantum Prisoner's Dilemma (PD) game as a natural extension of the classic PD game to resolve the dilemma. Here, we establish a new Nash equilibrium principle of the game, propose the notion of convergence and discover the convergence and phase-transition phenomena of the evolutionary games on networks. We investigate the many-body extension of the game or evolutionary games in networks. For homogeneous networks, we show that entanglement guarantees a quick convergence of super cooperation, that there is a phase transition from the convergence of defection to the convergence of super cooperation, and that the threshold for the phase transitions is principally determined by the Nash equilibrium principle of the game, with an accompanying perturbation by the variations of structures of networks. For heterogeneous networks, we show that the equilibrium frequencies of super-cooperators are divergent, that entanglement guarantees emergence of super-cooperation and that there is a phase transition of the emergence with the threshold determined by the Nash equilibrium principle, accompanied by a perturbation by the variations of structures of networks. Our results explore systematically, for the first time, the dynamics, morphogenesis and convergence of evolutionary games in interacting and competing systems. PMID:27118882

  20. Epidemiological game-theory dynamics of chickenpox vaccination in the USA and Israel

    PubMed Central

    Liu, Jingzhou; Kochin, Beth F.; Tekle, Yonas I.; Galvani, Alison P.

    2012-01-01

    The general consensus from epidemiological game-theory studies is that vaccination coverage driven by self-interest (Nash vaccination) is generally lower than group-optimal coverage (utilitarian vaccination). However, diseases that become more severe with age, such as chickenpox, pose an exception to this general consensus. An individual choice to be vaccinated against chickenpox has the potential to harm those not vaccinated by increasing the average age at infection and thus the severity of infection as well as those already vaccinated by increasing the probability of breakthrough infection. To investigate the effects of these externalities on the relationship between Nash and utilitarian vaccination coverages for chickenpox, we developed a game-theory epidemic model that we apply to the USA and Israel, which has different vaccination programmes, vaccination and treatment costs, as well as vaccination coverage levels. We find that the increase in chickenpox severity with age can reverse the typical relationship between utilitarian and Nash vaccination coverages in both the USA and Israel. Our model suggests that to obtain herd immunity of chickenpox vaccination, subsidies or external regulation should be used if vaccination costs are high. By contrast, for low vaccination costs, improving awareness of the vaccine and the potential cost of chickenpox infection is crucial. PMID:21632611

  1. Epidemiological game-theory dynamics of chickenpox vaccination in the USA and Israel.

    PubMed

    Liu, Jingzhou; Kochin, Beth F; Tekle, Yonas I; Galvani, Alison P

    2012-01-07

    The general consensus from epidemiological game-theory studies is that vaccination coverage driven by self-interest (Nash vaccination) is generally lower than group-optimal coverage (utilitarian vaccination). However, diseases that become more severe with age, such as chickenpox, pose an exception to this general consensus. An individual choice to be vaccinated against chickenpox has the potential to harm those not vaccinated by increasing the average age at infection and thus the severity of infection as well as those already vaccinated by increasing the probability of breakthrough infection. To investigate the effects of these externalities on the relationship between Nash and utilitarian vaccination coverages for chickenpox, we developed a game-theory epidemic model that we apply to the USA and Israel, which has different vaccination programmes, vaccination and treatment costs, as well as vaccination coverage levels. We find that the increase in chickenpox severity with age can reverse the typical relationship between utilitarian and Nash vaccination coverages in both the USA and Israel. Our model suggests that to obtain herd immunity of chickenpox vaccination, subsidies or external regulation should be used if vaccination costs are high. By contrast, for low vaccination costs, improving awareness of the vaccine and the potential cost of chickenpox infection is crucial.

