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Sample records for lactation promotes nonalcoholic

  1. Monitoring food and non-alcoholic beverage promotions to children.

    PubMed

    Kelly, B; King, L; Baur, L; Rayner, M; Lobstein, T; Monteiro, C; Macmullan, J; Mohan, S; Barquera, S; Friel, S; Hawkes, C; Kumanyika, S; L'Abbé, M; Lee, A; Ma, J; Neal, B; Sacks, G; Sanders, D; Snowdon, W; Swinburn, B; Vandevijvere, S; Walker, C

    2013-10-01

    Food and non-alcoholic beverage marketing is recognized as an important factor influencing food choices related to non-communicable diseases. The monitoring of populations' exposure to food and non-alcoholic beverage promotions, and the content of these promotions, is necessary to generate evidence to understand the extent of the problem, and to determine appropriate and effective policy responses. A review of studies measuring the nature and extent of exposure to food promotions was conducted to identify approaches to monitoring food promotions via dominant media platforms. A step-wise approach, comprising 'minimal', 'expanded' and 'optimal' monitoring activities, was designed. This approach can be used to assess the frequency and level of exposure of population groups (especially children) to food promotions, the persuasive power of techniques used in promotional communications (power of promotions) and the nutritional composition of promoted food products. Detailed procedures for data sampling, data collection and data analysis for a range of media types are presented, as well as quantifiable measurement indicators for assessing exposure to and power of food and non-alcoholic beverage promotions. The proposed framework supports the development of a consistent system for monitoring food and non-alcoholic beverage promotions for comparison between countries and over time.

  2. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

    PubMed Central

    Gentric, Géraldine; Maillet, Vanessa; Paradis, Valérie; Couton, Dominique; L’Hermitte, Antoine; Panasyuk, Ganna; Fromenty, Bernard; Celton-Morizur, Séverine; Desdouets, Chantal

    2015-01-01

    Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development. PMID:25621497

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  5. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

    PubMed Central

    Jiang, Changtao; Xie, Cen; Li, Fei; Zhang, Limin; Nichols, Robert G.; Krausz, Kristopher W.; Cai, Jingwei; Qi, Yunpeng; Fang, Zhong-Ze; Takahashi, Shogo; Tanaka, Naoki; Desai, Dhimant; Amin, Shantu G.; Albert, Istvan; Patterson, Andrew D.; Gonzalez, Frank J.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet–induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota–associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment. PMID:25500885

  6. Osteopontin is Induced by Hedgehog Pathway Activation and Promotes Fibrosis Progression in Nonalcoholic Steatohepatitis

    PubMed Central

    Syn, Wing-Kin; Choi, Steve S; Liaskou, Evaggelia; Karaca, Gamze F; Agboola, Kolade M; Oo, Ye Htun; Mi, Zhiyong; Pereira, Thiago A; Zdanowicz, Marzena; Malladi, Padmini; Chen, Yuping; Moylan, Cynthia; Jung, Youngmi; Bhattacharya, Syamal D.; Teaberry, Vanessa; Omenetti, A; Abdelmalek, Manal F.; Guy, Cynthia D; Adams, David H; Kuo, Paul C; Michelotti, Gregory A; Whitington, Peter F; Diehl, Anna Mae

    2010-01-01

    Background Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Recently, we showed that NASH-related cirrhosis is associated with Hedgehog (Hh) pathway activation. The gene encoding Osteopontin (OPN), a pro-fibrogenic extracellular matrix protein and cytokine, is a direct transcriptional target of the Hh pathway. Thus, we hypothesized that Hh signaling induces OPN to promote liver fibrosis in NASH. Methods Hepatic OPN expression and liver fibrosis were analyzed in wild-type (WT) mice, Patched-deficient (Ptc+/−) (overly-active Hh signaling) mice, and OPN-deficient mice before and after feeding methionine-choline deficient (MCD) diets to induce NASH-related fibrosis. Hepatic OPN was also quantified in human NASH and non-diseased livers. Hh signaling was manipulated in cultured liver cells to assess direct effects on OPN expression, and hepatic stellate cells (HSC) were cultured in medium with different OPN activities to determine effects on HSC phenotype. Results When fed MCD diets, Ptc+/− mice expressed more OPN and developed worse liver fibrosis (p<0.05) than WT mice, while OPN-deficient mice exhibited reduced fibrosis (p<0.05). In NASH patients, OPN was significantly up-regulated and correlated with Hh pathway activity and fibrosis stage. During NASH, ductular cells strongly expressed OPN. In cultured HSC, SAG (a Hh agonist) upregulated, while Cyclopamine (a Hh-antagonist) repressed, OPN expression (p<0.005). Cholangiocyte-derived OPN and recombinant OPN promoted fibrogenic responses in HSC (p<0.05); neutralizing OPN with RNA-aptamers attenuated this (p<0.05). Conclusions OPN is Hh-regulated and directly promotes pro-fibrogenic responses. OPN induction correlates with Hh pathway activity and fibrosis-stage Therefore, OPN inhibition may be beneficial in NASH. PMID:20967826

  7. Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis-promoted hepatocarcinogenesis in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Epidemiological and experimental studies provide supportive evidence that lycopene (LY), a major carotenoid from tomatoes and tomato products, may act as a chemopreventive agent against certain types of cancers. We recently showed that high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) ...

  8. Galactose promotes fat mobilization in obese lactating and nonlactating women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Galactose consumption as the only carbohydrate source, results in little increase in plasma glucose and insulin concentrations when compared with fasting. Lower insulin might promote endogenous lipolysis during meal absorption, which may facilitate fat loss. The objective was to test the hypothesis ...

  9. Fine Tuning of the Lactate and Diacetyl Production through Promoter Engineering in Lactococcus lactis

    PubMed Central

    Guo, Tingting; Kong, Jian; Zhang, Li; Zhang, Chenchen; Hu, Shumin

    2012-01-01

    Lactococcus lactis is a well-studied bacterium widely used in dairy fermentation and capable of producing metabolites with organoleptic and nutritional characteristics. For fine tuning of the distribution of glycolytic flux at the pyruvate branch from lactate to diacetyl and balancing the production of the two metabolites under aerobic conditions, a constitutive promoter library was constructed by randomizing the promoter sequence of the H2O-forming NADH oxidase gene in L. lactis. The library consisted of 30 promoters covering a wide range of activities from 7,000 to 380,000 relative fluorescence units using a green fluorescent protein as reporter. Eleven typical promoters of the library were selected for the constitutive expression of the H2O-forming NADH oxidase gene in L. lactis, and the NADH oxidase activity increased from 9.43 to 58.17-fold of the wild-type strain in small steps of activity change under aerobic conditions. Meanwhile, the lactate yield decreased from 21.15±0.08 mM to 9.94±0.07 mM, and the corresponding diacetyl production increased from 1.07±0.03 mM to 4.16±0.06 mM with the intracellular NADH/NAD+ ratios varying from 0.711±0.005 to 0.383±0.003. The results indicated that the reduced pyruvate to lactate flux was rerouted to the diacetyl with an almost linear flux variation via altered NADH/NAD+ ratios. Therefore, we provided a novel strategy to precisely control the pyruvate distribution for fine tuning of the lactate and diacetyl production through promoter engineering in L. lactis. Interestingly, the increased H2O-forming NADH oxidase activity led to 76.95% lower H2O2 concentration in the recombinant strain than that of the wild-type strain after 24 h of aerated cultivation. The viable cells were significantly elevated by four orders of magnitude within 28 days of storage at 4°C, suggesting that the increased enzyme activity could eliminate H2O2 accumulation and prolong cell survival. PMID:22558426

  10. OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease.

    PubMed

    Akie, Thomas E; Liu, Lijun; Nam, Minwoo; Lei, Shi; Cooper, Marcus P

    2015-01-01

    OXPHOS is believed to play an important role in non-alcoholic fatty liver disease (NAFLD), however, precise mechanisms whereby OXPHOS influences lipid homeostasis are incompletely understood. We previously reported that ectopic expression of LRPPRC, a protein that increases cristae density and OXPHOS, promoted fatty acid oxidation in cultured primary hepatocytes. To determine the biological significance of that observation and define underlying mechanisms, we have ectopically expressed LRPPRC in mouse liver in the setting of NAFLD. Interestingly, ectopic expression of LRPPRC in mouse liver completely interdicted NAFLD, including inflammation. Consistent with mitigation of NAFLD, two markers of hepatic insulin resistance--ROS and PKCε activity--were both modestly reduced. As reported by others, improvement of NAFLD was associated with improved whole-body insulin sensitivity. Regarding hepatic lipid homeostasis, the ratio of NAD+ to NADH was dramatically increased in mouse liver replete with LRPPRC. Pharmacological activators and inhibitors of the cellular respiration respectively increased and decreased the [NAD+]/[NADH] ratio, indicating respiration-mediated control of the [NAD+]/[NADH] ratio. Supporting a prominent role for NAD+, increasing the concentration of NAD+ stimulated complete oxidation of fatty acids. Importantly, NAD+ rescued impaired fatty acid oxidation in hepatocytes deficient for either OXPHOS or SIRT3. These data are consistent with a model whereby augmented hepatic OXPHOS increases NAD+, which in turn promotes complete oxidation of fatty acids and protects against NAFLD.

  11. Adipose tissue-derived stem cells promote the reversion of non-alcoholic fatty liver disease: An in vivo study.

    PubMed

    Liao, Naishun; Pan, Fan; Wang, Yingchao; Zheng, Youshi; Xu, Bo; Chen, Wenwei; Gao, Yunzhen; Cai, Zhixiong; Liu, Xiaolong; Liu, Jingfeng

    2016-05-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver injury and seriously affects human health. In the present study, we aimed to investigate whether adipose tissue-derived stem cell (ADSC) transplantation in combination with dietary modification was capable of reversing the progression of NAFLD. After establishing a rat model of NAFLD by feeding them a high-fat diet (HFD), ADSCs were transplanted via the portal vein into rats with HFD-induced NAFLD, and simultaneously fed a modified diet. Thereafter, gross liver morphology, the hepatosomatic (HSI) index and indicators of liver function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were evaluated. Subsequently, the serum levels of total cholesterol (TC), triglycerides (TGs) and fatty acids (FAs) were also assayed. Furthermore, H&E and oil red O staining were used to confirm the pathological effects of NAFLD in the rat livers. Although dietary modification alone caused liver function to recover, ADSC transplantation in combination with dietary modification further decreased the HSI index, the serum levels of ALT, TBIL, TC, TGs, FAs, reduced lipid accumulation to normal levels, and reversed the hepatic pathological changes in the rat livers. Taken together, these findings suggest that ADSC transplantation assists in the reversion of NAFLD by improving liver function and promoting lipid metabolism, thereby exerting hepatoprotective effects. Thus, we suggest that ADSC transplantation is a promising, potential therapeutic strategy for NAFLD treatment. PMID:26986083

  12. TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease-related hepatocellular carcinoma.

    PubMed

    Ki Kim, Soo; Ueda, Yoshihide; Hatano, Etsuro; Kakiuchi, Nobuyuki; Takeda, Haruhiko; Goto, Tomoyuki; Shimizu, Takahiro; Yoshida, Kenichi; Ikura, Yoshihiro; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Uemoto, Shinji; Chiba, Tsutomu; Ogawa, Seishi; Marusawa, Hiroyuki

    2016-12-01

    The number of patients with nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing. To understand the molecular features of the tumor phenotype, we aimed to clarify the overall landscape of genetic aberrations accumulated in NAFLD-related HCC. Of 247 HCC patients who underwent hepatectomy during 2010 to 2014 at a single center in Japan, 10 were diagnosed with NAFLD-HCC based on strict clinical and pathologic criteria. We analyzed the genetic aberrations of 11 NAFLD-HCC tumor samples from these 10 patients by whole-exome sequencing, targeted sequencing of the selected genes, and copy number variation studies. Whole-exome sequencing revealed a mean somatic mutation rate of 1.86 per megabase, and 12 genes were recurrently mutated in NAFLD-HCCs. Targeted sequencing of the 26 selected genes (12 recurrently mutated genes in whole-exome sequencing and 14 representative HCC-associated genes) revealed that TERT promoter mutations occurred in 9 of 11 HCCs (82%), followed by CTNNB1 (45%) and TP53 (36%) mutations. Array-based copy number variation studies identified recurrent gains at 1q and 8q, and recurrent losses at 1p, 4q, 6q, 8p, 13q, 16p, 17p, and 18q. Notably, chromosome 8p loss occurred in all of the NAFLD-HCC samples. The current study provided the characteristics of genetic aberrations in NAFLD-HCC and suggested that TERT promoter mutations and chromosome 8p loss mainly contribute to NAFLD-related liver carcinogenesis.

  13. TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease-related hepatocellular carcinoma.

    PubMed

    Ki Kim, Soo; Ueda, Yoshihide; Hatano, Etsuro; Kakiuchi, Nobuyuki; Takeda, Haruhiko; Goto, Tomoyuki; Shimizu, Takahiro; Yoshida, Kenichi; Ikura, Yoshihiro; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Uemoto, Shinji; Chiba, Tsutomu; Ogawa, Seishi; Marusawa, Hiroyuki

    2016-12-01

    The number of patients with nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing. To understand the molecular features of the tumor phenotype, we aimed to clarify the overall landscape of genetic aberrations accumulated in NAFLD-related HCC. Of 247 HCC patients who underwent hepatectomy during 2010 to 2014 at a single center in Japan, 10 were diagnosed with NAFLD-HCC based on strict clinical and pathologic criteria. We analyzed the genetic aberrations of 11 NAFLD-HCC tumor samples from these 10 patients by whole-exome sequencing, targeted sequencing of the selected genes, and copy number variation studies. Whole-exome sequencing revealed a mean somatic mutation rate of 1.86 per megabase, and 12 genes were recurrently mutated in NAFLD-HCCs. Targeted sequencing of the 26 selected genes (12 recurrently mutated genes in whole-exome sequencing and 14 representative HCC-associated genes) revealed that TERT promoter mutations occurred in 9 of 11 HCCs (82%), followed by CTNNB1 (45%) and TP53 (36%) mutations. Array-based copy number variation studies identified recurrent gains at 1q and 8q, and recurrent losses at 1p, 4q, 6q, 8p, 13q, 16p, 17p, and 18q. Notably, chromosome 8p loss occurred in all of the NAFLD-HCC samples. The current study provided the characteristics of genetic aberrations in NAFLD-HCC and suggested that TERT promoter mutations and chromosome 8p loss mainly contribute to NAFLD-related liver carcinogenesis. PMID:27511114

  14. Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth

    PubMed Central

    Balliet, Renee M; Capparelli, Claudia; Guido, Carmela; Pestell, Timothy G; Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Whitaker-Menezes, Diana; Chiavarina, Barbara; Pestell, Richard G; Howell, Anthony

    2011-01-01

    Increasing chronological age is the most significant risk factor for cancer. Recently, we proposed a new paradigm for understanding the role of the aging and the tumor microenvironment in cancer onset. In this model, cancer cells induce oxidative stress in adjacent stromal fibroblasts. This, in turn, causes several changes in the phenotype of the fibroblast including mitochondrial dysfunction, hydrogen peroxide production and aerobic glycolysis, resulting in high levels of L-lactate production. L-lactate is then transferred from these glycolytic fibroblasts to adjacent epithelial cancer cells and used as “fuel” for oxidative mitochondrial metabolism. Here, we created a new pre-clinical model system to directly test this hypothesis experimentally. To synthetically generate glycolytic fibroblasts, we genetically-induced mitochondrial dysfunction by knocking down TFAM using an sh-RNA approach. TFAM is mitochondrial transcription factor A, which is important in functionally maintaining the mitochondrial respiratory chain. Interestingly, TFAM-deficient fibroblasts showed evidence of mitochondrial dysfunction and oxidative stress, with the loss of certain mitochondrial respiratory chain components, and the over-production of hydrogen peroxide and L-lactate. Thus, TFAM-deficient fibroblasts underwent metabolic reprogramming towards aerobic glycolysis. Most importantly, TFAM-deficient fibroblasts significantly promoted tumor growth, as assayed using a human breast cancer (MDA-MB-231) xenograft model. These increases in glycolytic fibroblast driven tumor growth were independent of tumor angiogenesis. Mechanistically, TFAM-deficient fibroblasts increased the mitochondrial activity of adjacent epithelial cancer cells in a co-culture system, as seen using MitoTracker. Finally, TFAM-deficient fibroblasts also showed a loss of caveolin-1 (Cav-1), a known breast cancer stromal biomarker. Loss of stromal fibroblast Cav-1 is associated with early tumor recurrence, metastasis

  15. Lactate promotes PGE2 synthesis and gluconeogenesis in monocytes to benefit the growth of inflammation-associated colorectal tumor

    PubMed Central

    Wei, Libin; Zhou, Yuxin; Yao, Jing; Qiao, Chen; Ni, Ting; Guo, Ruichen; Guo, Qinglong; Lu, Na

    2015-01-01

    Reprogramming energy metabolism, such as enhanced glycolysis, is an Achilles' heel in cancer treatment. Most studies have been performed on isolated cancer cells. Here, we studied the energy-transfer mechanism in inflammatory tumor microenvironment. We found that human THP-1 monocytes took up lactate secreted from tumor cells through monocarboxylate transporter 1. In THP-1 monocytes, the oxidation product of lactate, pyruvate competed with the substrate of proline hydroxylase and inhibited its activity, resulting in the stabilization of HIF-1α under normoxia. Mechanistically, activated hypoxia-inducible factor 1-α in THP-1 monocytes promoted the transcriptions of prostaglandin-endoperoxide synthase 2 and phosphoenolpyruvate carboxykinase, which were the key enzyme of prostaglandin E2 synthesis and gluconeogenesis, respectively, and promote the growth of human colon cancer HCT116 cells. Interestingly, lactate could not accelerate the growth of colon cancer directly in vivo. Instead, the human monocytic cells affected by lactate would play critical roles to ‘feed’ the colon cancer cells. Thus, recycling of lactate for glucose regeneration was reported in cancer metabolism. The anabolic metabolism of monocytes in inflammatory tumor microenvironment may be a critical event during tumor development, allowing accelerated tumor growth. PMID:25938544

  16. The Comparative Effects of Sports Massage, Active Recovery, and Rest in Promoting Blood Lactate Clearance After Supramaximal Leg Exercise

    PubMed Central

    Martin, Nancy A.; Zoeller, Robert F.; Robertson, Robert J.; Lephart, Scott M.