  2. Non-alcoholic fatty liver disease–From the cardiologist perspective

    PubMed Central

    Sîrbu, Oana; Floria, Mariana; Dăscălița, Petru; Şorodoc, Victorița; Şorodoc, Laurențiu

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) includes a range of disorders characterized by excess accumulation of triglycerides within the liver. While simple steatosis may be clinically stable, non-alcoholic steatohepatitis (NASH) can be progressive. Inflammation is believed to be the driving force behind NASH and the progression to fibrosis and subsequent cirrhosis. NAFLD is globally considered a significant health concern not only because of its incidence but also because of its economic impact. The fact that NAFLD is associated with cardiovascular disease is widely recognized, as well as the fact that NAFLD patient mortality rises when such an association is present. In particular, NAFLD is associated with coronary and carotid atherosclerosis, endothelial dysfunction and arterial rigidity, ventricles function, valves morphology, congestive heart failure, and arrhythmias (especially atrial fibrillation). Additionally, the hypercoagulability status in NAFLD patient may be suggested by the presence of inflammatory and coagulation markers. In order to differentiate between milder forms and the more severe ones that necessitate aggressive therapy, individualized risk scores may be used. This narrative review will analyze and interpret the papers published in PubMed in the last 16 years, in an attempt to expand our understanding of the NASH as a possible cardiovascular risk factor. PMID:27389154

  3. Changes in drug transport and metabolism and their clinical implications in non-alcoholic fatty liver disease.

    PubMed

    Dietrich, Christoph G; Rau, Monika; Jahn, Daniel; Geier, Andreas

    2017-06-01

    The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.

  4. Power allocation for target detection in radar networks based on low probability of intercept: A cooperative game theoretical strategy

    NASA Astrophysics Data System (ADS)

    Shi, Chenguang; Salous, Sana; Wang, Fei; Zhou, Jianjiang

    2017-08-01

    Distributed radar network systems have been shown to have many unique features. Due to their advantage of signal and spatial diversities, radar networks are attractive for target detection. In practice, the netted radars in radar networks are supposed to maximize their transmit power to achieve better detection performance, which may be in contradiction with low probability of intercept (LPI). Therefore, this paper investigates the problem of adaptive power allocation for radar networks in a cooperative game-theoretic framework such that the LPI performance can be improved. Taking into consideration both the transmit power constraints and the minimum signal to interference plus noise ratio (SINR) requirement of each radar, a cooperative Nash bargaining power allocation game based on LPI is formulated, whose objective is to minimize the total transmit power by optimizing the power allocation in radar networks. First, a novel SINR-based network utility function is defined and utilized as a metric to evaluate power allocation. Then, with the well-designed network utility function, the existence and uniqueness of the Nash bargaining solution are proved analytically. Finally, an iterative Nash bargaining algorithm is developed that converges quickly to a Pareto optimal equilibrium for the cooperative game. Numerical simulations and theoretic analysis are provided to evaluate the effectiveness of the proposed algorithm.

  5. Bistability of Evolutionary Stable Vaccination Strategies in the Reinfection SIRI Model.

    PubMed

    Martins, José; Pinto, Alberto

    2017-04-01

    We use the reinfection SIRI epidemiological model to analyze the impact of education programs and vaccine scares on individuals decisions to vaccinate or not. The presence of the reinfection provokes the novelty of the existence of three Nash equilibria for the same level of the morbidity relative risk instead of a single Nash equilibrium as occurs in the SIR model studied by Bauch and Earn (PNAS 101:13391-13394, 2004). The existence of three Nash equilibria, with two of them being evolutionary stable, introduces two scenarios with relevant and opposite features for the same level of the morbidity relative risk: the low-vaccination scenario corresponding to the evolutionary stable vaccination strategy, where individuals will vaccinate with a low probability; and the high-vaccination scenario corresponding to the evolutionary stable vaccination strategy, where individuals will vaccinate with a high probability. We introduce the evolutionary vaccination dynamics for the SIRI model and we prove that it is bistable. The bistability of the evolutionary dynamics indicates that the damage provoked by false scares on the vaccination perceived morbidity risks can be much higher and much more persistent than in the SIR model. Furthermore, the vaccination education programs to be efficient they need to implement a mechanism to suddenly increase the vaccination coverage level.

  6. Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet.

    PubMed

    Kawaratani, Hideto; Tsujimoto, Tatsuhiro; Kitazawa, Toshiyuki; Kitade, Mitsuteru; Yoshiji, Hitoshi; Uemura, Masahito; Fukui, Hiroshi

    2008-11-21

    To investigate the innate immune reactivity of tumor necrosis factor-alpha (TNF-alpha), Toll-like receptor 4 (TLR4), and CD14 in the liver of non-alcoholic steatohepatitis (NASH) model rats. Male F344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet. The rats were killed after 4 or 8 wk of the diet, and their livers were removed for immunohistochemical investigation and RNA extraction. The liver specimens were immunostained for TNF-alpha, TLR4, and CD14. The gene expressions of TNF-alpha, TLR4, and CD14 were determined by reverse-transcriptase polymerase chain reaction (RT-PCR). Kupffer cells were isolated from the liver by Percoll gradient centrifugation, and were then cultured to measure TNF-alpha production. The serum and liver levels of TNF-alpha in the CDAA-fed rats increased significantly as compared with the control group, as did the immunohistochemical values and gene expressions of TNF-alpha, TLR4, and CD14 with the progression of steatohepatitis. TNF-alpha production from the isolated Kupffer cells of the CDAA-fed rats was elevated by lipopolysaccharide stimulation. The expressions of TNF-alpha, TLR4, and CD14 increased in the NASH model, suggesting that TLR4 and CD14-mediated endotoxin liver damage may also occur in NASH.

  7. Nutritional Approaches to Achieve Weight Loss in Nonalcoholic Fatty Liver Disease123

    PubMed Central

    Hsu, Christine C; Ness, Erik; Kowdley, Kris V

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) can range in spectrum from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is characterized by lipotoxicity, hepatocellular ballooning, and inflammation and can progress to cirrhosis. Weight loss is the cornerstone treatment for NAFLD and NASH. Various randomized controlled trials have shown that weight loss of ≥5–10% leads to significant improvements in hepatic steatosis. Diets high in sodium and fructose have been implicated in the pathogenesis of NAFLD. Although some clinical studies suggest that an isocaloric high-fructose diet does not worsen NAFLD, these clinical studies are often short in duration. More recently, the Dietary Approaches to Stop Hypertension diet, a sodium-restricted diet, has been associated with less prevalence of NAFLD and has been shown to improve NAFLD. In addition, the Mediterranean diet has been promising in improving hepatic steatosis, and a larger randomized controlled trial is currently enrolling subjects. For those who are unable to pursue weight loss through dietary approaches, bariatric surgery has been shown to improve hepatic steatosis and steatohepatitis. This method has been variable in improving hepatic fibrosis. In conclusion, weight loss is crucial to the improvement of NAFLD and NASH, and patients should attempt various diets in an attempt to achieve weight loss. PMID:28298270

  8. Nutritional Approaches to Achieve Weight Loss in Nonalcoholic Fatty Liver Disease.

    PubMed

    Hsu, Christine C; Ness, Erik; Kowdley, Kris V

    2017-03-01

    Nonalcoholic fatty liver disease (NAFLD) can range in spectrum from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is characterized by lipotoxicity, hepatocellular ballooning, and inflammation and can progress to cirrhosis. Weight loss is the cornerstone treatment for NAFLD and NASH. Various randomized controlled trials have shown that weight loss of ≥5-10% leads to significant improvements in hepatic steatosis. Diets high in sodium and fructose have been implicated in the pathogenesis of NAFLD. Although some clinical studies suggest that an isocaloric high-fructose diet does not worsen NAFLD, these clinical studies are often short in duration. More recently, the Dietary Approaches to Stop Hypertension diet, a sodium-restricted diet, has been associated with less prevalence of NAFLD and has been shown to improve NAFLD. In addition, the Mediterranean diet has been promising in improving hepatic steatosis, and a larger randomized controlled trial is currently enrolling subjects. For those who are unable to pursue weight loss through dietary approaches, bariatric surgery has been shown to improve hepatic steatosis and steatohepatitis. This method has been variable in improving hepatic fibrosis. In conclusion, weight loss is crucial to the improvement of NAFLD and NASH, and patients should attempt various diets in an attempt to achieve weight loss. © 2017 American Society for Nutrition.