    1998-01-01

    Objective: To determine the comparative effect of sports massage, active recovery, and rest on promoting blood lactate clearance after maximal anaerobic (supramaximal) leg exercise. Design and Setting: A counterbalanced experimental design with repeated measures was used. The repeated measures were the three treatment conditions. The order of the conditions was determined by random assignment to a counterbalanced test sequence. All data were collected in the Human Energy Research Laboratory at the University of Pittsburgh. Subjects: Ten male competitive cyclists volunteered for this investigation. Measurements: Serial venous blood samples were drawn and analyzed for blood lactate concentration for each test condition. Results: There were significant main effects for both absolute and relative values of blood lactate concentration between the three treatment groups and across time within groups. Conclusions: After supramaximal leg exercise, active recovery produced significant decreases in both absolute and relative measures of blood lactate concentration when compared with the sports massage and rest conditions. No significant difference was found between sports massage and rest for either absolute or relative changes in blood lactate concentration. PMID:16558481

  17. The demands of lactation promote differential regulation of lipid stores in fasting elephant seals.

    PubMed

    Fowler, Melinda A; Debier, Cathy; Champagne, Cory D; Crocker, Daniel E; Costa, Daniel P

    2016-01-01

    Fasting animals must ration stored reserves appropriately for metabolic demands. Animals that experience fasting concomitant with other metabolically demanding activities are presented with conflicting demands of energy conservation and expenditure. Our objective was to understand how fasting northern elephant seals regulate the mobilization of lipid reserves and subsequently milk lipid content during lactation. We sampled 36 females early and 39 at the end of lactation. To determine the separate influences of lactation from fasting, we also sampled fasting but non-lactating females early and late (8 and 6 seals, respectively) in their molting fasting period. Mass and adiposity were measured, as well as circulating non-esterified fatty acid (NEFA), triacylglycerol (TAG), cortisol, insulin and growth hormone levels. Milk was collected from lactating females. Milk lipid content increased from 31% in early to 51% in late lactation. In lactating females plasma NEFA was positively related to cortisol and negatively related to insulin, but in molting seals, only variation in cortisol was related to NEFA. Milk lipid content varied with mass, adiposity, NEFA, TAG, cortisol and insulin. Surprisingly, growth hormone concentration was not related to lipid metabolites or milk lipid. Suppression of insulin release appears to be the differential regulator of lipolysis in lactating versus molting seals, facilitating mobilization of stored lipids and maintenance of high NEFA concentrations for milk synthesis. Milk lipid was strongly impacted by the supply of substrate to the mammary gland, indicating regulation at the level of mobilization of lipid reserves.

  18. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

    PubMed Central

    Yang, Jiangyan; Ruchti, Evelyne; Petit, Jean-Marie; Jourdain, Pascal; Grenningloh, Gabriele; Allaman, Igor; Magistretti, Pierre J.

    2014-01-01

    l-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons l-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. l-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, l-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of l-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of l-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived l-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of l-lactate as a signaling molecule for neuronal plasticity. PMID:25071212

  19. The demands of lactation promote differential regulation of lipid stores in fasting elephant seals.

    PubMed

    Fowler, Melinda A; Debier, Cathy; Champagne, Cory D; Crocker, Daniel E; Costa, Daniel P

    2016-01-01

    Fasting animals must ration stored reserves appropriately for metabolic demands. Animals that experience fasting concomitant with other metabolically demanding activities are presented with conflicting demands of energy conservation and expenditure. Our objective was to understand how fasting northern elephant seals regulate the mobilization of lipid reserves and subsequently milk lipid content during lactation. We sampled 36 females early and 39 at the end of lactation. To determine the separate influences of lactation from fasting, we also sampled fasting but non-lactating females early and late (8 and 6 seals, respectively) in their molting fasting period. Mass and adiposity were measured, as well as circulating non-esterified fatty acid (NEFA), triacylglycerol (TAG), cortisol, insulin and growth hormone levels. Milk was collected from lactating females. Milk lipid content increased from 31% in early to 51% in late lactation. In lactating females plasma NEFA was positively related to cortisol and negatively related to insulin, but in molting seals, only variation in cortisol was related to NEFA. Milk lipid content varied with mass, adiposity, NEFA, TAG, cortisol and insulin. Surprisingly, growth hormone concentration was not related to lipid metabolites or milk lipid. Suppression of insulin release appears to be the differential regulator of lipolysis in lactating versus molting seals, facilitating mobilization of stored lipids and maintenance of high NEFA concentrations for milk synthesis. Milk lipid was strongly impacted by the supply of substrate to the mammary gland, indicating regulation at the level of mobilization of lipid reserves. PMID:26407500

  20. Comparison between a pediatric health promotion center and a pediatric obesity clinic in detecting metabolic syndrome and non-alcoholic fatty liver disease in children.

    PubMed

    Yang, Hye Ran; Yi, Dae Yong; Choi, Hyoung Soo

    2014-12-01

    This study was done to evaluate the efficacy of health check-ups in children in detecting metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) by comparing the pediatric health promotion center with the pediatric obesity clinic. Children who visited a pediatric health promotion center (n=218) or a pediatric obesity clinic (n=178) were included. Anthropometric data, blood pressure, laboratory tests, and abdominal ultrasonography were evaluated. Two different criteria were applied to diagnose metabolic syndrome. The prevalence of metabolic syndrome in the 2 units was 3.2%-3.7% in a pediatric health promotion center and 23%-33.2% in a pediatric obesity clinic. Significant differences were observed in the prevalence of each component of metabolic syndrome between the 2 units including abdominal adiposity, blood pressure, serum triglycerides, and fasting blood glucose (P<0.05). The prevalence of NAFLD was 8.7% and 71.9% in the 2 units according to liver enzymes and 5.9% and 61.8% according to ultrasonography (P<0.05). The prevalence of metabolic syndrome and NAFLD was higher among patients visiting the obesity clinic targeting obese children than that among patients visiting the health promotion center offering routine check-ups. An obesity-oriented approach is required to prevent obesity-related health problems in children.

  1. Postnatal overfeeding promotes early onset and exaggeration of high-fat diet-induced nonalcoholic fatty liver disease through disordered hepatic lipid metabolism in rats.

    PubMed

    Ji, Chenlin; Dai, Yanyan; Jiang, Weiwei; Liu, Juan; Hou, Miao; Wang, Junle; Burén, Jonas; Li, Xiaonan

    2014-11-01

    Exposure to overnutrition in critical or sensitive developmental periods may increase the risk of developing obesity and metabolic syndrome in adults. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, but the relationship among postnatal nutrition, lipid metabolism, and NAFLD progression during development remains poorly understood. Here we investigated in a rat model whether postnatal overfeeding increases susceptibility to NAFLD in response to a high-fat diet. Litters from Sprague-Dawley dams were culled to three (small litters) or ten (normal litters) pups and then weaned onto a standard or high-fat diet at postnatal day 21 to generate normal-litter, small-litter, normal-litter/high-fat, and small-litter/high-fat groups. At age 16 weeks, the small-litter and both high-fat groups showed obesity, dyslipidemia, and insulin resistance. Hepatic disorders appeared earlier in the small-litter/high-fat rats with greater liver mass gain and higher hepatic triglycerides and steatosis score versus normal-litter/high-fat rats. Hepatic acetyl-CoA carboxylase activity and mRNA expression were increased in small-litter rats and aggravated in small-litter/high-fat rats but not in normal-litter/high-fat rats. The high expression in small-litter/high-fat rats coincided with high sterol regulatory element-binding protein-1c mRNA and protein expression. However, mRNA expression of enzymes involved in hepatic fatty acid oxidation (carnitine palmitoyltransferase 1) and output (microsomal triglyceride transfer protein) was decreased under a high-fat diet regardless of litter size. In conclusion, overfeeding related to small-litter rearing during lactation contributes to the NAFLD phenotype when combined with a high-fat diet, possibly through up-regulated hepatic lipogenesis.

  2. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems.

    PubMed

    Thevenet, Jonathan; De Marchi, Umberto; Domingo, Jaime Santo; Christinat, Nicolas; Bultot, Laurent; Lefebvre, Gregory; Sakamoto, Kei; Descombes, Patrick; Masoodi, Mojgan; Wiederkehr, Andreas

    2016-05-01

    Medium-chain triglycerides have been used as part of a ketogenic diet effective in reducing epileptic episodes. The health benefits of the derived medium-chain fatty acids (MCFAs) are thought to result from the stimulation of liver ketogenesis providing fuel for the brain. We tested whether MCFAs have direct effects on energy metabolism in induced pluripotent stem cell-derived human astrocytes and neurons. Using single-cell imaging, we observed an acute pronounced reduction of the mitochondrial electrical potential and a concomitant drop of the NAD(P)H signal in astrocytes, but not in neurons. Despite the observed effects on mitochondrial function, MCFAs did not lower intracellular ATP levels or activate the energy sensor AMP-activated protein kinase. ATP concentrations in astrocytes were unaltered, even when blocking the respiratory chain, suggesting compensation through accelerated glycolysis. The MCFA decanoic acid (300 μM) promoted glycolysis and augmented lactate formation by 49.6%. The shorter fatty acid octanoic acid (300 μM) did not affect glycolysis but increased the rates of astrocyte ketogenesis 2.17-fold compared with that of control cells. MCFAs may have brain health benefits through the modulation of astrocyte metabolism leading to activation of shuttle systems that provide fuel to neighboring neurons in the form of lactate and ketone bodies.-Thevenet, J., De Marchi, U., Santo Domingo, J., Christinat, N., Bultot, L., Lefebvre, G., Sakamoto, K., Descombes, P., Masoodi, M., Wiederkehr, A. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems.

  3. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems.

    PubMed

    Thevenet, Jonathan; De Marchi, Umberto; Domingo, Jaime Santo; Christinat, Nicolas; Bultot, Laurent; Lefebvre, Gregory; Sakamoto, Kei; Descombes, Patrick; Masoodi, Mojgan; Wiederkehr, Andreas

    2016-05-01

    Medium-chain triglycerides have been used as part of a ketogenic diet effective in reducing epileptic episodes. The health benefits of the derived medium-chain fatty acids (MCFAs) are thought to result from the stimulation of liver ketogenesis providing fuel for the brain. We tested whether MCFAs have direct effects on energy metabolism in induced pluripotent stem cell-derived human astrocytes and neurons. Using single-cell imaging, we observed an acute pronounced reduction of the mitochondrial electrical potential and a concomitant drop of the NAD(P)H signal in astrocytes, but not in neurons. Despite the observed effects on mitochondrial function, MCFAs did not lower intracellular ATP levels or activate the energy sensor AMP-activated protein kinase. ATP concentrations in astrocytes were unaltered, even when blocking the respiratory chain, suggesting compensation through accelerated glycolysis. The MCFA decanoic acid (300 μM) promoted glycolysis and augmented lactate formation by 49.6%. The shorter fatty acid octanoic acid (300 μM) did not affect glycolysis but increased the rates of astrocyte ketogenesis 2.17-fold compared with that of control cells. MCFAs may have brain health benefits through the modulation of astrocyte metabolism leading to activation of shuttle systems that provide fuel to neighboring neurons in the form of lactate and ketone bodies.-Thevenet, J., De Marchi, U., Santo Domingo, J., Christinat, N., Bultot, L., Lefebvre, G., Sakamoto, K., Descombes, P., Masoodi, M., Wiederkehr, A. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems. PMID:26839375

  4. SnoN regulates mammary gland alveologenesis and onset of lactation by promoting prolactin/Stat5 signaling.

    PubMed

    Jahchan, Nadine S; Wang, Douglas; Bissell, Mina J; Luo, Kunxin

    2012-09-01

    Mammary epithelial cells undergo structural and functional differentiation at late pregnancy and parturition to produce and secrete milk. Both TGF-β and prolactin pathways are crucial regulators of this process. However, how the activities of these two antagonistic pathways are orchestrated to initiate lactation has not been well defined. Here, we show that SnoN, a negative regulator of TGF-β signaling, coordinates TGF-β and prolactin signaling to control alveologenesis and lactogenesis. SnoN expression is induced at late pregnancy by the coordinated actions of TGF-β and prolactin. The elevated SnoN promotes Stat5 signaling by enhancing its stability, thereby sharply increasing the activity of prolactin signaling at the onset of lactation. SnoN-/- mice display severe defects in alveologenesis and lactogenesis, and mammary epithelial cells from these mice fail to undergo proper morphogenesis. These defects can be rescued by an active Stat5. Thus, our study has identified a new player in the regulation of milk production and revealed a novel function of SnoN in mammary alveologenesis and lactogenesis in vivo through promotion of Stat5 signaling.

  5. A lactate electrochemical biosensor with a titanate nanotube as direct electron transfer promoter

    NASA Astrophysics Data System (ADS)

    Yang, Mingli; Wang, Jin; Li, Huaqing; Zheng, Jian-Guo; Wu, Nianqiang Nick

    2008-02-01

    Hydrogen titanate (H2Ti3O7) nanotubes (TNTs) have been synthesized by a one-step hydrothermal processing. Lactate oxidase (LOx) enzyme has been immobilized on the three-dimensional porous TNT network to make an electrochemical biosensor for lactate detection. Cyclic voltammetry and amperometry tests reveal that the LOx enzyme, which is supported on TNTs, maintains their substrate-specific catalytic activity. The nanotubes offer the pathway for direct electron transfer between the electrode surface and the active redox centers of LOx, which enables the biosensor to operate at a low working potential and to avoid the influence of the presence of O2 on the amperometric current response. The biosensor exhibits a sensitivity of 0.24 µA cm-2 mM-1, a 90% response time of 5 s, and a linear response in the range from 0.5 to 14 mM and the redox center of enzyme obviates the need of redox mediators for electrochemical enzymatic sensors, which is attractive for the development of reagentless biosensors.

  6. The complement component C5 promotes liver steatosis and inflammation in murine non-alcoholic liver disease model.

    PubMed

    Bavia, Lorena; Cogliati, Bruno; Dettoni, Juliano Bertollo; Ferreira Alves, Venancio Avancini; Isaac, Lourdes

    2016-09-01

    Non-Alcoholic Fatty Liver Disease (NALD) is considering a hepatic manifestation of metabolic syndrome. Although the pathogenesis of NALD is not completely understood, insulin resistance and inflammatory cytokines are implicated. Considering that component C5 is a central mediator of inflammation, we investigated the role of C5 in the establishment of NALD. Eight to ten-week old B6 C5(+) and A/J C5(-) male mice were fed a high fat diet containing glucose (HFDG) for 6 and 10 weeks. We observed that B6 C5(+) mice HFDG-fed for 10 weeks developed hepatomegaly, triglycerides (TG) accumulation, steatosis and enhanced liver TNF-α, IL-6, IL-12p70 and IL-17 levels when compared to A/J C5(-) mice. Next, B6 C5(+) mice were compared with congenic B6 C5(-) mice. Again, B6 C5(+) HFDG-fed mice developed more steatosis, liver centro-lobular inflammation and presented higher levels of liver IL-1β, IL-12p70, IL-17 and TFG-β than B6 C5(-) mice under the same conditions. B6 C5(+) mice HFDG-fed also presented lower concentrations of serum albumin, serum cholesterol, blood leukocytes and liver NO production when compared with B6 C5(-) mice. We concluded that murine C5 contributes effectively to liver steatosis and inflammation in NALD pathogenesis. In addition, C5 is also important to control serum cholesterol and albumin levels in the C57BL/6 genetic background. PMID:27477770

  7. The complement component C5 promotes liver steatosis and inflammation in murine non-alcoholic liver disease model.

    PubMed

    Bavia, Lorena; Cogliati, Bruno; Dettoni, Juliano Bertollo; Ferreira Alves, Venancio Avancini; Isaac, Lourdes

    2016-09-01

    Non-Alcoholic Fatty Liver Disease (NALD) is considering a hepatic manifestation of metabolic syndrome. Although the pathogenesis of NALD is not completely understood, insulin resistance and inflammatory cytokines are implicated. Considering that component C5 is a central mediator of inflammation, we investigated the role of C5 in the establishment of NALD. Eight to ten-week old B6 C5(+) and A/J C5(-) male mice were fed a high fat diet containing glucose (HFDG) for 6 and 10 weeks. We observed that B6 C5(+) mice HFDG-fed for 10 weeks developed hepatomegaly, triglycerides (TG) accumulation, steatosis and enhanced liver TNF-α, IL-6, IL-12p70 and IL-17 levels when compared to A/J C5(-) mice. Next, B6 C5(+) mice were compared with congenic B6 C5(-) mice. Again, B6 C5(+) HFDG-fed mice developed more steatosis, liver centro-lobular inflammation and presented higher levels of liver IL-1β, IL-12p70, IL-17 and TFG-β than B6 C5(-) mice under the same conditions. B6 C5(+) mice HFDG-fed also presented lower concentrations of serum albumin, serum cholesterol, blood leukocytes and liver NO production when compared with B6 C5(-) mice. We concluded that murine C5 contributes effectively to liver steatosis and inflammation in NALD pathogenesis. In addition, C5 is also important to control serum cholesterol and albumin levels in the C57BL/6 genetic background.

  8. Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease.

    PubMed

    Guo, Liang; Zhou, Shui-Rong; Wei, Xiang-Bo; Liu, Yuan; Chang, Xin-Xia; Liu, Yang; Ge, Xin; Dou, Xin; Huang, Hai-Yan; Qian, Shu-Wen; Li, Xi; Lei, Qun-Ying; Gao, Xin; Tang, Qi-Qun

    2016-10-15

    Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein α-subunit (MTPα) functions as a critical enzyme for fatty acid β-oxidation, but whether dysregulation of MTPα is pathogenically connected to NAFLD is poorly understood. We show that MTPα is acetylated at lysine residues 350, 383, and 406 (MTPα-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTPα-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTPα. Replacement of MTPα-3K with either MTPα-3KR or MTPα-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTPα-3K mutant expression in mouse livers, and MTPα-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTPα and MTPα-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTPα regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD. PMID:27457618

  9. Nicotine promotes Streptococcus mutans extracellular polysaccharide synthesis, cell aggregation and overall lactate dehydrogenase activity.

    PubMed

    Huang, R; Li, M; Gregory, R L

    2015-08-01

    Several epidemiology studies have reported a positive relationship between smoking and dental caries. Nicotine, an alkaloid component of tobacco, has been demonstrated to stimulate biofilm formation and metabolic activity of Streptococcus mutans, one of the most important pathogens of dental caries. The first aim of the present study was to explore the possible mechanisms leading to increased biofilm by nicotine treatment from three aspects, extracellular polysaccharides (EPS) synthesis, glucosyltransferase (Gtf) synthesis and glucan-binding protein (Gbp) synthesis at the mRNA and protein levels. The second aim was to investigate how nicotine affects S. mutans virulence, particular in lactate dehydrogenase (LDH) activity. Confocal laser scanning microscopy results demonstrated that both biofilm bacterial cell numbers and EPS were increased by nicotine. Gtf and GbpA protein expression of S. mutans planktonic cells were upregulated while GbpB protein expression of biofilm cells were downregulated by nicotine. The mRNA expression trends of those genes were mostly consistent with results on protein level but not statistically significant, and gtfD and gbpD of biofilm cells were inhibited. Nicotine was not directly involved in S. mutans LDH activity. However, since it increases the total number of bacterial cells in biofilm, the overall LDH activity of S. mutans biofilm is increased. In conclusion, nicotine stimulates S. mutans planktonic cell Gtf and Gbp expression. This leads to more planktonic cells attaching to the dental biofilm. Increased cell numbers within biofilm results in higher overall LDH activity. This contributes to caries development in smokers.

  10. Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer.

    PubMed

    Wang, Jian; Wang, Hui; Liu, Aifen; Fang, Changge; Hao, Jianguo; Wang, Zhenghui

    2015-08-14

    Reprogramming metabolism of tumor cells is a hallmark of cancer. Lactate dehydrogenase A (LDHA) is frequently overexpressed in tumor cells. Previous studies has shown higher levels of LDHA is related with colorectal cancer (CRC), but its role in tumor maintenance and underlying molecular mechanisms has not been established. Here, we investigated miRNAs-induced changes in LDHA expression. We reported that colorectal cancer express higher levels of LDHA compared with adjacent normal tissue. Knockdown of LDHA resulted in decreased lactate and ATP production, and glucose uptake. Colorectal cancer cells with knockdown of LDHA had much slower growth rate than control cells. Furthermore, we found that miR-34a, miR-34c, miR-369-3p, miR-374a, and miR-4524a/b target LDHA and regulate glycolysis in cancer cells. There is a negative correlation between these miRNAs and LDHA expression in colorectal cancer tissues. More importantly, we identified a genetic loci newly associated with increased colorectal cancer progression, rs18407893 at 11p15.4 (in 3'-UTR of LDHA), which maps to the seed sequence recognized by miR-374a. Cancer cells overexpressed miR-374a has decreased levels of LDHA compared with miR-374a-MUT (rs18407893 at 11p15.4). Taken together, these novel findings provide more therapeutic approaches to the Warburg effect and therapeutic targets of cancer energy metabolism. PMID:26062441

  11. Synbiotics suppress the release of lactate dehydrogenase, promote non-specific immunity and integrity of jejunum mucosa in piglets.

    PubMed

    Andrejčáková, Zuzana; Sopková, Drahomíra; Vlčková, Radoslava; Kulichová, Lucia; Gancarčíková, Soňa; Almášiová, Viera; Holovská, Katarína; Petrilla, Vladimír; Krešáková, Lenka

    2016-09-01

    The aim of our experiment was to study how synbiotics are able to deal with the problems of post-weaning piglets. Lactobacillus plantarum - Biocenol(TM) LP96 (CCM 7512), Lactobacillus fermentum - Biocenol(TM) LF99 (CCM 7514) and flaxseed (rich in n-3 polyunsaturated fatty acids) were administered to 36 conventional piglets from a problematic breed with confirmed presence of enterotoxigenic Escherichia coli and Coronavirus. The experimental piglets were supplied with probiotic cheeses and crushed flax-seed in the period starting 10 days before weaning and lasting up to 14 days post-weaning. Piglets in the control group were supplied only control cheese. The impact of such additives on the release of lactate dehydrogenase (LDH; spectroscopic and electrophoretic assay), alteration of immunity (index of metabolic activity), jejunum histology (light microscopy), and health of conventional piglets from a problematic breed (monitoring of hematology, consistency and moisture of feces and body temperature) were examined. We found significant decrease in LDH leakage in the blood serum and tissue extracts, indicating better cell membrane integrity in the individual organs of animals. Probiotics and flaxseed applied together seem to be a good source of nutrients to improve the immune status and the integrity of jejunum mucosa during infection. © 2015 Japanese Society of Animal Science. PMID:27581561

  12. The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease

    PubMed Central

    Daugherity, Erin K.; Balmus, Gabriel; Al Saei, Ahmed; Moore, Elizabeth S.; Abi Abdallah, Delbert; Rogers, Arlin B.; Weiss, Robert S.; Maurer, Kirk J.

    2012-01-01

    Steatoapoptosis is a hallmark of non-alcoholic fatty liver disease (NAFLD) and is an important factor in liver disease progression. We hypothesized that increased reactive oxygen species resulting from excess dietary fat contribute to liver disease by causing DNA damage and apoptotic cell death, and tested this by investigating the effects of feeding mice high fat or standard diets for 8 weeks. High fat diet feeding resulted in increased hepatic H2O2, superoxide production, and expression of oxidative stress response genes, confirming that the high fat diet induced hepatic oxidative stress. High fat diet feeding also increased hepatic steatosis, hepatitis and DNA damage as exemplified by an increase in the percentage of 8-hydroxyguanosine (8-OHG) positive hepatocytes in high fat diet fed mice. Consistent with reports that the DNA damage checkpoint kinase Ataxia Telangiectasia Mutated (ATM) is activated by oxidative stress, ATM phosphorylation was induced in the livers of wild type mice following high fat diet feeding. We therefore examined the effects of high fat diet feeding in Atm-deficient mice. The prevalence of apoptosis and expression of the pro-apoptotic factor PUMA were significantly reduced in Atm-deficient mice fed the high fat diet when compared with wild type controls. Furthermore, high fat diet fed Atm−/− mice had significantly less hepatic fibrosis than Atm+/+ or Atm+/− mice fed the same diet. Together, these data demonstrate a prominent role for the ATM pathway in the response to hepatic fat accumulation and link ATM activation to fatty liver-induced steatoapoptosis and fibrosis, key features of NAFLD progression. PMID:22544329

  13. Microbiota and nonalcoholic steatohepatitis.

    PubMed

    Imajo, Kento; Yoneda, Masato; Ogawa, Yuji; Wada, Koichiro; Nakajima, Atsushi

    2014-01-01

    The recent rise in obesity-related diseases, such as nonalcoholic fatty liver disease and its strong association with microbiota, has elicited interest in the underlying mechanisms of these pathologies. Experimental models have highlighted several mechanisms connecting microbiota to the development of liver dysfunction in nonalcoholic steatohepatitis (NASH) such as increased energy harvesting from the diet, small intestine bacterial overgrowth, modulation of the intestinal barrier by glucagon-like peptide-2 secretions, activation of innate immunity through the lipopolysaccharide-CD14 axis caused by obesity-induced leptin, periodontitis, and sterile inflammation. The manipulation of microbiota through probiotics, prebiotics, antibiotics, and periodontitis treatment yields encouraging results for the treatment of obesity, diabetes, and NASH, but data in humans is scarce. PMID:24337650

  14. Etiopathogenesis of nonalcoholic steatohepatitis.

    PubMed

    Chitturi, S; Farrell, G C

    2001-01-01

    The definable causes of nonalcoholic steatohepatitis (NASH) include jejunoileal bypass surgery (JIB), other causes of rapid and profound weight loss in obese subjects, total parenteral nutrition, drugs, industrial toxins, copper toxicity, and disorders characterized by extreme insulin resistance. However, the etiopathogenesis in most cases of NASH appears multifactorial. Obesity, type 2 diabetes, and hypertriglyceridemia are often associated with hepatic steatosis, and although this does not invariably lead to NASH, the fatty liver is vulnerable to hepatocellular injury initiated by reactive oxygen species (ROS). It is critical to understand not only the triggers for hepatitis (injury and inflammation) in NASH but also how this is perpetuated as chronic liver disease. The present focus is on whether the biochemical processes that generate oxidative stress lead to hepatocyte injury and secondary recruitment of inflammation or whether inflammation is the primary mediator of liver cell injury. Insulin resistance is a reproducible pathogenic factor in NASH. It favors accumulation of free fatty acids in the liver and predisposes to oxidative stress by stimulating microsomal lipid peroxidases and by the direct effects of high insulin levels in decreasing mitochondrial beta-oxidation. CYP2E1 is normally suppressed by insulin but is invariably increased in the livers of patients with NASH. In rodent dietary models of steatohepatitis, CYP2E1 is the catalyst of microsomal lipid peroxidation, while in Cyp 2e1 nullizygous mice, CYP4A proteins are induced and function as alternative microsomal lipid peroxidases. Other studies implicate activation of peroxisome proliferator-activated receptor-alpha (PPAR alpha) as leading to NASH; PPAR alpha is a transcription factor that governs both microsomal (via CYP4A) and peroxisomal (beta-oxidation) pathways of lipid oxidation and ultimately production of ROS. Increased lipid peroxidation is a crucial difference between the livers of

  15. Dinosaur lactation?

    PubMed

    Else, Paul L

    2013-02-01

    Lactation is a process associated with mammals, yet a number of birds feed their newly hatched young on secretions analogous to the milk of mammals. These secretions are produced from various sections (crop organ, oesophageal lining and proventriculus) of the upper digestive tract and possess similar levels of fat and protein, as well as added carotenoids, antibodies and, in the case of pigeons and doves, epidermal growth factor. Parental care in avian species has been proposed to originate from dinosaurs. This study examines the possibility that some dinosaurs used secretory feeding to increase the rate of growth of their young, estimated to be similar to that of present day birds and mammals. Dinosaur 'lactation' could also have facilitated immune responses as well as extending parental protection as a result of feeding newly hatched young in nest environments. While the arguments for dinosaur lactation are somewhat generic, a case study for lactation in herbivorous site-nesting dinosaurs is presented. It is proposes that secretory feeding could have been used to bridge the gap between hatching and establishment of the normal diet in some dinosaurs.

  16. Pathogenesis of Nonalcoholic Steatohepatitis.

    PubMed

    Machado, Mariana Verdelho; Diehl, Anna Mae

    2016-06-01

    Nonalcoholic steatohepatitis (NASH) is a necro-inflammatory response that ensues when hepatocytes are injured by lipids (lipotoxicity). NASH is a potential outcome of nonalcoholic fatty liver (NAFL), a condition that occurs when lipids accumulate in hepatocytes. NASH may be reversible, but it can also result in cirrhosis and primary liver cancer. We are beginning to learn about the mechanisms of progression of NAFL and NASH. NAFL does not inevitably lead to NASH because NAFL is a heterogeneous condition. This heterogeneity exists because different types of lipids with different cytotoxic potential accumulate in the NAFL, and individuals with NAFL differ in their ability to defend against lipotoxicity. There are no tests that reliably predict which patients with NAFL will develop lipotoxicity. However, NASH encompasses the spectrum of wound-healing responses induced by lipotoxic hepatocytes. Differences in these wound-healing responses among individuals determine whether lipotoxic livers regenerate, leading to stabilization or resolution of NASH, or develop progressive scarring, cirrhosis, and possibly liver cancer. We review concepts that are central to the pathogenesis of NASH.

  17. [Nonalcoholic steatohepatitis in children].

    PubMed

    Cubelić, Sandra; Misak, Zrinjka; Gasparov, Slavko; Kolacek, Sanja

    2004-01-01

    Nonalcoholic steatohepatitis (NASH) occurs not only in adults but also in children. NASH is diagnosed in obese children with increased aminotranspherases, characteristic ultrasonography and typical percutneous liver biopsy (fat vacuoles in hepatocytes, different stages of inflammation with or without liver fibrosis) when other possible causes of steatosis are excluded. It is important to diagnose NASH and start the treatment as early as possible in order to prevent irreversible liver damage. The first line therapy consists of reduction of body weight by low-calorie diet and exercising. Ursodeoxycholic acid has been used as adjuvant therapy mainly in adults, and vitamin E also in children. We presented 5 cases with NASH (2 girls, 3 boys; age 11-15 years). All were obese and had increased transaminases, and ultrasonography and liver biopsy typical for NASH. With low-calorie diet in all our patients BMI declined, symptoms vanished and transaminases decreased (in two patients transaminases normalized).

  18. Does fructose consumption contribute to non-alcoholic fatty liver disease?

    PubMed

    Tappy, Luc; Lê, Kim-Anne

    2012-12-01

    Fructose is mainly consumed with added sugars (sucrose and high fructose corn syrup), and represents up to 10% of total energy intake in the US and in several European countries. This hexose is essentially metabolized in splanchnic tissues, where it is converted into glucose, glycogen, lactate, and, to a minor extent, fatty acids. In animal models, high fructose diets cause the development of obesity, insulin resistance, diabetes mellitus, and dyslipidemia. Ectopic lipid deposition in the liver is an early occurrence upon fructose exposure, and is tightly linked to hepatic insulin resistance. In humans, there is strong evidence, based on several intervention trials, that fructose overfeeding increases fasting and postprandial plasma triglyceride concentrations, which are related to stimulation of hepatic de novo lipogenesis and VLDL-TG secretion, together with decreased VLDL-TG clearance. However, in contrast to animal models, fructose intakes as high as 200 g/day in humans only modestly decreases hepatic insulin sensitivity, and has no effect on no whole body (muscle) insulin sensitivity. A possible explanation may be that insulin resistance and dysglycemia develop mostly in presence of sustained fructose exposures associated with changes in body composition. Such effects are observed with high daily fructose intakes, and there is no solid evidence that fructose, when consumed in moderate amounts, has deleterious effects. There is only limited information regarding the effects of fructose on intrahepatic lipid concentrations. In animal models, high fructose diets clearly stimulate hepatic de novo lipogenesis and cause hepatic steatosis. In addition, some observations suggest that fructose may trigger hepatic inflammation and stimulate the development of hepatic fibrosis. This raises the possibility that fructose may promote the progression of non-alcoholic fatty liver disease to its more severe forms, i.e. non-alcoholic steatohepatitis and cirrhosis. In humans, a

  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. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis.

    PubMed

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K; Mukherjee, Rathin; Reddy, Duvvur N; Rao, Padaki N

    2015-06-01

    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.

  1. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis.

    PubMed

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K; Mukherjee, Rathin; Reddy, Duvvur N; Rao, Padaki N

    2015-06-01

    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

  2. Non-Alcoholic Fatty Liver Disease (NAFLD)

    MedlinePlus

    Non-Alcoholic Fatty Liver Disease What is Non-alcoholic fatty liver disease (NAFLD)? FAT N AFLD is a name that is given to a ... and under “Liver Health Information view ‘Nonalcoholic fatty liver Disease (NAFLD/NASH)’ IMPORTANT REMINDER: This information from the ...