  9. Symmetry warrants rational cooperation by co-action in Social Dilemmas.

    PubMed

    Sasidevan, V; Sinha, Sitabhra

    2015-08-12

    Is it rational for selfish individuals to cooperate? The conventional answer based on analysis of games such as the Prisoners Dilemma (PD) is that it is not, even though mutual cooperation results in a better outcome for all. This incompatibility between individual rationality and collective benefit lies at the heart of questions about the evolution of cooperation, as illustrated by PD and similar games. Here, we argue that this apparent incompatibility is due to an inconsistency in the standard Nash framework for analyzing non-cooperative games and propose a new paradigm, that of the co-action equilibrium. As in the Nash solution, agents know that others are just as rational as them and taking this into account lead them to realize that others will independently adopt the same strategy, in contrast to the idea of unilateral deviation central to Nash equilibrium thinking. Co-action equilibrium results in better collective outcomes for games representing social dilemmas, with relatively "nicer" strategies being chosen by rational selfish individuals. In particular, the dilemma of PD gets resolved within this framework, suggesting that cooperation can evolve in nature as the rational outcome even for selfish agents, without having to take recourse to additional mechanisms for promoting it.

  10. The Effect of Artichoke Leaf Extract on Alanine Aminotransferase and Aspartate Aminotransferase in the Patients with Nonalcoholic Steatohepatitis.

    PubMed

    Rangboo, Vajiheh; Noroozi, Mostafa; Zavoshy, Roza; Rezadoost, Seyed Amirmansoor; Mohammadpoorasl, Asghar

    2016-01-01

    Background. Based on recent basic and clinical investigations, the extract of artichoke (Cynara scolymus) leaf has been revealed to be used for hepatoprotective and cholesterol reducing purposes. We aimed to assess the therapeutic effects of artichoke on biochemical and liver biomarkers in patients with nonalcoholic steatohepatitis (NASH). Methods. In a randomized double blind clinical trial, 60 consecutive patients suffering NASH were randomly assigned to receive Cynara scolymus extract (as 6 tablets per day consisting of 2700 mg extract of the herb) as the intervention group or placebo as the control group for two months. Results. Comparing changes in study markers following interventions showed improvement in liver enzymes. The levels of triglycerides and cholesterol were significantly reduced in the group treated with Cynara scolymus when compared to placebo group. To compare the role of Cynara scolymus use with placebo in changes in study parameters, multivariate linear regression models were employed indicating higher improvement in liver enzymes and also lipid profile particularly triglycerides and total cholesterol following administration of Cynara scolymus in comparison with placebo use. Conclusion. This study sheds light on the potential hepatoprotective activity and hypolipidemic effect of Cynara scolymus in management of NASH. This clinical trial is registered in the IRCT, Iranian Registry of Clinical Trials, by number IRCT2014070218321N1.

  11. [Clinical, biochemical and hepatic histological findings in overweight and obese Peruvian adults: first national prospective study].