  3. Antioxidant Mechanisms in Nonalcoholic Fatty Liver Disease.

    PubMed

    Liu, Wensheng; Baker, Susan S; Baker, Robert D; Zhu, Lixin

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents a broad spectrum of histological abnormalities with clinical presentations ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH). Some NAFLD patients may progress to cirrhosis and ultimately hepatocellular carcinoma (HCC). Hepatic steatosis, the hallmark of NAFLD, is defined by the accumulation of triglycerides (TGs) in more than 5% of the hepatocytes. NASH is characterized by inflammation along with variable degrees of fibrosis in addition to steatosis. NAFLD has been considered to be the hepatic manifestation of metabolic syndrome (MS), as it is frequently associated with MS conditions such as insulin resistance (IR) and obesity. Hepatic steatosis mainly results from disrupted homeostasis of lipid metabolism in the setting of IR. Although the mechanism underlying the progression from steatosis to NASH is still not fully elucidated, mounting evidence has suggested oxidative stress (OS) to be a key driving force. Elevated OS has been well documented in NAFLD patients. OS can cause direct damages to lipid, protein, and DNA molecules and trigger the inflammatory and fibrogenesis signaling pathways, which promotes the progression from steatosis to NASH. OS may also have various effects on antioxidant defense mechanisms. Overproduced reactive oxygen species (ROS) may directly deplete antioxidant molecules such as glutathione (GSH) and inhibit the activities of antioxidant enzymes such as superoxide dismutase (SOD). ROS may also induce the expression of antioxidant genes to counteract the OS effects. The aim of this review is to discuss oxidative stress and antioxidant mechanisms in NAFLD.

  4. Lactation Consultant

    MedlinePlus

    ... about infant and child feeding; utilize a pragmatic problem-solving approach, sensitive to the learner’s culture, questions and concerns; provide anticipatory guidance to promote optimal breastfeeding practices ... or complications; provide positive feedback and emotional support ...

  5. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis

    PubMed Central

    2013-01-01

    Liver plays a central role in the biogenesis of major metabolites including glucose, fatty acids, and cholesterol. Increased incidence of obesity in the modern society promotes insulin resistance in the peripheral tissues in humans, and could cause severe metabolic disorders by inducing accumulation of lipid in the liver, resulting in the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD, which is characterized by increased fat depots in the liver, could precede more severe diseases such as non-alcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma. Accumulation of lipid in the liver can be traced by increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, or the increased incidence of de novo lipogenesis. In this review, I would like to focus on the roles of individual pathways that contribute to the hepatic steatosis as a precursor for the NAFLD. PMID:24133660

  6. 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. PMID:26447961

  7. Nonalcoholic fatty pancreas disease1

    PubMed Central

    Mathur, Abhishek; Marine, Megan; Lu, Debao; Swartz-Basile, Deborah A.; Saxena, Romil; Zyromski, Nicholas J.

    2007-01-01

    Background. Obesity leads to fat infiltration of multiple organs including the heart, kidneys, and liver. Under conditions of oxidative stress, fat-derived cytokines are released locally and result in an inflammatory process and organ dysfunction. In the liver, fat infiltration has been termed nonalcoholic fatty liver disease, which may lead to nonalcoholic steatohepatitis. No data are available, however, on the influence of obesity on pancreatic fat and cytokines, and nonalcoholic fatty pancreas disease (NAFPD) has not been described. Therefore, we designed a study to determine whether obesity is associated with increased pancreatic fat and cytokines. Materials and methods. Thirty C57BL/6J lean control and 30 leptin-deficient obese female mice were fed a 15% fat diet for 4 weeks. At 12 weeks of age all animals underwent total pancreatectomy. Pancreata from each strain were pooled for measurement of a) wet and dry weight, b) histologic presence of fat, c) triglycerides, free fatty acids (FFAs), cholesterol, phospholipids, and total fat, and d) interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α). Data were analyzed by Student's t test and Fisher's exact test. Results. Pancreata from obese mice were heavier (p<0.05) and had more fat histologically (p<0.05). Pancreata from obese mice had more triglycerides, FFAs, cholesterol, and total fat (p<0.05). Triglycerides represented 11% of pancreatic fat in lean mice compared with 67% of pancreatic fat in obese mice (p<0.01). Cytokines IL-1β and TNF-α also were elevated in the pancreata of obese mice (p<0.05). Conclusions. These data suggest that obese mice have 1) heavier pancreata, 2) more pancreatic fat, especially triglycerides and FFAs, and 3) increased cytokines. We conclude that obesity leads to nonalcoholic fatty pancreatic disease. PMID:18345311

  8. Imaging Pregnant and Lactating Patients.

    PubMed

    Tirada, Nikki; Dreizin, David; Khati, Nadia J; Akin, Esma A; Zeman, Robert K

    2015-10-01

    As use of imaging in the evaluation of pregnant and lactating patients continues to increase, misperceptions of radiation and safety risks have proliferated, which has led to often unwarranted concerns among patients and clinicians. When radiologic examinations are appropriately used, the benefits derived from the information gained usually outweigh the risks. This review describes appropriateness and safety issues, estimated doses for imaging examinations that use iodizing radiation (ie, radiography, computed tomography, nuclear scintigraphy, and fluoroscopically guided interventional radiology), radiation risks to the mother and conceptus during various stages of pregnancy, and use of iodinated or gadolinium-based contrast agents and radiotracers in pregnant and lactating women. Maternal radiation risk must be weighed with the potential consequences of missing a life-threatening diagnosis such as pulmonary embolus. Fetal risks (ie, spontaneous abortion, teratogenesis, or carcinogenesis) vary with gestational age and imaging modality and should be considered in the context of the potential benefit of medically necessary diagnostic imaging. When feasible and medically indicated, modalities that do not use ionizing radiation (eg, magnetic resonance imaging) are preferred in pregnant and lactating patients. Radiologists should strive to minimize risks of radiation to the mother and fetus, counsel patients effectively, and promote a realistic understanding of risks related to imaging during pregnancy and lactation. PMID:26466183

  9. Lactation and reproduction*

    PubMed Central

    Thomson, A. M.; Hytten, F. E.; Black, A. E.

    1975-01-01

    The authors review the literature on the effect of lactation on fertility in the absence of contraception and on the effects of contraceptive measures on lactation. They examine data from several countries on the intervals between births and on the return of menstruation and ovulation after childbirth, comparing lactating with nonlactating women. They conclude that lactation is an inefficient contraceptive for the individual, but that in populations sustained lactation is associated with reduced fertility. Possible physiological mechanisms causing lactation amenorrhoea are discussed. Though much of the literature on the effect of contraceptives on lactation is inadequate, there is general agreement that the estrogen component of hormonal preparations has an adverse effect on lactation, but that progestins alone do not. Many questions remain. Is this effect seen in established lactation, or only in the puerperal period? Is it a direct pharmacological effect, or are pill-users the mothers least motivated to maintain breast-feeding? Does a close relationship exist between hormones given and lactation performance? The authors comment on some of the technical deficiencies of previous studies in this field and discuss practical possibilities of, and limitations to, obtaining adequate scientific information in the future. PMID:1084804

  10. Surfactant-promoted Prussian Blue-modified carbon electrodes: enhancement of electro-deposition step, stabilization, electrochemical properties and application to lactate microbiosensors for the neurosciences.

    PubMed

    Salazar, P; Martín, M; O'Neill, R D; Roche, R; González-Mora, J L

    2012-04-01

    We report here for the first time a comparison of the beneficial effects of different cationic surfactants - cetyl trimethyl ammonium bromide (CTAB), benzethonium chloride (BZT) and cetylpyridinium chloride (CPC) - for the electrochemical synthesis of Prussian Blue (PB) films, using cyclic voltammetry (CV), on screen-printed carbon electrodes (SPCEs). Their electrochemical properties were investigated, paying special attention to parameters such as the amount of PB deposited, film thickness, charge transfer rate, permeability, reversibility, stability and sensitivity to hydrogen peroxide detection. All surfactant-enhanced PB-modified SPCEs displayed a significant improvement in their electrochemical properties compared with PB-modified SPCEs formed in the absence of surfactants. Surfactant-modified electrodes displayed a consistently higher PB surface concentration value of 2.1±0.4×10(-8) mol cm(-2) (mean±SD, n=3) indicating that PB deposition efficiency was improved 2-3 fold. K(+) and Na(+) permeability properties of the films were also studied, as were kinetic parameters, such as the surface electron transfer rate constant (k(s)) and the transfer coefficient (α). The hydrogen peroxide sensitivity of surfactant-modified PB films generated by 10 electro-deposition CV cycles gave values of 0.63 A M(-1) cm(-2), which is higher than those reported previously for SPCEs by other authors. Finally, the first lactate microbiosensor described in the literature based on BZT-modified PB-coated carbon fiber electrodes is presented. Its very small cross-section (~10 μm diameter) makes it particularly suitable for neuroscience studies in vivo.

  11. Hepatocellular carcinoma and non-alcoholic steatohepatitis: The state of play

    PubMed Central

    Charrez, Bérénice; Qiao, Liang; Hebbard, Lionel

    2016-01-01

    Hepatocellular carcinoma (HCC) is now the fifth cancer of greatest frequency and the second leading cause of cancer related deaths worldwide. Chief amongst the risks of HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The latter can promote non-alcoholic fatty liver disease (NAFLD), that can lead to the inflammatory form non-alcoholic steatohepatitis (NASH), and can in turn promote HCC. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give a summary of the recent findings that describe and associate NAFLD and NASH with the subsequent HCC progression. We will focus our discussion on clinical and genomic associations that describe new risks for NAFLD and NASH promoted HCC. In addition, we will consider novel murine models that clarify some of the mechanisms that drive NASH HCC formation. PMID:26937137

  12. [Lactate-guanidinium and lactate-lactate weak interactions in aqueous solutions].

    PubMed

    Horváth, P; Gergely, A; Noszál, B

    1995-07-01

    Spectropolarimetry was used to quantify the guanidinium-lactate and lactate-lactate equilibrium reactions. Association constants for the guanidinium-lactate and lactate-lactate formations are 6.11 and 1.12, respectively, in aqueous solution. The value 6.11 is certainly high among electrostatic interactions in water. This stability, however, can not account for the extremely strong lactate-protein binding, observed by NMR spectroscopy. The molar rotation coefficients for both the heteroassociation and homoassociation complexes are also calculated. The homoassociative lactate-lactate binding is the first such interaction, whose constant has been determined by spectropolarimetry in aqueous solution.

  13. Physiology of lactation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The breast changes in size, shape, and function during puberty, pregnancy, and lactation. The physiology of lactation is reviewed here. The breast is composed of fat and connective tissue that supports a tubuloalveolar structure. During development, anatomic changes involving new lobule formation an...

  14. [Psychopharmacotherapy in pregnancy and lactation. 2: Lactation].

    PubMed

    Lanczik, M; Knoche, M; Fritze, J

    1998-01-01

    Whilst the incidence of psychiatric disorders decreases during pregnancy, the risk during the postpartum period increases significantly, often leading to the necessity of psychopharmacological intervention during the puerperium, and subsequently during lactation and breast-feeding. The necessity for lithium prophylaxis in manic-depressive women after childbirth has been identified, and it is recommended that weaning rather than omission of psychopharmacological treatment is preferable during the puerperium. PMID:9522328

  15. Inhibition of endogenous lactate turnover with lactate infusion in humans

    SciTech Connect

    Searle, G.L.; Feingold, K.R.; Hsu, F.S.; Clark, O.H.; Gertz, E.W.; Stanley, W.C. )

    1989-11-01

    The extent to which lactate infusion may inhibit endogenous lactate production, though previously considered, has never been critically assessed. To examine this proposition, single injection tracer methodology (U-{sup 14}C Lactate) has been used for the estimation of lactate kinetics in 12 human subjects under basal conditions and with the infusion of sodium lactate. The basal rate of lactate turnover was measured on a day before the study with lactate infusion, and averaged 63.7 + 5.5 mg/kg/h. Six of these individuals received a stable lactate infusion at an approximate rate of 160 mg/kg/h, while the remaining six individuals were infused at the approximate rate of 100 mg/kg/h. It has been found that stable lactate infused at rates approximating 160 mg/kg/h consistently produced a complete inhibition of endogenous lactate production. Infusion of lactate at 100 mg/kg/h caused a lesser and more variable inhibition of endogenous lactate production (12% to 64%). In conclusion, lactate infusion significantly inhibits endogenous lactate production.

  16. Non-alcoholic fatty liver disease.

    PubMed

    Pearce, Lynne

    2016-08-24

    Essential facts Non-alcoholic fatty liver disease (NAFLD) is an excess of fat in the liver that is not the result of excessive alcohol consumption or other secondary causes, such as hepatitis C. According to the National Institute for Health and Care Excellence, fatty liver - steatosis - affects between 20% and 30% of the population and its prevalence is increasing. PMID:27641564

  17. Nonalcoholic steatohepatitis and hepatocellular carcinoma: Brazilian survey

    PubMed Central

    Cotrim, Helma P.; Oliveira, Claudia P.; Coelho, Henrique Sérgio M.; Alvares-da-Silva, Mario R.; Nabuco, Leticia; Parise, Edison Roberto; Ivantes, Claúdia; Martinelli, Ana LC; Galizzi-Filho, João; Carrilho, Flair J.

    2016-01-01

    OBJECTIVE: The majority of cases of hepatocellular carcinoma have been reported in individuals with cirrhosis due to chronic viral hepatitis and alcoholism, but recently, the prevalence has become increasingly related to nonalcoholic steatohepatitis around the world. The study aimed to evaluate the clinical and histophatological characteristics of hepatocellular carcinoma in Brazilians' patients with nonalcoholic steatohepatitis at the present time. METHODS: Members of the Brazilian Society of Hepatology were invited to complete a survey regarding patients with hepatocellular carcinoma related to nonalcoholic steatohepatitis. Patients with a history of alcohol intake (>20 g/day) and other liver diseases were excluded. Hepatocellular carcinoma diagnosis was performed by liver biopsy or imaging methods according to the American Association for the Study of Liver Diseases' 2011 guidelines. RESULTS: The survey included 110 patients with a diagnosis of hepatocellular carcinoma and nonalcoholic fatty liver disease from nine hepatology units in six Brazilian states (Bahia, Minas Gerais, Rio de Janeiro, São Paulo, Paraná and Rio Grande do Sul). The mean age was 67±11 years old, and 65.5% were male. Obesity was observed in 52.7% of the cases; diabetes, in 73.6%; dyslipidemia, in 41.0%; arterial hypertension, in 60%; and metabolic syndrome, in 57.2%. Steatohepatitis without fibrosis was observed in 3.8% of cases; steatohepatitis with fibrosis (grades 1-3), in 27%; and cirrhosis, in 61.5%. Histological diagnosis of hepatocellular carcinoma was performed in 47.2% of the patients, with hepatocellular carcinoma without cirrhosis accounting for 7.7%. In total, 58 patients with cirrhosis had their diagnosis by ultrasound confirmed by computed tomography or magnetic resonance imaging. Of these, 55% had 1 nodule; 17%, 2 nodules; and 28%, ≥3 nodules. CONCLUSIONS: Nonalcoholic steatohepatitis is a relevant risk factor associated with hepatocellular carcinoma in patients with and

  18. The role of the gut microbiota in nonalcoholic fatty liver disease.

    PubMed

    Abu-Shanab, Ahmed; Quigley, Eamonn M M

    2010-12-01

    Important metabolic functions have been identified for the gut microbiota in health and disease. Several lines of evidence suggest a role for the gut microbiota in both the etiology of nonalcoholic fatty liver disease (NAFLD) and progression to its more advanced state, nonalcoholic steatohepatitis (NASH). Both NAFLD and NASH are strongly linked to obesity, type 2 diabetes mellitus and the metabolic syndrome and, accordingly, have become common worldwide problems. Small intestinal bacterial overgrowth of Gram-negative organisms could promote insulin resistance, increase endogenous ethanol production and induce choline deficiency, all factors implicated in NAFLD. Among the potential mediators of this association, lipopolysaccharide (a component of Gram-negative bacterial cell walls) exerts relevant metabolic and proinflammatory effects. Although the best evidence to support a role for the gut microbiota in NAFLD and NASH comes largely from animal models, data from studies in humans (albeit at times contradictory) is accumulating and could lead to new therapeutic avenues for these highly prevalent conditions.

  19. Laboratory Prototype of Bioreactor for Oxidation of Toxic D-Lactate Using Yeast Cells Overproducing D-Lactate Cytochrome c Oxidoreductase.

    PubMed

    Karkovska, Maria; Smutok, Oleh; Gonchar, Mykhailo

    2016-01-01

    D-lactate is a natural component of many fermented foods like yogurts, sour milk, cheeses, and pickles vegetable products. D-lactate in high concentrations is toxic for children and people with short bowel syndrome and provokes encephalopathy. These facts convincingly demonstrate a need for effective tools for the D-lactate removal from some food products. The main idea of investigation is focused on application of recombinant thermotolerant methylotrophic yeast Hansenula polymorpha "tr6," overproducing D-lactate: cytochrome c oxidoreductase (EC 1.1.2.4, D-lactate cytochrome c oxidoreductase, D-lactate dehydrogenase (cytochrome), DLDH). In addition to 6-fold overexpression of DLDH under a strong constitutive promoter (prAOX), the strain of H. polymorpha "tr6" (gcr1 catX/Δcyb2, prAOX_DLDH) is characterized by impairment in glucose repression of AOX promoter, devoid of catalase and L-lactate-cytochrome c oxidoreductase activities. Overexpression of DLDH coupling with the deletion of L-lactate-cytochrome c oxidoreductase activity opens possibility for usage of the strain as a base for construction of bioreactor for removing D-lactate from fermented products due to oxidation to nontoxic pyruvate. A laboratory prototype of column-type bioreactor for removing a toxic D-lactate from model solution based on permeabilized cells of the H. polymorpha "tr6" and alginate gel was constructed and efficiency of this process was tested. PMID:27446952

  20. Laboratory Prototype of Bioreactor for Oxidation of Toxic D-Lactate Using Yeast Cells Overproducing D-Lactate Cytochrome c Oxidoreductase

    PubMed Central

    Karkovska, Maria

    2016-01-01

    D-lactate is a natural component of many fermented foods like yogurts, sour milk, cheeses, and pickles vegetable products. D-lactate in high concentrations is toxic for children and people with short bowel syndrome and provokes encephalopathy. These facts convincingly demonstrate a need for effective tools for the D-lactate removal from some food products. The main idea of investigation is focused on application of recombinant thermotolerant methylotrophic yeast Hansenula polymorpha “tr6,” overproducing D-lactate: cytochrome c oxidoreductase (EC 1.1.2.4, D-lactate cytochrome c oxidoreductase, D-lactate dehydrogenase (cytochrome), DLDH). In addition to 6-fold overexpression of DLDH under a strong constitutive promoter (prAOX), the strain of H. polymorpha “tr6” (gcr1 catX/Δcyb2, prAOX_DLDH) is characterized by impairment in glucose repression of AOX promoter, devoid of catalase and L-lactate-cytochrome c oxidoreductase activities. Overexpression of DLDH coupling with the deletion of L-lactate-cytochrome c oxidoreductase activity opens possibility for usage of the strain as a base for construction of bioreactor for removing D-lactate from fermented products due to oxidation to nontoxic pyruvate. A laboratory prototype of column-type bioreactor for removing a toxic D-lactate from model solution based on permeabilized cells of the H. polymorpha “tr6” and alginate gel was constructed and efficiency of this process was tested. PMID:27446952

  1. Hepatitis C Virus Infection and Nonalcoholic Steatohepatitis

    PubMed Central

    Patel, Anish

    2012-01-01

    Nonalcoholic fatty-liver disease (NAFLD) is one of the most prevalent liver diseases in the Western hemisphere. The rising rates of obesity and diabetes mellitus correlate with the increasing incidence of NAFLD, which is the hepatic manifestation of metabolic syndrome. Hepatitis C virus infection is another common cause of liver disease worldwide. Up to 70% of patients with chronic hepatitis C (CHC) will have concomitant steatosis. The presence of NAFLD has been implicated as a cause of lower viral response rates in CHC patients who are treated with pegylated interferon and ribavirin. This review will focus on the factors that lead to NAFLD in the setting of hepatitis C virus infection, including viral and host factors—in particular, inflammatory mediators, cytokines, and lipid peroxidation. This paper will also discuss the implications of NAFLD and nonalcoholic steatohepatitis regarding fibrosis progression, risk of hepatocellular carcinoma, and limitations with antiviral therapy. PMID:22933860

  2. Micronutrient Antioxidants and Nonalcoholic Fatty Liver Disease

    PubMed Central

    Chen, Guanliang; Ni, Yinhua; Nagata, Naoto; Xu, Liang; Ota, Tsuguhito

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most important chronic liver diseases worldwide and has garnered increasing attention in recent decades. NAFLD is characterized by a wide range of liver changes, from simple steatosis to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. The blurred pathogenesis of NAFLD is very complicated and involves lipid accumulation, insulin resistance, inflammation, and fibrogenesis. NAFLD is closely associated with complications such as obesity, diabetes, steatohepatitis, and liver fibrosis. During the progression of NAFLD, reactive oxygen species (ROS) are activated and induce oxidative stress. Recent attempts at establishing effective NAFLD therapy have identified potential micronutrient antioxidants that may reduce the accumulation of ROS and finally ameliorate the disease. In this review, we present the molecular mechanisms involved in the pathogenesis of NAFLD and introduce some dietary antioxidants that may be used to prevent or cure NAFLD, such as vitamin D, E, and astaxanthin. PMID:27563875

  3. Histopathology of nonalcoholic fatty liver disease

    PubMed Central

    Brunt, Elizabeth M; Tiniakos, Dina G

    2010-01-01

    Histological analysis of liver biopsies remains a standard against which other methods of assessment for the presence and amount of hepatic injury due to nonalcoholic fatty liver disease (NAFLD) are measured. Histological evaluation remains the sole method of distinguishing steatosis from advanced forms of NAFLD, i.e. nonalcoholic steatohepatitis (NASH) and fibrosis. Included in the lesions of NAFLD are steatosis, lobular and portal inflammation, hepatocyte injury in the forms of ballooning and apoptosis, and fibrosis. However, patterns of these lesions are as distinguishing as the lesions themselves. Liver injury in adults and children due to NAFLD may have different histological patterns. In this review, the rationale for liver biopsy, as well as the histopathological lesions, the microscopically observable patterns of injury, and the differential diagnoses of NAFLD and NASH are discussed. PMID:21072891

  4. The Immune Landscape in Nonalcoholic Steatohepatitis

    PubMed Central

    Narayanan, Sowmya; Surette, Fionna A.

    2016-01-01

    The liver lies at the intersection of multiple metabolic pathways and consequently plays a central role in lipid metabolism. Pathological disturbances in hepatic lipid metabolism are characteristic of chronic metabolic diseases, such as obesity-mediated insulin resistance, which can result in nonalcoholic fatty liver disease (NAFLD). Tissue damage induced in NAFLD activates and recruits liver-resident and non-resident immune cells, resulting in nonalcoholic steatohepatitis (NASH). Importantly, NASH is associated with an increased risk of significant clinical sequelae such as cirrhosis, cardiovascular diseases, and malignancies. In this review, we describe the immunopathogenesis of NASH by defining the known functions of immune cells in the progression and resolution of disease. PMID:27340383

  5. A comparative proteomic analysis of Bacillus coagulans in response to lactate stress during the production of L-lactic acid.

    PubMed

    Wang, Xiuwen; Qin, Jiayang; Wang, Landong; Xu, Ping

    2014-12-01

    The growth rate and maximum biomass of Bacillus coagulans 2-6 were inhibited by lactate; inhibition by sodium lactate was stronger than by calcium lactate. The differences of protein expressions by B. coagulans 2-6 under the lactate stress were determined using two-dimensional electrophoresis coupled with mass spectrometric identification. Under the non-stress condition, calcium lactate stress and sodium lactate stress, the number of detected protein spots was 1,571 ± 117, 1,281 ± 231 and 904 ± 127, respectively. Four proteins with high expression under lactate stress were identified: lactate dehydrogenase, cysteine synthase A, aldo/keto reductase and ribosomal protein L7/L12. These proteins are thus potential targets for the reconstruction of B. coagulans to promote its resistance to lactate stress.

  6. Nonalcoholic fatty liver disease: new treatments

    PubMed Central

    Hardy, Timothy; Anstee, Quentin M.; Day, Christopher P.

    2015-01-01

    Purpose of review Nonalcoholic fatty liver disease is the most common cause of liver dysfunction in the western world because of its close association with obesity, insulin resistance and dyslipidaemia. Nonalcoholic steatohepatitis (NASH) is a particular health concern due to the increased morbidity and mortality associated with progressive disease. At present, without specific targeted pharmacological therapies, the mainstay of therapy remains weight loss through dietary modification and lifestyle change; thus, the purpose of this review is to summarize the recent evidence for current and emerging therapies in NASH. Recent findings Some existing medications, including pioglitazones and angiotensin receptor antagonists, may be repurposed to help treat this condition. Vitamin E may improve histology in NASH, but safety issues limit its use. Recently, a number of novel agents specifically targeting nonalcoholic fatty liver disease pathogenesis have entered clinical trials, including the farnesoid X receptor agonist obeticholic acid, which has shown significant histological improvements in steatohepatitis and fibrosis. Summary Diet/lifestyle modification remains the mainstay of treatment. For patients with NASH and advanced fibrosis, current liver-directed pharmacotherapy with vitamin E and pioglitazone offer some benefits; obeticholic acid appears promising and is currently being tested. Comorbidities must be diagnosed and treated; cardiovascular disease remains a primary cause of death in these patients. PMID:25774446

  7. Proteomics analysis of human nonalcoholic fatty liver.

    PubMed

    Rodriguez-Suarez, Eva; Mato, Jose M; Elortza, Felix

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as a major cause of liver-related morbidity and mortality. Given the increasing prevalence of obesity in western countries, NAFLD has become an important public health problem. The principal aim of this study was to find differences in protein expression between patients with NAFLD and healthy controls. Changes in protein expression of liver samples from controls, nonalcoholic steatosis, and nonalcoholic steatohepatitis (NASH) subjects were analyzed by two-dimensional differential in-gel electrophoresis (DIGE). With this proteomic technique, hundreds of proteins can be analyzed simultaneously and their relative abundance can be calculated. Proteins showing significant changes (ratio ≥ 1.5, p < 0.05) were identified by MALDI TOF/TOF mass spectrometry. Western blot of tissue homogenates was then used as a complementary method to validate protein expression changes observed by DIGE. With the aim to have a noninvasive approach to detect changes produced in NAFLD-affected liver, validated proteins were further tested in serum samples of different cohorts of patients. Following this approach, we identified two candidate markers CPS1 and GRP78 that were differentially expressed between control, steatosis, and NASH. This proteomics approach demonstrates that DIGE combined with MALDI TOF/TOF and Western blot analysis of tissue and serum samples is a useful approach to identify candidate markers associated with NAFLD.

  8. 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. PMID:27477408

  9. Prevalence of Nonalcoholic Steatohepatitis Among Patients with Resectable Intrahepatic Cholangiocarcinoma

    PubMed Central

    Reddy, Srinevas K.; Hyder, Omar; Marsh, J. Wallis; Sotiropoulos, Georgios C.; Paul, Andreas; Alexandrescu, Sorin; Marques, Hugo; Pulitano, Carlo; Barroso, Eduardo; Aldrighetti, Luca; Geller, David A.; Sempoux, Christine; Herlea, Vlad; Popescu, Irinel; Anders, Robert; Rubbia-Brandt, Laura; Gigot, Jean-Francois; Mentha, Giles; Pawlik, Timothy M.

    2014-01-01

    Background and Aims The objective of this report was to determine the prevalence of underlying nonalcoholic steatohepatitis in resectable intrahepatic cholangiocarcinoma. Methods Demographics, comorbidities, clinicopathologic characteristics, surgical treatments, and outcomes from patients who underwent resection of intrahepatic cholangiocarcinoma at one of eight hepatobiliary centers between 1991 and 2011 were reviewed. Results Of 181 patients who underwent resection for intrahepatic cholangiocarcinoma, 31 (17.1 %) had underlying nonalcoholic steatohepatitis. Patients with nonalcoholic steatohepatitis were more likely obese (median body mass index, 30.0 vs. 26.0 kg/m2, p<0.001) and had higher rates of diabetes mellitus (38.7 vs. 22.0 %, p=0.05) and the metabolic syndrome (22.6 vs. 10.0 %, p=0.05) compared with those without nonalcoholic steatohepatitis. Presence and severity of hepatic steatosis, lobular inflammation, and hepatocyte ballooning were more common among nonalcoholic steatohepatitis patients (all p<0.001). Macrovascular (35.5 vs. 11.3 %, p=0.01) and any vascular (48.4 vs. 26.7 %, p=0.02) tumor invasion were more common among patients with nonalcoholic steatohepatitis. There were no differences in recurrence-free (median, 17.0 versus 19.4 months, p=0.42) or overall (median, 31.5 versus 36.3 months, p=0.97) survival after surgical resection between patients with and without nonalcoholic steatohepatitis. Conclusions Nonalcoholic steatohepatitis affects up to 20 % of patients with resectable intrahepatic cholangiocarcinoma. PMID:23355033

  10. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.

    PubMed

    Cusi, Kenneth

    2012-04-01

    As obesity reaches epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a frequent cause of patient referral to gastroenterologists. There is a close link between dysfunctional adipose tissue in NAFLD and common conditions such as metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. This review focuses on the pathophysiology of interactions between adipose tissue and target organs in obesity and the resulting clinical implications for the management of nonalcoholic steatohepatitis. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, caused by the accumulation of triglyceride-derived toxic metabolites in ectopic tissues (liver, muscle, pancreatic beta cells) and subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. The cross talk between dysfunctional adipocytes and the liver involves multiple cell populations, including macrophages and other immune cells, that in concert promote the development of lipotoxic liver disease, a term that more accurately describes the pathophysiology of nonalcoholic steatohepatitis. At the clinical level, adipose tissue insulin resistance contributes to type 2 diabetes mellitus and cardiovascular disease. Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity (eg, significant weight loss, exercise, thiazolidinediones) or preventing activation of inflammatory pathways and oxidative stress (ie, vitamin E, thiazolidinediones) hold promise in the treatment of NAFLD, although their long-term safety and efficacy remain to be established. Better understanding of pathways that link dysregulated adipose tissue, metabolic dysfunction, and liver lipotoxicity will result in improvements in the clinical management of these challenging patients. PMID:22326434

  11. Lactate in bitches with pyometra.

    PubMed

    Volpato, R; Rodello, L; Abibe, R B; Lopes, M D

    2012-12-01

    Lactate is a compound produced by the anaerobic metabolism of glucose, and hyperlactataemia occurs when the rate of production of lactate exceeds the rate of elimination. This occurs in situations of hypoxia and tissue hypoperfusion. Lactate has been considered a useful prognostic indicator in critically ill patients. Pyometra is a disease of adult female dogs characterized by inflammation of the uterus with an accumulation of exudate, which occurs during the luteal phase. It is one of the most common diseases that occur in the genital tract of female dogs. A total of 31 dogs were diagnosed with pyometra. The diagnosis was confirmed at ultrasonography. Of the 31 dogs, 25 females had open cervix pyometra and six had closed cervix pyometra. Plasma lactate concentrations were determined by an enzymatic colorimetric method. The average concentration (±SD) of plasma lactate in all 31 bitches with pyometra was 3.55 ± 0.46 mm. Healthy dogs had plasma lactate concentrations between 0.3 and 2.5 mm (mean ± SD). Concentrations ranged from 0.8 to 2.9 mm when plasma lactate was measured with a portable device and 0.4-2.6 mm with the blood gas analyser. Even though plasma lactate values vary between several studies and equipment used to measure concentrations, our results for dogs with pyometra are higher indicating hyperlactataemia (Thorneloe et al. , Can Vet J 48, 283-288). Plasma lactate in dogs with closed cervix pyometra was mean ± SD and in dogs with open cervix pyometra, it was mean ± SD. The plasma lactate concentration in dogs with pyometra was higher than in healthy bitches, and there was no influence of patency of the cervix on the concentration of plasma lactate concentrations. Plasma lactate concentrations were similar for animals with open and closed pyometra (3.54 ± 0.52 to 3.64 ± 1.03 mm). PMID:23279532

  12. 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

  13. The Plasma Lipidomic Signature of Nonalcoholic Steatohepatitis

    PubMed Central

    Puri, Puneet; Wiest, Michelle M.; Cheung, Onpan; Mirshahi, Faridoddin; Sargeant, Carol; Min, Hae-Ki; Contos, Melissa J.; Sterling, Richard K.; Fuchs, Michael; Zhou, Huiping; Watkins, Steven M.; Sanyal, Arun J.

    2016-01-01

    Specific alterations in hepatic lipid composition characterize the spectrum of nonalcoholic fatty liver disease (NAFLD), which extends from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). However, the plasma lipidome of NAFLD and whether NASH has a distinct plasma lipidomic signature are unknown. A comprehensive analysis of plasma lipids and eicosanoid metabolites quantified by mass spectrometry was performed in NAFL (n = 25) and NASH (n = 50) subjects and compared with lean normal controls (n = 50). The key findings include significantly increased total plasma monounsaturated fatty acids driven by palmitoleic (16:1 n7) and oleic (18:1 n9) acids content (P < 0.01 for both acids in both NAFL and NASH). The levels of palmitoleic acid, oleic acid, and palmitoleic acid to palmitic acid (16:0) ratio were significantly increased in NAFLD across multiple lipid classes. Linoleic acid (8:2n6) was decreased (P < 0.05), with a concomitant increase in γ-linolenic (18:3n6) and dihomo γ-linolenic (20:3n6) acids in both NAFL and NASH (P < 0.001 for most lipid classes). The docosahexanoic acid (22:6 n3) to docosapentenoic acid (22:5n3) ratio was significantly decreased within phosphatidylcholine (PC), and phosphatidylethanolamine (PE) pools, which was most marked in NASH subjects (P < 0.01 for PC and P < 0.001 for PE). The total plasmalogen levels were significantly decreased in NASH compared with controls (P < 0.05). A stepwise increase in lipoxygenase (LOX) metabolites 5(S)-hydroxyeicosatetraenoic acid (5-HETE), 8-HETE, and 15-HETE characterized progression from normal to NAFL to NASH. The level of 11-HETE, a nonenzymatic oxidation product of arachidonic (20:4) acid, was significantly increased in NASH only. Conclusions: Although increased lipogenesis, desaturases, and LOX activities characterize NAFL and NASH, impaired peroxisomal polyunsaturated fatty acid (PUFA) metabolism and nonenzymatic oxidation is associated with progression to NASH. PMID

  14. Managing non-alcoholic fatty liver disease

    PubMed Central

    Ngu, Jing Hieng; Goh, George Boon Bee; Poh, Zhongxian; Soetikno, Roy

    2016-01-01

    The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly with the obesity and diabetes mellitus epidemics. It is rapidly becoming the most common cause of liver disease worldwide. NAFLD can progress to serious complications such as cirrhosis, hepatocellular carcinoma and death. Therefore, it is important to recognise this condition so that early intervention can be implemented. Lifestyle modifications and strict control of metabolic risk factors are the mainstay of treatment. As disease progression is slow in the majority of NAFLD patients, most can be managed well by primary care physicians. NAFLD patients with advanced liver fibrosis should be referred to specialist care for further assessment. PMID:27439352

  15. Mammary candidosis in lactating women.

    PubMed

    Heinig, M J; Francis, J; Pappagianis, D

    1999-12-01

    Though perceived to be a growing problem by lactation professionals, fungal infection of the breast (mammary candidosis) is largely unstudied. Candida albicans, a commensal organism encountered frequently in the vagina and gastrointestinal tract of humans, has been reported to be responsible for both superficial (cutaneous) and localized (ductal) infection of the mammary gland in lactating women, though the latter association is not universally accepted. Severe pain is considered to be characteristic of yeast infection of the breast and may be a cause of premature weaning among lactating mothers. Given that pain is often the complaint that prompts mothers to consult lactation professionals, it is important that healthcare providers working with lactating women be knowledgeable about this disease. In this article, current research regarding yeast infection of the breast is summarized, including morphology and pathology, diagnosis, risk factors, and common treatment options.