    PubMed

    Tagle A, Martín; Poggi M, Luis; Ferrari G, Natalia; Siu G, Hugo; Aguinaga, Melina; Luna C, Eduardo; Scavino L, Yolanda

    2008-01-01

    We conducted a prospective, descriptive study in the Clinica Anglo Americana, a prívate institution taking care of patients from a medium-high socioeconomic level in Lima. The goal of the study was to determine the frequency of histologic findings in liver biopsies performed by laparoscopy or percutaneously in patients with overweight (body mass index > 25 kg/m2) or obesity (body mass index > 30 kg/m2), and to evaluate the correlation with antropometric variables such as BMI, waist circumference, history of diabetes or hyperlypidemia, and biochemical variables like glycemia, lipid profile, aminotransferases and AST/ALT ratio. Between the years 2001 and 2006 50 patients were biopsied, 29 with overweight and 21 with obesity. Eighteen had simple steatosis and 22 had Non-alcoholic steatohepatitis (NASH) (44%), so 40 patients (80%) had some form of fatty liver. Five patients (10%) had cirrhosis confirmed by biopsy, and in all of them the finding of cirrhosis was completely incidental. Sixty four percent of patients with NASH were obese, like the 5 cirrhotics in our series. Herein we illustrate that in a relatively small sample of patients with obesity and overweight like ours, we found all the forms of the liver steatosis spectrum, from simple steatosis to cirrhosis, with a high frequency of NASH.

  12. MicroRNA-21 is associated with fibrosis in a rat model of nonalcoholic steatohepatitis and serves as a plasma biomarker for fibrotic liver disease.

    PubMed

    Takeuchi-Yorimoto, Ayano; Yamaura, Yu; Kanki, Masayuki; Ide, Tetsuya; Nakata, Ayumi; Noto, Takahisa; Matsumoto, Masahiro

    2016-09-06

    Evidence indicates that hepatic fibrosis is the initial lesion of cirrhosis or hepatocellular carcinoma in diseases such as nonalcoholic steatohepatitis (NASH). To induce NASH, we fed rats a choline-deficient and iron-supplemented L-amino acid-defined (CDAA) diet. Histopathological examination revealed that fibrosis appeared from week 4 and progressed to bridging fibrosis from week 12. Using qRT-PCR assays, we detected increased expression of miR-21, Mmp-9, and Timp-1 in liver that peaked during week 4, when fibrosis was first detected. The expression pattern of miR-21 in plasma paralleled that in liver. Fibrosis tended to be resolved within 12 weeks of a recovery period after 12 weeks of feeding, and the expression of miR-21, Timp-1, and Mmp-9 decreased in liver. Comprehensive analyses of miRNA and mRNA expression in the liver using samples acquired at week 4 detected 16 miRNAs and 11 mRNAs that are mutually-interacting fibrosis-related factors. We therefore conclude that miR-21 was closely associated with fibrosis in a rat model of NASH and has potential as a plasma biomarker for hepatic fibrosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Effects of low-calorie diet on steatohepatitis in rats with obesity and hyperlipidemia

    PubMed Central

    Fan, Jian-Gao; Zhong, Lan; Xu, Zheng-Jie; Tia, Li-Yan; Ding, Xiao-Dong; Li, Min-Sheng; Wang, Guo-Liang

    2003-01-01

    AIM: To evaluate the effects of low calorie diet (LCD) on nonalcoholic steatohepatitis (NASH) in rats with obesity and hyperlipidemia. METHODS: 29 Sprague-Dawley (SD) rats were randomly divided into three groups. The animals in control (n = 9) and NASH group (n = 10) were fed on standard rat diet and high fat diet respectively for 12 weeks, ten rats in LCD group were fed on high fat diet for 10 weeks and then low calorie diet for 2 weeks. At the end of the experiment, body weight, abdominal adipose content, liver function, and hepatopathological changes were examined to evaluate the effect of different feeding protocols on the experimental animals. RESULTS: There was no death of animal in the experimental period. All rats in the NASH group developed steatohepatitis according to liver histological findings. Compared with the control group, body weight (423.5 ± 65.2 vs 351.1 ± 43.0 g, P < 0.05), abdominal adipose content (14.25 ± 1.86 vs 9.54 ± 1.43, P < 0.05), liver index (3.784 ± 0.533 vs 2.957 ± 0.301%, P < 0.01), total serum cholesterol (1.60 ± 0.41 vs 1.27 ± 0.17 mmol/L, P < 0.05) and free fatty acids (728.2 ± 178.5 vs 429.2 ± 96.7 mmol/L, P < 0.01), serum alanine aminotransferase (1257.51 ± 671.34 vs 671.34 ± 118.57 nkat/L, P < 0.05) and aspartic aminotransferse (2760.51 ± 998.66 vs 1648.29 ± 414.16 nkat/L, P < 0.01) were significantly increased in the NASH group. Whereas, when rats were fed on LCD protocol, their body weight (329.5 ± 38.4 g, P < 0.01), abdominal adipose content (310.21 ± 1.52 g, P < 0.05), liver index (3.199 ± 0.552%, P < 0.05), and serum alanine aminotransferase (683.03 ± 245.49 nkat/L, P < 0.05) were significantly decreased, and the degree of hepatic steatosis (P < 0.05) was markedly improved compared with those in the NASH group. However, no significant difference was found in serum lipid variables and hepatic inflammatory changes between the two groups. CONCLUSION: LCD might play a role in the prevention and treatment of

  14. The I148M PNPLA3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls.

    PubMed

    Valenti, Luca; Rametta, Raffaela; Ruscica, Massimiliano; Dongiovanni, Paola; Steffani, Liliana; Motta, Benedetta Maria; Canavesi, Elena; Fracanzani, Anna Ludovica; Mozzi, Enrico; Roviaro, Giancarlo; Magni, Paolo; Fargion, Silvia

    2012-08-16

    Reduced adiponectin is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), and the I148M Patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism predisposes to NAFLD and liver damage progression in NASH and chronic hepatitis C (CHC) by still undefined mechanisms, possibly involving regulation of adipose tissue function. Aim of this study was to evaluate whether the I148M PNPLA3 polymorphism influences serum adiponectin in liver diseases and healthy controls. To this end, we considered 144 consecutive Italian patients with NAFLD, 261 with CHC, 35 severely obese subjects, and 257 healthy controls with very low probability of steatosis, all with complete clinical and genetic characterization, including adiponectin (ADIPOQ) genotype. PNPLA3 rs738409 (I148M) and ADIPOQ genotypes were evaluated by Taqman assays, serum adiponectin by ELISA. Adiponectin mRNA levels were evaluated by quantitative real-time PCR in the visceral adipose tissue (VAT) of 35 obese subjects undergoing bariatric surgery. Adiponectin levels were independently associated with the risk of NAFLD and with the histological severity of the disease. Adiponectin levels decreased with the number of 148 M PNPLA3 alleles at risk of NASH both in patients with NAFLD (p = 0.03), and in healthy subjects (p = 0.04). At multivariate analysis, PNPLA3 148 M alleles were associated with low adiponectin levels (<6 mg/ml, median value) independently of NAFLD diagnosis, age, gender, BMI, and ADIPOQ genotype (OR 1.67, 95% c.i. 1.07-2.1 for each 148 M allele). The p.148 M PNPLA3 variant was associated with decreased adiponectin mRNA levels in the VAT of obese patients (p < 0.05) even in the absence of NASH. In contrast, in CHC, characterized by adiponectin resistance, low adiponectin was associated with male gender and steatosis, but not with PNPLA3 and ADIPOQ genotypes and viral features. The I148M PNPLA3 variant is associated with

  15. [Effects of telmisartan on resistin expression in a rat model of nonalcoholic steatohepatitis and insulin resistance].