  16. Secondary causes of nonalcoholic fatty liver disease

    PubMed Central

    Kneeman, Jacob M.; Misdraji, Joseph

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is becoming the most common cause of chronic liver disease in the developing world, found in 17-30% of the population in Western countries and 2-4% worldwide. Defined as the accumulation of fatty acid content greater than 5% of liver weight, NAFLD is a spectrum of disease ranging from simple steatosis to nonalcoholic steatohepatitis. The pathophysiology of NAFLD involves increased de novo synthesis of fatty acids in hepatocytes, the retention of lipids due to impaired hepatocyte apolipoprotein secretion or beta-oxidation. The well-known primary causes of NAFLD are obesity, type II diabetes, dyslipidemia, and insulin resistance. However, other less common conditions can cause a similar clinical and histologic picture, and should be considered in patients who present with NAFLD but do not have traditional risk factors. In this review, we discuss uncommon but important causes of NAFLD, including inborn errors of metabolism, iatrogenic causes, viral hepatitis, and nutritional disorders to provide practicing clinicians with an understanding of the less well recognized causes of NAFLD. PMID:22570680

  17. Nonmedicinal interventions in nonalcoholic fatty liver disease

    PubMed Central

    Neuman, Manuela G; Nanau, Radu M; Cohen, Lawrence B

    2015-01-01

    Unhealthy diet and lack of physical exercise are responsible for fat accumulation in the liver, which may lead to liver disease. Histologically, the severity of the disease has two stages: nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). NAFLD is defined by the presence of steatosis with no evidence of cellular injury such as hepatocyte ballooning. NASH is a distinct entity from NAFLD, and is characterized by the presence of inflammation with hepatocytes damage, with or without fibrosis. While several therapeutic strategies have been proposed to improve this condition, the present review aims to discuss nonmedicinal interventions used to reduce liver involvement or to prevent the disease altogether. The authors investigated dietary patterns and vitamin deficiencies associated with NAFLD, and their role in enhancing disease severity. Additionally, they reviewed the role of exercise and the use of interventions, such as as intragastric balloon and bariatric surgery, for improving disease progression. The authors propose monitoring disease progression or repair by following changes in cytoadipokine levels. PMID:26076224

  18. Iron and non-alcoholic fatty liver disease.

    PubMed

    Britton, Laurence J; Subramaniam, V Nathan; Crawford, Darrell Hg

    2016-09-28

    The mechanisms that promote liver injury in non-alcoholic fatty liver disease (NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis. PMID:27688653

  19. Iron and non-alcoholic fatty liver disease

    PubMed Central

    Britton, Laurence J; Subramaniam, V Nathan; Crawford, Darrell HG

    2016-01-01

    The mechanisms that promote liver injury in non-alcoholic fatty liver disease (NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis.

  20. Iron and non-alcoholic fatty liver disease

    PubMed Central

    Britton, Laurence J; Subramaniam, V Nathan; Crawford, Darrell HG

    2016-01-01

    The mechanisms that promote liver injury in non-alcoholic fatty liver disease (NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis. PMID:27688653

  1. Mechanisms linking nonalcoholic fatty liver disease with coronary artery disease.

    PubMed

    Nseir, W; Shalata, A; Marmor, A; Assy, N

    2011-12-01

    The most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) is coronary artery disease (CAD), not chronic liver disease. Fatty liver increases cardiovascular risk by classical (dyslipidemia, hypertension, diabetes) and by less conventional mechanisms. Common pathways involved in the pathogenesis of fatty liver and CAD includes hepatic insulin resistance and sub clinical inflammation. The hepatic insulin resistance state of fatty liver infiltration is characterized by increased FFA, which causes lipotoxicity and impairs endothelium-dependent vasodilatation, increases oxidative stress, and has a cardio toxic effect. Additional metabolic risk factors include leptin, adiponectin, pro inflammatory cytokines [such as IL-6, C-reactive protein and plasminogen activator inhibitor-1 (PAI-1)], which together lead to increased oxidative stress and endothelial dysfunction, finally promoting coronary artery disease (CAD). When classical risk factors are superimposed on fatty liver accumulation, they may further increase the new metabolic risk factors, exacerbating CAD. The clinical implication is that patients with NAFLD are at higher risk (steatohepatitis, diabetes, obesity, atherogenic dyslipidemia) and should undergo periodic cardiovascular risk assessment including the Framingham score, cardiac effort test, and measurement of intimae-media thickening of the carotids arteries. This may improve risk stratification for CAD. PMID:21655948

  2. Induction of triglyceride accumulation and mitochondrial maintenance in muscle cells by lactate.

    PubMed

    Sun, Jingquan; Ye, Xin; Xie, Minhao; Ye, Jianping

    2016-01-01

    Muscle exercise induces intramuscular triglyceride (TG) accumulation and promotes mitochondrial maintenance in myotubes. However, the mechanism underlying exercise effects remains unknown. In this study, lactic acid was tested as a signaling molecule in C2C12 myotubes to understand the mechanism. Intracellular TG storage was induced in the cells by sodium lactate. The lactate activity was observed with an inhibition of the cAMP-PKA pathway as indicated by a reduction in the phosphorylation status of CREB (pCREB). Induction of pCREB signal by forskolin was blocked by pretreatment of cells with lactate. The impact of lactate on mitochondrial function was examined with a focus on the activities of two enzymes, MCAT (malonylCoA:ACP transferase) and PDH (pyruvate dehydrogenase). The enzyme activities were induced in the cells by lactate. Expression of the lactate receptor (GPR81) and lactate transporters (MCT1/4) were induced as well by lactate. The lactate activities were observed at concentrations between 4-64 mM, and were not dependent on the increase in intracellular pyruvate. Pyruvate treatment did not generate the same effects in the cells. Those results suggest that lactate may induce intramuscular TG storage and mitochondrial maintenance in myotubes through inhibition of the cAMP pathway by activation of GPR81 in a positive feedback manner. PMID:27645401

  3. Induction of triglyceride accumulation and mitochondrial maintenance in muscle cells by lactate

    PubMed Central

    Sun, Jingquan; Ye, Xin; Xie, Minhao; Ye, Jianping

    2016-01-01

    Muscle exercise induces intramuscular triglyceride (TG) accumulation and promotes mitochondrial maintenance in myotubes. However, the mechanism underlying exercise effects remains unknown. In this study, lactic acid was tested as a signaling molecule in C2C12 myotubes to understand the mechanism. Intracellular TG storage was induced in the cells by sodium lactate. The lactate activity was observed with an inhibition of the cAMP-PKA pathway as indicated by a reduction in the phosphorylation status of CREB (pCREB). Induction of pCREB signal by forskolin was blocked by pretreatment of cells with lactate. The impact of lactate on mitochondrial function was examined with a focus on the activities of two enzymes, MCAT (malonylCoA:ACP transferase) and PDH (pyruvate dehydrogenase). The enzyme activities were induced in the cells by lactate. Expression of the lactate receptor (GPR81) and lactate transporters (MCT1/4) were induced as well by lactate. The lactate activities were observed at concentrations between 4–64 mM, and were not dependent on the increase in intracellular pyruvate. Pyruvate treatment did not generate the same effects in the cells. Those results suggest that lactate may induce intramuscular TG storage and mitochondrial maintenance in myotubes through inhibition of the cAMP pathway by activation of GPR81 in a positive feedback manner. PMID:27645401

  4. Induction of triglyceride accumulation and mitochondrial maintenance in muscle cells by lactate.

    PubMed

    Sun, Jingquan; Ye, Xin; Xie, Minhao; Ye, Jianping

    2016-09-20

    Muscle exercise induces intramuscular triglyceride (TG) accumulation and promotes mitochondrial maintenance in myotubes. However, the mechanism underlying exercise effects remains unknown. In this study, lactic acid was tested as a signaling molecule in C2C12 myotubes to understand the mechanism. Intracellular TG storage was induced in the cells by sodium lactate. The lactate activity was observed with an inhibition of the cAMP-PKA pathway as indicated by a reduction in the phosphorylation status of CREB (pCREB). Induction of pCREB signal by forskolin was blocked by pretreatment of cells with lactate. The impact of lactate on mitochondrial function was examined with a focus on the activities of two enzymes, MCAT (malonylCoA:ACP transferase) and PDH (pyruvate dehydrogenase). The enzyme activities were induced in the cells by lactate. Expression of the lactate receptor (GPR81) and lactate transporters (MCT1/4) were induced as well by lactate. The lactate activities were observed at concentrations between 4-64 mM, and were not dependent on the increase in intracellular pyruvate. Pyruvate treatment did not generate the same effects in the cells. Those results suggest that lactate may induce intramuscular TG storage and mitochondrial maintenance in myotubes through inhibition of the cAMP pathway by activation of GPR81 in a positive feedback manner.

  5. Medications in pregnancy and lactation.

    PubMed

    McCarter-Spaulding, Deborah E

    2005-01-01

    The issue of medication use during pregnancy is of concern because the physiology of pregnancy affects the pharmokinetics of medications used, and certain medications can reach the fetus and cause harm. Studying medication safety in pregnancy and lactation is challenging; thus, the U.S. Food and Drug Administration (FDA) categories of medication risk in pregnancy are limited, especially for the lactating mother. A better understanding of the role of physiologic changes in pregnancy, placental function, effects of medication on the fetus, and the mechanisms of drug transfer into breast milk can help nurses teach their patients both preconceptionally and during pregnancy and lactation. This article provides a review of current literature so nurses can become more aware of the basic principles involved in medication use for pregnant and lactating women.

  6. 21 CFR 73.165 - Ferrous lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Ferrous lactate. 73.165 Section 73.165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION Foods § 73.165 Ferrous lactate. (a) Identity. The color additive ferrous lactate is the ferrous lactate defined...

  7. Lactate levels with glioblastoma multiforme

    PubMed Central

    Kahlon, Arunpreet Singh; Alexander, Mariam; Kahlon, Arundeep

    2016-01-01

    A 37-year-old woman with known glioblastoma multiforme was admitted for treatment of new deep vein thrombosis. Anion gap and plasma lactate levels were found to be elevated. Magnetic resonance imaging of the brain showed a stable, advanced glioblastoma multiforme. All causes of lactic acidosis, including infections and medications, were ruled out. Aggressive tumors have been shown to produce lactate levels in minute quantities in their microenvironment, which helps them metastasize and evade immune response and even radiation. PMID:27365883

  8. Lipoprotein metabolism in nonalcoholic fatty liver disease

    PubMed Central

    Jiang, Zhenghui Gordon; Robson, Simon C.; Yao, Zemin

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD), an escalating health problem worldwide, covers a spectrum of pathologies characterized by fatty accumulation in hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellular role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metabolism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD. PMID:23554788

  9. Probiotics and Nonalcoholic Fatty liver Disease

    PubMed Central

    Eslamparast, Tannaz; Eghtesad, Sareh; Hekmatdoost, Azita; Poustchi, Hossein

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, both in adults and in children. NAFLD represents a spectrum of liver diseases that range from hepatic steatosis to steatohepatitis and cirrhosis. However, NAFLD is more prevalent in overweight and obese individuals. Evidences thus far suggest that hepatic triglyceride accumulation is not always derived from obesity; gut microbiota can also play a role in the development of insulin resistance, hepatic steatosis, necroinflammation and fibrosis. On the other hand, probiotics can strengthen the intestinal wall, reducing its permeability, bacterial translocation, and endotoxemia according to animal and human studies. They can also reduce oxidative and inflammatory liver damage, while improving the histological state in certain situations. This review article focuses on research that has been conducted on probiotics and NAFLD, highlighting their efficacy as a novel therapeutic option for the treatment of this condition. PMID:24829682

  10. Herbal medicines and nonalcoholic fatty liver disease.

    PubMed

    Yao, Hong; Qiao, Yu-Jie; Zhao, Ya-Li; Tao, Xu-Feng; Xu, Li-Na; Yin, Lian-Hong; Qi, Yan; Peng, Jin-Yong

    2016-08-14

    Nonalcoholic fatty liver disease (NAFLD), which is characterized by excessive fat accumulation in the liver of patients who consume little or no alcohol, becomes increasingly common with rapid economic development. Long-term excess fat accumulation leads to NAFLD and represents a global health problem with no effective therapeutic approach. NAFLD is considered to be a series of complex, multifaceted pathological processes involving oxidative stress, inflammation, apoptosis, and metabolism. Over the past decades, herbal medicines have garnered growing attention as potential therapeutic agents to prevent and treat NAFLD, due to their high efficacy and low risk of side effects. In this review, we evaluate the use of herbal medicines (including traditional Chinese herbal formulas, crude extracts from medicinal plants, and pure natural products) to treat NAFLD. These herbal medicines are natural resources that can inform innovative drug research and the development of treatments for NAFLD in the future. PMID:27570425

  11. Herbal medicines and nonalcoholic fatty liver disease

    PubMed Central

    Yao, Hong; Qiao, Yu-Jie; Zhao, Ya-Li; Tao, Xu-Feng; Xu, Li-Na; Yin, Lian-Hong; Qi, Yan; Peng, Jin-Yong

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD), which is characterized by excessive fat accumulation in the liver of patients who consume little or no alcohol, becomes increasingly common with rapid economic development. Long-term excess fat accumulation leads to NAFLD and represents a global health problem with no effective therapeutic approach. NAFLD is considered to be a series of complex, multifaceted pathological processes involving oxidative stress, inflammation, apoptosis, and metabolism. Over the past decades, herbal medicines have garnered growing attention as potential therapeutic agents to prevent and treat NAFLD, due to their high efficacy and low risk of side effects. In this review, we evaluate the use of herbal medicines (including traditional Chinese herbal formulas, crude extracts from medicinal plants, and pure natural products) to treat NAFLD. These herbal medicines are natural resources that can inform innovative drug research and the development of treatments for NAFLD in the future. PMID:27570425

  12. Herbal medicines and nonalcoholic fatty liver disease.

    PubMed

    Yao, Hong; Qiao, Yu-Jie; Zhao, Ya-Li; Tao, Xu-Feng; Xu, Li-Na; Yin, Lian-Hong; Qi, Yan; Peng, Jin-Yong

    2016-08-14

    Nonalcoholic fatty liver disease (NAFLD), which is characterized by excessive fat accumulation in the liver of patients who consume little or no alcohol, becomes increasingly common with rapid economic development. Long-term excess fat accumulation leads to NAFLD and represents a global health problem with no effective therapeutic approach. NAFLD is considered to be a series of complex, multifaceted pathological processes involving oxidative stress, inflammation, apoptosis, and metabolism. Over the past decades, herbal medicines have garnered growing attention as potential therapeutic agents to prevent and treat NAFLD, due to their high efficacy and low risk of side effects. In this review, we evaluate the use of herbal medicines (including traditional Chinese herbal formulas, crude extracts from medicinal plants, and pure natural products) to treat NAFLD. These herbal medicines are natural resources that can inform innovative drug research and the development of treatments for NAFLD in the future.

  13. Nonalcoholic fatty liver disease and cardiovascular disease.

    PubMed

    Liu, Hong; Lu, Hong-Yun

    2014-07-14

    Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) are two diseases that are common in the general population. To date, many studies have been conducted and demonstrate a direct link between NAFLD and CVD, but the exact mechanisms for this complex relationship are not well established. A systematic search of the PubMed database revealed that several common mechanisms are involved in many of the local and systemic manifestations of NAFLD and lead to an increased cardiovascular risk. The possible mechanisms linking NAFLD and CVD include inflammation, oxidative stress, insulin resistance, ectopic adipose tissue distribution, dyslipidemia, endothelial dysfunction, and adiponectin, among others. The clinical implication is that patients with NAFLD are at an increased risk of CVD and should undergo periodic cardiovascular risk assessment. PMID:25024598

  14. How to Diagnose Nonalcoholic Fatty Liver Disease.

    PubMed

    de Alwis, Nimantha M W; Anstee, Quentin M; Day, Christopher P

    2016-01-01

    Patients with nonalcoholic fatty liver disease (NAFLD) are asymptomatic and present with either unexplained abnormal liver blood tests or a bright liver on ultrasonography. Some patients will have normal liver blood tests raising the issue of whether patients with risk factors for NAFLD (diabetes and/or metabolic syndrome [MS]) should be screened for its presence with biomarkers, such as the fatty liver index (FLI). The diagnosis of NAFLD requires the exclusion of other causes of chronic liver disease and steatosis, especially heavy alcohol consumption and viral hepatitis particularly HCV genotype 3. Diagnostic work-up should include evaluation of family and personal history of components of the MS and assessment of liver tests, fasting blood glucose, triglycerides and HDL levels. A drug history is important due to a number being associated with steatosis. To confirm the diagnosis of NAFLD and quantify steatosis, ultrasound (US) and MRI-based techniques are available but none are in routine use outside clinical trials. Standard US is no more accurate than biomarkers such as FLI. The accurate staging of NAFLD requires liver biopsy; however, this is clearly impractical for such a prevalent disease. Accordingly, a number of imaging and blood-based biomarker tests have been evaluated. While none have proved reliable for the diagnosis of nonalcoholic steatohepatitis, several have proved accurate in diagnosing the presence of stage 3 or 4 fibrosis, including the NAFLD fibrosis score, fibrosis-4 and the enhanced liver fibrosis test. Of the imaging techniques, elastography has received the most attention and is being used in routine clinical practice. US acoustic radiation force impulse imaging, and MR-based elastography have recently been described but none are sufficiently accurate to replace liver biopsy for clinical trials as yet or are cost effective for use in routine clinical settings. PMID:27547937

  15. Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Ur Rahman, Zia; Hurairah, Abu

    2016-01-01

    Our objective was to study nonalcoholic fatty liver disease (NAFLD) as a relevant risk factor associated with hepatocellular carcinoma (HCC) in patients with and without cirrhosis. HCC is a common cancer worldwide that predominantly involves patients with hepatic cirrhosis. HCC has recently been linked to NAFLD, the hepatic manifestation of obesity and related metabolic disorders. This association is alarming due to the high prevalence of NAFLD globally, which may contribute to the rising incidence of HCC. A 31-year-old female with a history of dyslipidemia, hypertension, and diabetes mellitus presented with abdominal pain that persisted for six months. The pain was associated with gastrointestinal symptoms and weight loss. She was drug-free and a nonalcoholic and a nonsmoker. The physical examination was unremarkable. The abdominal exam showed a soft and non-tender abdomen, with no organomegaly or ascites. The laboratory evaluation was unremarkable. The imaging studies showed a hypodense lesion in the right hepatic lobe with strong arterial enhancement. Subsequently, the patient underwent a liver biopsy. The histopathology results were consistent with HCC. The patient underwent an uneventful segment VI liver resection and tumor-free margins were achieved. In our patient, NAFLD was designated as an independent etiology for HCC, without cirrhosis. Our patient recovered well and has been disease free for over a year. HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk of HCC. These results provide new targets for surveillance, prevention, early recognition, and effective treatment of HCC associated with NAFLD. PMID:27733959

  16. Sales impact of displaying alcoholic and non-alcoholic beverages in end-of-aisle locations: an observational study.

    PubMed

    Nakamura, Ryota; Pechey, Rachel; Suhrcke, Marc; Jebb, Susan A; Marteau, Theresa M

    2014-05-01

    In-store product placement is perceived to be a factor underpinning impulsive food purchasing but empirical evidence is limited. In this study we present the first in-depth estimate of the effect of end-of-aisle display on sales, focussing on alcohol. Data on store layout and product-level sales during 2010-11 were obtained for one UK grocery store, comprising detailed information on shelf space, price, price promotion and weekly sales volume in three alcohol categories (beer, wine, spirits) and three non-alcohol categories (carbonated drinks, coffee, tea). Multiple regression techniques were used to estimate the effect of end-of-aisle display on sales, controlling for price, price promotion, and the number of display locations for each product. End-of-aisle display increased sales volumes in all three alcohol categories: by 23.2% (p = 0.005) for beer, 33.6% (p < 0.001) for wine, and 46.1% (p < 0.001) for spirits, and for three non-alcohol beverage categories: by 51.7% (p < 0.001) for carbonated drinks, 73.5% (p < 0.001) for coffee, and 113.8% (p < 0.001) for tea. The effect size was equivalent to a decrease in price of between 4% and 9% per volume for alcohol categories, and a decrease in price of between 22% and 62% per volume for non-alcohol categories. End-of-aisle displays appear to have a large impact on sales of alcohol and non-alcoholic beverages. Restricting the use of aisle ends for alcohol and other less healthy products might be a promising option to encourage healthier in-store purchases, without affecting availability or cost of products.

  17. Sales impact of displaying alcoholic and non-alcoholic beverages in end-of-aisle locations: An observational study

    PubMed Central

    Nakamura, Ryota; Pechey, Rachel; Suhrcke, Marc; Jebb, Susan A.; Marteau, Theresa M.

    2014-01-01

    In-store product placement is perceived to be a factor underpinning impulsive food purchasing but empirical evidence is limited. In this study we present the first in-depth estimate of the effect of end-of-aisle display on sales, focussing on alcohol. Data on store layout and product-level sales during 2010–11 were obtained for one UK grocery store, comprising detailed information on shelf space, price, price promotion and weekly sales volume in three alcohol categories (beer, wine, spirits) and three non-alcohol categories (carbonated drinks, coffee, tea). Multiple regression techniques were used to estimate the effect of end-of-aisle display on sales, controlling for price, price promotion, and the number of display locations for each product. End-of-aisle display increased sales volumes in all three alcohol categories: by 23.2% (p = 0.005) for beer, 33.6% (p < 0.001) for wine, and 46.1% (p < 0.001) for spirits, and for three non-alcohol beverage categories: by 51.7% (p < 0.001) for carbonated drinks, 73.5% (p < 0.001) for coffee, and 113.8% (p < 0.001) for tea. The effect size was equivalent to a decrease in price of between 4% and 9% per volume for alcohol categories, and a decrease in price of between 22% and 62% per volume for non-alcohol categories. End-of-aisle displays appear to have a large impact on sales of alcohol and non-alcoholic beverages. Restricting the use of aisle ends for alcohol and other less healthy products might be a promising option to encourage healthier in-store purchases, without affecting availability or cost of products. PMID:24632050

  18. Fructose, high fructose corn syrup, sucrose, and non-alcoholic liver disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nonalcoholic fatty liver disease (NAFLD), formerly called nonalcoholic steatohepatitis, is characterized by hepatic steatosis and abnormal triglyceride accumulation in liver cells. Its etiology, pathophysiology, and pathogenesis are still poorly understood. Some have suggested that the increased in...

  19. Quantitative studies of skeletal muscle lactate metabolism

    SciTech Connect

    Pagliassotti, M.J.

    1988-01-01

    In Situ, single-pass perfusions were employed on three isolated rabbit skeletal muscle preparations of differing fiber type and oxidative capacity to investigate the influence of fiber type and oxidative capacity per se on net carbon, {sup 14}C-lactate, and {sup 3}H-glucose fluxes. Preparations were exposed to six lactate concentrations ranging from 1-11mM. At basal lactate concentrations all preparations displayed net lactate release, {sup 14}C-lactate removal and {sup 14}CO{sub 2} release, all were linearly correlated with lactate concentration. By 4mM all preparations switched to net lactate uptake and {sup 14}C-lactate removal always exceeded net lactate uptake. To quantify the fate of net carbon, {sup 14}C-lactate, and {sup 3}H-glucose removal preparations were perfused at either basal or elevated lactate. Under basal conditions net carbon influx from glucose and glycogen was removed primarily via net lactate release in the glycolytic and mixed preparations and oxidation and net lactate release in the oxidative preparation. At elevated lactate, net carbon influx from lactate, pyruvate and glucose was removed primarily by net glycogen synthesis in the glycolytic preparation and both alanine release and oxidation in the mixed and oxidative preparations.

  20. Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease.

    PubMed

    Hyötyläinen, Tuulia; Jerby, Livnat; Petäjä, Elina M; Mattila, Ismo; Jäntti, Sirkku; Auvinen, Petri; Gastaldelli, Amalia; Yki-Järvinen, Hannele; Ruppin, Eytan; Orešič, Matej

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD. PMID:26839171

  1. Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease

    PubMed Central

    Hyötyläinen, Tuulia; Jerby, Livnat; Petäjä, Elina M.; Mattila, Ismo; Jäntti, Sirkku; Auvinen, Petri; Gastaldelli, Amalia; Yki-Järvinen, Hannele; Ruppin, Eytan; Orešič, Matej

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD. PMID:26839171

  2. Highly efficient L-lactate production using engineered Escherichia coli with dissimilar temperature optima for L-lactate formation and cell growth

    PubMed Central

    2014-01-01

    L-Lactic acid, one of the most important chiral molecules and organic acids, is produced via pyruvate from carbohydrates in diverse microorganisms catalyzed by an NAD+-dependent L-lactate dehydrogenase. Naturally, Escherichia coli does not produce L-lactate in noticeable amounts, but can catabolize it via a dehydrogenation reaction mediated by an FMN-dependent L-lactate dehydrogenase. In aims to make the E. coli strain to produce L-lactate, three L-lactate dehydrogenase genes from different bacteria were cloned and expressed. The L-lactate producing strains, 090B1 (B0013-070, ΔldhA::diflldD::Pldh-ldhLca), 090B2 (B0013-070, ΔldhA::diflldD::Pldh-ldhStrb) and 090B3 (B0013-070, ΔldhA::diflldD::Pldh-ldhBcoa) were developed from a previously developed D-lactate over-producing strain, E. coli strain B0013-070 (ack-ptappspflBdldpoxBadhEfrdA) by: (1) deleting ldhA to block D-lactate formation, (2) deleting lldD to block the conversion of L-lactate to pyruvate, and (3) expressing an L-lactate dehydrogenase (L-LDH) to convert pyruvate to L-lactate under the control of the ldhA promoter. Fermentation tests were carried out in a shaking flask and in a 25-l bioreactor. Strains 090B1, 090B2 or 090B3 were shown to metabolize glucose to L-lactate instead of D-lactate. However, L-lactate yield and cell growth rates were significantly different among the metabolically engineered strains which can be attributed to a variation between temperature optimum for cell growth and temperature optimum for enzymatic activity of individual L-LDH. In a temperature-shifting fermentation process (cells grown at 37°C and L-lactate formed at 42°C), E. coli 090B3 was able to produce 142.2 g/l of L-lactate with no more than 1.2 g/l of by-products (mainly acetate, pyruvate and succinate) accumulated. In conclusion, the production of lactate by E. coli is limited by the competition relationship between cell growth and lactate synthesis. Enzymatic properties, especially the thermodynamics of an L

  3. Probiotics as a Novel Treatment for Non-Alcoholic Fatty Liver Disease; A Systematic Review on the Current Evidences

    PubMed Central

    Kelishadi, Roya; Farajian, Sanam; Mirlohi, Maryam

    2013-01-01

    Context Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with 5-10% of liver having extra fat. Increase in its prevalence in all age groups is linked with obesity and Type II diabetes. The treatment of NAFLD remains controversial. A growing body of evidence suggests a relation between overgrowth of gut microbiota with NAFLD and non-alcoholic steatohepatitis (NASH). The objective of this review is to provide an overview on experimental and clinical studies assessing all positive and negative effects of probiotics. Evidence Acquisition We made a critical appraisal on various types of documents published from 1999 to March 2012 in journals, electronic books, seminars, and symposium contexts including Medline, PubMed, and Cochrane Central Register of Controlled Trials databases. We used the key words: “non-alcoholic fatty liver disease, probiotics, non-alcoholic steatohepatitis, liver disease, and fatty liver”. Results Probiotics, as biological factors, control the gut microbiota and result in its progression. It is in this sense that they are suggestive of a new and a natural way of promoting liver function. Correspondingly, limited evidence suggests that probiotics could be considered as a new way of treatment for NAFLD. Conclusions Various experimental studies and clinical trials revealed promising effects of probiotics in improving NAFLD; however given the limited experience in this field, generalization of probiotics as treatment of NAFLD needs substantiation through more trials with a larger sample sizes and with longer-term follow up. PMID:23885277

  4. Lactate does not activate NF-κB in oxidative tumor cells

    PubMed Central

    Van Hée, Vincent F.; Pérez-Escuredo, Jhudit; Cacace, Andrea; Copetti, Tamara; Sonveaux, Pierre

    2015-01-01

    The lactate anion is currently emerging as an oncometabolite. Lactate, produced and exported by glycolytic and glutaminolytic cells in tumors, can be recycled as an oxidative fuel by oxidative tumors cells. Independently of hypoxia, it can also activate transcription factor hypoxia-inducible factor-1 (HIF-1) in tumor and endothelial cells, promoting angiogenesis. These protumoral activities of lactate depend on lactate uptake, a process primarily facilitated by the inward, passive lactate-proton symporter monocarboxylate transporter 1 (MCT1); the conversion of lactate and NAD+ to pyruvate, NADH and H+ by lactate dehydrogenase-1 (LDH-1); and a competition between pyruvate and α-ketoglutarate that inhibits prolylhydroxylases (PHDs). Endothelial cells do not primarily use lactate as an oxidative fuel but, rather, as a signaling agent. In addition to HIF-1, lactate can indeed activate transcription factor nuclear factor-κB (NF-κB) in these cells, through a mechanism not only depending on PHD inhibition but also on NADH alimenting NAD(P)H oxidases to generate reactive oxygen species (ROS). While NF-κB activity in endothelial cells promotes angiogenesis, NF-κB activation in tumor cells is known to stimulate tumor progression by conferring resistance to apoptosis, stemness, pro-angiogenic and metastatic capabilities. In this study, we therefore tested whether exogenous lactate could activate NF-κB in oxidative tumor cells equipped for lactate signaling. We report that, precisely because they are oxidative, HeLa and SiHa human tumor cells do not activate NF-κB in response to lactate. Indeed, while lactate-derived pyruvate is well-known to inhibit PHDs in these cells, we found that NADH aliments oxidative phosphorylation (OXPHOS) in mitochondria rather than NAD(P)H oxidases in the cytosol. These data were confirmed using oxidative human Cal27 and MCF7 tumor cells. This new information positions the malate-aspartate shuttle as a key player in the oxidative metabolism

  5. Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis

    PubMed Central

    Katayama, Akihiro; Nakatsuka, Atsuko; Eguchi, Jun; Murakami, Kazutoshi; Teshigawara, Sanae; Kanzaki, Motoko; Nunoue, Tomokazu; Hida, Kazuyuki; Wada, Nozomu; Yasunaka, Tetsuya; Ikeda, Fusao; Takaki, Akinobu; Yamamoto, Kazuhide; Kiyonari, Hiroshi; Makino, Hirofumi; Wada, Jun

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity. PMID:26581806

  6. Mitochondrial Molecular Pathophysiology of Nonalcoholic Fatty Liver Disease: A Proteomics Approach.

    PubMed

    Nuño-Lámbarri, Natalia; Barbero-Becerra, Varenka J; Uribe, Misael; Chávez-Tapia, Norberto C

    2016-03-15

    Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that can progress to nonalcoholic steatohepatitis, cirrhosis and cancer. It is considered an emerging health problem due to malnourishment or a high-fat diet (HFD) intake, which is observed worldwide. It is well known that the hepatocytes' apoptosis phenomenon is one of the most important features of NAFLD. Thus, this review focuses on revealing, through a proteomics approach, the complex network of protein interactions that promote fibrosis, liver cell stress, and apoptosis. According to different types of in vitro and murine models, it has been found that oxidative/nitrative protein stress leads to mitochondrial dysfunction, which plays a major role in stimulating NAFLD damage. Human studies have revealed the importance of novel biomarkers, such as retinol-binding protein 4, lumican, transgelin 2 and hemoglobin, which have a significant role in the disease. The post-genome era has brought proteomics technology, which allows the determination of molecular pathogenesis in NAFLD. This has led to the search for biomarkers which improve early diagnosis and optimal treatment and which may effectively prevent fatal consequences such as cirrhosis or cancer.

  7. Knowing What’s Out There: Awareness of Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Ghevariya, Vishal; Sandar, Nan; Patel, Kishor; Ghevariya, Nehal; Shah, Ruchit; Aron, Joshua; Anand, Sury

    2014-01-01

    Background: Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder, which poses a significant health burden in the western countries. As the epidemic of obesity slides health downward, the incidence of NAFLD is evidently increasing. Aim: We aimed to ascertain the awareness of NAFLD and its risk factors in the general population, which may be helpful in designing educational tools to promote prevention, early detection, and treatment of this disorder. Methods: A survey of 5000 non-institutionalized residents of Brooklyn, NY, USA was conducted. Sixteen items were included in the survey questionnaire including awareness of fatty liver, predisposing factors of NAFLD, awareness of cirrhosis, and conditions that advance to cirrhosis. The questionnaire also addressed awareness of prevention, diagnostic methods and treatment of NAFLD, and education of physicians to their patients about NAFLD. Results: Overwhelming majority of the subjects was not aware of NAFLD and stated that their physicians did not have a discussion about NAFLD. Conclusion: Non-alcoholic fatty liver disease is a preventable liver disorder with limited treatment options. Thorough counseling by primary care physicians can be of paramount importance in preventive strategy for NAFLD. We should target our teenage population in an era of obesity epidemics of all times. PMID:25798442

  8. Non-alcoholic fatty liver disease in obese adults: clinical aspects and current management strategies.

    PubMed

    Pallayova, M; Taheri, S

    2014-10-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder whose prevalence is strongly linked to the current epidemic of obesity in many western countries. The prevalence of NAFLD is two to four times higher in populations with pre-existing metabolic comorbidities than in the general population. The diagnosis of primary NAFLD involves establishing the presence of hepatic steatosis or steatohepatitis by imaging or histology, along with establishing the non-alcoholic nature of the disease process and excluding competing aetiologies for hepatic steatosis. Among the indirect serum biomarkers, the NAFLD fibrosis score can help to identify patients with NAFLD and with higher likelihood of having fibrosis or cirrhosis. A liver biopsy should be considered in NAFLD patients at increased risk for steatohepatitis/advanced fibrosis and in cases where a liver biopsy is necessary to exclude co-existing chronic liver diseases and other aetiologies for hepatic steatosis. The treatment and management recommendations for obesity-associated NAFLD are aimed towards weight reduction. The currently available interventions employed to promote weight loss and improve the metabolic responses in NAFLD include lifestyle modification, pharmacotherapy and bariatric surgery.