    PubMed

    Zhang, Qiuzan; Wang, Yanrong; Liu, Yingli; Yang, Qian; Wang, Xiuru; Wang, Qiang; Zhang, Chenming; Wang, Bangmao

    2015-04-01

    To investigate the effects of telmisartan on expression of resistin in serum and liver under conditions of nonalcoholic steatohepatitis (NASH) and insulin resistance using a rat model system. Forty-five male Sprague-Dawley rats were randomly divided into a normal control group (NC, n=10), a model control group (MC, n=15), a polyene phosphatidylcholine prevention group (PP, n=10), and a telmisartan prevention group (TP, n=10). The NC group was given a standard diet and the other groups were given a high-fat diet for 16 weeks in order to induce NASH. At the end of week 12, 5 rats in the MC group were sacrificed for pathology confirmation of the NASH model. At the end of week 12, the TP group was given telmisartan (8.0 mg/kg/d) and the PP group was given polyene phosphatidylcholine (8.4 mg/kg/d) for an additional 4 weeks by intragastric administration. At the end of week 16, all rats were sacrificed and body weights recorded. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG), resistin, insulin and fasting blood glucose were measured. The insulin resistance value, HOMA-IR, was assessed by homeostasis mode assessment. Liver expression of the resistin protein was detected by western blotting and of the resistin mRNA was detected by RT-PCR. The F test and LSD test were used for statistical analyses. Compared to the NC group, the body weight and HOMA-IR of rats in the MC group were significantly increased (P<0.01). The levels of serum resistin, and of resistin protein and mRNA in liver, were significantly higher in the MC group than in the NC group of rats (all P less than 0.01). The body weight of rats in the TP group was significantly lower than those in the MC group (P<0.05). The levels of serrn resistin, resistin protein and mRNA in the liver, and insulin resistance were significantly lower in the TP group than in the MC group of rats (all P<0.01). The PP group did not show significant

  16. Liver Function in Patients With Nonalcoholic Fatty Liver Disease Randomized to Roux-en-Y Gastric Bypass Versus Sleeve Gastrectomy: A Secondary Analysis of a Randomized Clinical Trial.

    PubMed

    Kalinowski, Piotr; Paluszkiewicz, Rafał; Ziarkiewicz-Wróblewska, Bogna; Wróblewski, Tadeusz; Remiszewski, Piotr; Grodzicki, Mariusz; Krawczyk, Marek

    2017-11-01

    The aim of the study was to compare the influence of sleeve gastrectomy (SG) versus Roux-en-Y gastric bypass (RYGB) on liver function in bariatric patients with non-alcoholic fatty liver disease (NAFLD) in a randomized clinical trial (NCT01806506). Rapid weight loss and malabsorption after bariatric surgery in patients with NAFLD or steatohepatitis (NASH) may impair liver function. Sixty-six morbidly obese patients randomized to SG or RYGB were included in a secondary outcome analysis. Intraoperative liver biopsies were categorized with NAFLD Activity Score (NAS) and liver function tests were done before surgery and after 1, 6 and 12 months. NASH was present in 54.5% RYGB and 51.5% SG patients (P > 0.05). At 12 months excess weight loss was 68.7 ± 19.7% after SG and 62.8 ± 18.5% after RYGB (P > 0.05). At 1 month international normalized ratio (INR) increased after RYGB (0.98 ± 0.05 vs 1.14 ± 0.11; P < 0.05) and SG (0.99 ± 0.06 vs 1.04 ± 0.06; P < 0.05), RYGB induced significantly greater increase in INR in the whole group and NASH patients than SG. After RYGB albumin decreased at 1 month (41.2 ± 2.7 vs 39.0 ± 3.2 g/L; P < 0.05). At 12 months, INR and albumin returned to baseline. At 12 months in NASH group, SG induced significant improvement in aspartate aminotransferase (32.4 ± 17.4 vs 21.5 ± 6.9U/L), alanine aminotransferase (39.9 ± 28.6U/L vs 23.8 ± 14.1U/L), gamma-glutamyl transpeptidase (34.3 ± 16.6 vs 24.5 ± 16.8U/L), and lactate dehydrogenase (510.8 ± 33 vs 292.4 ± 29). Variables predictive of INR change after 1 month included operation type, NAS ≥ 5, bilirubin, body mass index, hemoglobin A1C, and dyslipidemia. Patients with NASH undergoing RYGB are more susceptible to early transient deterioration of liver function than after SG.

  17. Alcoholic and non-alcoholic steatohepatitis

    PubMed Central

    Neuman, Manuela G.; French, Samuel W.; French, Barbara A.; Seitz, Helmut K.; Cohen, Lawrence B.; Mueller, Sebastian; Osna, Natalia A.; Kharbanda, Kusum K.; Seth, Devanshi; Bautista, Abraham; Thompson, Kyle J.; McKillop, Iain H.; Kirpich, Irina A.; McClain, Craig J.; Bataller, Ramon; Nanau, Radu M.; Voiculescu, Mihai; Opris, Mihai; Shen, Hong; Tillman, Brittany; Li, Jun; Liu, Hui; Thomas, Paul G.; Ganesan, Murali; Malnick, Steve

    2015-01-01

    This paper is based upon the “Charles Lieber Satellite Symposia” organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its comorbidities with chronic viral hepatitis in the presence or absence of human deficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible

  18. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hao, He; Sun, Yannan; Carroll, Thomas E.

    We propose a coordination algorithm for cooperative power allocation among a collection of commercial buildings within a campus. We introduced thermal and power models of a typical commercial building Heating, Ventilation, and Air Conditioning (HVAC) system, and utilize model predictive control to characterize their power flexibility. The power allocation problem is formulated as a cooperative game using the Nash Bargaining Solution (NBS) concept, in which buildings collectively maximize the product of their utilities subject to their local flexibility constraints and a total power limit set by the campus coordinator. To solve the optimal allocation problem, a distributed protocol is designedmore » using dual decomposition of the Nash bargaining problem. Numerical simulations are performed to demonstrate the efficacy of our proposed allocation method« less

  19. NARSTO SOS99NASH G-1 AIR CHEMISTRY DATA

    Atmospheric Science Data Center

    2018-04-09

    ... Order:   E arthdata Search Parameters:  Carbon Monoxide Ultraviolet Radiation Atmospheric Pressure Atmospheric ... Nitrogen Oxides Ozone Aerosol Extinction Sulfur Dioxide Aerosol Backscatter Particulate Matter Order Data:  ...

  20. Continuous Positive Airway Pressure in Patients With Obstructive Sleep Apnea and Non-Alcoholic Steatohepatitis: A Systematic Review and Meta-Analysis.

    PubMed

    Labarca, Gonzalo; Cruz, Rodrigo; Jorquera, Jorge

    2018-01-15

    Several studies have reported an association between obstructive sleep apnea (OSA) and several extra-pulmonary issues, such as arterial hypertension and insulin resistance. In recent years, the associations between OSA, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis (NASH) have been published; however, there is a gap between experimental and clinical studies regarding the efficacy of continuous positive airway pressure (CPAP) treatment in patient populations with these conditions. This issue should be considered when deciding on CPAP treatment in patients with OSA, especially in patients with moderate OSA. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) using the following databases: MEDLINE, Lilacs, and CENTRAL. Two independent reviewers performed the search, analysis, data extraction, and critical analysis. From 622 identified studies, we included 5 RCTs that involved patients with OSA and NASH and who were treated with a CPAP device. After CPAP treatment, no changes in liver steatosis, liver fibrosis, and aminotransferase levels (alanine aminotransferase and aspartate aminotransferase) were found. Finally, the quality of evidence using the GRADE approach was low and very low for several outcomes. According to the current analysis, no data regarding the efficacy of CPAP in patients with NASH are available to make recommendations. PROSPERO; ID: CRD42015027981; URL: https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42015027981. © 2018 American Academy of Sleep Medicine