  9. Mitochondrial Molecular Pathophysiology of Nonalcoholic Fatty Liver Disease: A Proteomics Approach

    PubMed Central

    Nuño-Lámbarri, Natalia; Barbero-Becerra, Varenka J.; Uribe, Misael; Chávez-Tapia, Norberto C.

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that can progress to nonalcoholic steatohepatitis, cirrhosis and cancer. It is considered an emerging health problem due to malnourishment or a high-fat diet (HFD) intake, which is observed worldwide. It is well known that the hepatocytes’ apoptosis phenomenon is one of the most important features of NAFLD. Thus, this review focuses on revealing, through a proteomics approach, the complex network of protein interactions that promote fibrosis, liver cell stress, and apoptosis. According to different types of in vitro and murine models, it has been found that oxidative/nitrative protein stress leads to mitochondrial dysfunction, which plays a major role in stimulating NAFLD damage. Human studies have revealed the importance of novel biomarkers, such as retinol-binding protein 4, lumican, transgelin 2 and hemoglobin, which have a significant role in the disease. The post-genome era has brought proteomics technology, which allows the determination of molecular pathogenesis in NAFLD. This has led to the search for biomarkers which improve early diagnosis and optimal treatment and which may effectively prevent fatal consequences such as cirrhosis or cancer. PMID:26999105

  10. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

    PubMed

    Watanabe, Sumio; Hashimoto, Etsuko; Ikejima, Kenichi; Uto, Hirofumi; Ono, Masafumi; Sumida, Yoshio; Seike, Masataka; Takei, Yoshiyuki; Takehara, Tetsuo; Tokushige, Katsutoshi; Nakajima, Atsushi; Yoneda, Masashi; Saibara, Toshiji; Shiota, Goshi; Sakaida, Isao; Nakamuta, Makoto; Mizuta, Toshihiko; Tsubouchi, Hirohito; Sugano, Kentaro; Shimosegawa, Tooru

    2015-04-01

    Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various noninvasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 to January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.

  11. Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer.

    PubMed

    Kennedy, Kelly M; Scarbrough, Peter M; Ribeiro, Anthony; Richardson, Rachel; Yuan, Hong; Sonveaux, Pierre; Landon, Chelsea D; Chi, Jen-Tsan; Pizzo, Salvatore; Schroeder, Thies; Dewhirst, Mark W

    2013-01-01

    Lactate accumulation in tumors has been associated with metastases and poor overall survival in cancer patients. Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast cancer: 1. at relevant concentrations, 2. under aerobic vs. hypoxic conditions, 3. under conditions of normo vs. hypoglucosis. We also compared the avidity of tumors for lactate vs. glucose and identified key lactate catabolites to reveal how breast cancer cells process it. Lactate was non-toxic at clinically relevant concentrations. It was taken up and catabolized to alanine and glutamate by all cell lines. Kinetic uptake rates of lactate in vivo surpassed that of glucose in R3230Ac mammary carcinomas. The uptake appeared specific to aerobic tumor regions, consistent with the proposed "metabolic symbiont" model; here lactate produced by hypoxic cells is used by aerobic cells. We investigated whether treatment with alpha-cyano-4-hydroxycinnamate (CHC), a MCT1 inhibitor, would kill cells in the presence of high lactate. Both 0.1 mM and 5 mM CHC prevented lactate uptake in R3230Ac cells at lactate concentrations at ≤ 20 mM but not at 40 mM. 0.1 mM CHC was well-tolerated by R3230Ac and MCF7 cells, but 5 mM CHC killed both cell lines ± lactate, indicating off-target effects. This study showed that breast cancer cells tolerate and use lactate at clinically relevant concentrations in vitro (± glucose) and in vivo. We provided additional support for the metabolic symbiont model and discovered that breast cells prevailingly take up and catabolize lactate, providing rationale for future studies on manipulation of lactate catabolism pathways for therapy.

  12. Endocrine causes of nonalcoholic fatty liver disease

    PubMed Central

    Marino, Laura; Jornayvaz, François R

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed. PMID:26494962

  13. Nonalcoholic Lipid Accumulation and Hepatocyte Malignant Transformation

    PubMed Central

    Gu, Juanjuan; Yao, Min; Yao, Dengbing; Wang, Li; Yang, Xuli; Yao, Dengfu

    2016-01-01

    Abstract Worldwide incidence of hepatocellular carcinoma (HCC) is steadily increasing, highlighting its status as a public health concern, particularly due to its significant association with other comorbidities, such as diabetes. However, nonalcoholic fatty liver disease (NAFLD) has emerged as a primary risk factor, with its own prevalence increasing in recent years, and it has gradually caught up with the historical primary etiological factors of infection with hepatitis B virus and hepatitis C virus, exposure to aflatoxin, or alcohol liver disease. The deeply worrisome aspects of all of these high risk factors, however, are their remarkable presence within populations. Systemic and genetic mechanisms involved in the malignant transformation of liver cells, as well as useful biomarkers of early stage HCC are being investigated. However, the exact mechanisms underlying the interrelation of NAFLD and HCC remain largely unknown. In this review, some of the recent advances in our understanding of liver lipid accumulation are summarized and discussed to provide insights into the relationship between NAFLD and hepatocyte malignant transformation. PMID:27350942

  14. Endocrine causes of nonalcoholic fatty liver disease.

    PubMed

    Marino, Laura; Jornayvaz, François R

    2015-10-21

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed.

  15. [Nonalcoholic fatty liver disease in children].

    PubMed

    Bojórquez-Ramos, María del Carmen

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of liver disease in children and adolescents in the United States of America (USA) and probably in the entire western hemisphere, due to the increase in the prevalence of overweight and obesity. Steatosis can progress to inflammation, fibrosis and even cirrhosis, which increases the morbidity and mortality associated to liver disease. In every overweight and obese child a thorough analysis should be performed including liver function tests and liver ultrasound, in order to establish a timely diagnosis. The liver biopsy is the most specific study to rule out other potentially treatable entities. It is necessary to count on non-invasive methods to detect children with NAFLD and identify those in risk of progression. Biomarkers related to inflammation, oxidative stress, apoptosis and fibrosis have been reported. The main goal of the treatment is to modify the life style, starting with a healthy diet and an increase of physical activity. Regarding pharmacological treatment, there is evidence of histological improvement with vitamin E use, as opposed to metformin, but more conclusive studies regarding this subject are needed.

  16. Bariatric surgery and nonalcoholic fatty liver disease.

    PubMed

    Bower, Guy; Athanasiou, Thanos; Isla, Alberto M; Harling, Leanne; Li, Jia V; Holmes, Elaine; Efthimiou, Evangelos; Darzi, Ara; Ashrafian, Hutan

    2015-07-01

    The rising prevalence of nonalcoholic fatty liver disease (NAFLD) is associated with the increasing global pandemic of obesity. These conditions cluster with type II diabetes mellitus and the metabolic syndrome to result in obesity-associated liver disease. The benefits of bariatric procedures on diabetes and the metabolic syndrome have been recognized for some time, and there is now mounting evidence to suggest that bariatric procedures improve liver histology and contribute to the beneficial resolution of NAFLD in obese patients. These beneficial effects derive from a number of weight-dependent and weight-independent mechanisms including surgical BRAVE actions (bile flow changes, restriction of stomach size, anatomical gastrointestinal rearrangement, vagal manipulation, enteric hormonal modulation) and subsequent effects such as reduced lipid intake, adipocytokine secretion, modulation of gut flora, improvements in insulin resistance and reduced inflammation. Here, we review the clinical investigations on bariatric procedures for NAFLD, in addition to the mounting mechanistic data supporting these findings. Elucidating the mechanisms by which bariatric procedures may resolve NAFLD can help enhance surgical approaches for metabolic hepatic dysfunction and also contribute toward developing the next generation of therapies aimed at reducing the burden of obesity-associated liver disease.

  17. Dietary fructose in nonalcoholic fatty liver disease.

    PubMed

    Vos, Miriam B; Lavine, Joel E

    2013-06-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in adults and children. A number of genetic and environmental factors are known to predispose individuals to NAFLD. Certain dietary sugars, particularly fructose, are suspected to contribute to the development of NAFLD and its progression. The increasing quantity of fructose in the diet comes from sugar additives (most commonly sucrose and high fructose corn syrup) in beverages and processed foods. Substantial links have been demonstrated between increased fructose consumption and obesity, dyslipidemia, and insulin resistance. Growing evidence suggests that fructose contributes to the development and severity of NAFLD. In human studies, fructose is associated with increasing hepatic fat, inflammation, and possibly fibrosis. Whether fructose alone can cause NAFLD or if it serves only as a contributor when consumed excessively in the setting of insulin resistance, positive energy balance, and sedentary lifestyle is unknown. Sufficient evidence exists to support clinical recommendations that fructose intake be limited through decreasing foods and drinks high in added (fructose-containing) sugars. PMID:23390127

  18. [Non-alcoholic fatty liver disease and hepatocellular carcinoma - 2016].

    PubMed

    Pár, Alajos; Pár, Gabriella

    2016-06-19

    In the past decade non-alcoholic liver disease became the most frequently diagnosed liver disease in developed countries. At the same time, the dramatic rise in the incidence of hepatocellular carcinoma is attributed to this common metabolic disorder, and mainly to its severe form, non-alcoholic steatohepatitis. The risk factors of these associated diseases are genetic predisposition, obesity and diabetes as well as chronic low grade necro-infammation, which often leads to liver fibrosis. Free fatty acids, cytokines, lipotoxicity, insulin resistance, microRNS dysregulation and alteration in intestinal microbiota play a pivotal role in the pathogenesis. Treatment of non-alcoholic fatty liver disease - weight reduction and physical exercise in obesity, metformin in diabetes, statins in dyslipidemia and, as a new option, obeticholic acid - may diminish the risk of the hepatocellular carcinoma related to this metabolic disease. PMID:27287838

  19. [Non-alcoholic fatty liver disease and hepatocellular carcinoma - 2016].

    PubMed

    Pár, Alajos; Pár, Gabriella

    2016-06-19

    In the past decade non-alcoholic liver disease became the most frequently diagnosed liver disease in developed countries. At the same time, the dramatic rise in the incidence of hepatocellular carcinoma is attributed to this common metabolic disorder, and mainly to its severe form, non-alcoholic steatohepatitis. The risk factors of these associated diseases are genetic predisposition, obesity and diabetes as well as chronic low grade necro-infammation, which often leads to liver fibrosis. Free fatty acids, cytokines, lipotoxicity, insulin resistance, microRNS dysregulation and alteration in intestinal microbiota play a pivotal role in the pathogenesis. Treatment of non-alcoholic fatty liver disease - weight reduction and physical exercise in obesity, metformin in diabetes, statins in dyslipidemia and, as a new option, obeticholic acid - may diminish the risk of the hepatocellular carcinoma related to this metabolic disease.

  20. 21 CFR 582.5311 - Ferrous lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5311 Ferrous lactate. (a) Product. Ferrous lactate. (b) Conditions of use. This...

  1. 21 CFR 582.5311 - Ferrous lactate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5311 Ferrous lactate. (a) Product. Ferrous lactate. (b) Conditions of use. This...

  2. 21 CFR 582.5311 - Ferrous lactate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5311 Ferrous lactate. (a) Product. Ferrous lactate. (b) Conditions of use. This...

  3. 21 CFR 582.5311 - Ferrous lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5311 Ferrous lactate. (a) Product. Ferrous lactate. (b) Conditions of use. This...

  4. 21 CFR 582.5311 - Ferrous lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5311 Ferrous lactate. (a) Product. Ferrous lactate. (b) Conditions of use. This...

  5. Non-Alcoholic Fatty Liver Disease in Children

    PubMed Central

    SINGER, CRISTINA; STANCU, POLIXENIA; COŞOVEANU, SIMONA; BOTU, ALINA

    2014-01-01

    In the last years, there has been extremely much information which reveals an alarming increase of obesity in children and, at the same time, an increase of the incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD implies a wide range of affections starting from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH); the latter can evolve to cirrhosis and hepatic carcinoma. All these affections were noticed in children, too. The article presents data on the epidemiology, pathogeny, clinical and paraclinical findings, and treatment of NAFLD in children. PMID:25729601

  6. Current Pharmacologic Therapy for Nonalcoholic Fatty Liver Disease.

    PubMed

    Ganesh, Swaytha; Rustgi, Vinod K

    2016-05-01

    Weight loss, regular exercise, and diet composition modification seem to improve biochemical and histologic abnormalities. Other therapies directed at insulin resistance, oxidative stress, cytoprotection, and fibrosis may also offer benefits. Insulin sensitizers and vitamin E seem to be the most promising; however, they cause side effects. A multifaceted approach of lifestyle modifications, weight loss, and pharmacotherapy can be used in combination, but no single treatment approach has proved universally applicable to the general population with nonalcoholic steatohepatitis (NASH). Continuous clinical and preclinical studies on existing and potential drugs are needed to improve treatment of nonalcoholic fatty liver disease/NASH. PMID:27063274

  7. Cell–cell and intracellular lactate shuttles

    PubMed Central

    Brooks, George A

    2009-01-01

    Once thought to be the consequence of oxygen lack in contracting skeletal muscle, the glycolytic product lactate is formed and utilized continuously in diverse cells under fully aerobic conditions. ‘Cell–cell’ and ‘intracellular lactate shuttle’ concepts describe the roles of lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signalling. Examples of the cell–cell shuttles include lactate exchanges between between white-glycolytic and red-oxidative fibres within a working muscle bed, and between working skeletal muscle and heart, brain, liver and kidneys. Examples of intracellular lactate shuttles include lactate uptake by mitochondria and pyruvate for lactate exchange in peroxisomes. Lactate for pyruvate exchanges affect cell redox state, and by itself lactate is a ROS generator. In vivo, lactate is a preferred substrate and high blood lactate levels down-regulate the use of glucose and free fatty acids (FFA). As well, lactate binding may affect metabolic regulation, for instance binding to G-protein receptors in adipocytes inhibiting lipolysis, and thus decreasing plasma FFA availability. In vitro lactate accumulation upregulates expression of MCT1 and genes coding for other components of the mitochondrial reticulum in skeletal muscle. The mitochondrial reticulum in muscle and mitochondrial networks in other aerobic tissues function to establish concentration and proton gradients necessary for cells with high mitochondrial densities to oxidize lactate. The presence of lactate shuttles gives rise to the realization that glycolytic and oxidative pathways should be viewed as linked, as opposed to alternative, processes, because lactate, the product of one pathway, is the substrate for the other. PMID:19805739

  8. 21 CFR 184.1311 - Ferrous lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... reacting calcium lactate or sodium lactate with ferrous sulfate, direct reaction of lactic acid with iron filings, reaction of ferrous chloride with sodium lactate, or reaction of ferrous sulfate with ammonium... to 155, which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part...

  9. 21 CFR 184.1311 - Ferrous lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    .... (1996), pp. 154 to 155, which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR... prepared by reacting calcium lactate or sodium lactate with ferrous sulfate, direct reaction of lactic acid with iron filings, reaction of ferrous chloride with sodium lactate, or reaction of ferrous...

  10. 21 CFR 582.1207 - Calcium lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Calcium lactate. 582.1207 Section 582.1207 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additives § 582.1207 Calcium lactate. (a) Product. Calcium lactate. (b) Conditions of use. This substance...

  11. 21 CFR 582.1207 - Calcium lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Calcium lactate. 582.1207 Section 582.1207 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additives § 582.1207 Calcium lactate. (a) Product. Calcium lactate. (b) Conditions of use. This substance...

  12. 21 CFR 582.1207 - Calcium lactate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Calcium lactate. 582.1207 Section 582.1207 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additives § 582.1207 Calcium lactate. (a) Product. Calcium lactate. (b) Conditions of use. This substance...

  13. 21 CFR 582.1207 - Calcium lactate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Calcium lactate. 582.1207 Section 582.1207 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additives § 582.1207 Calcium lactate. (a) Product. Calcium lactate. (b) Conditions of use. This substance...

  14. 21 CFR 582.1207 - Calcium lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Calcium lactate. 582.1207 Section 582.1207 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additives § 582.1207 Calcium lactate. (a) Product. Calcium lactate. (b) Conditions of use. This substance...

  15. Expression of Lactate Dehydrogenase in Aspergillus niger for L-Lactic Acid Production

    PubMed Central

    Dave, Khyati K.; Punekar, Narayan S.

    2015-01-01

    Different engineered organisms have been used to produce L-lactate. Poor yields of lactate at low pH and expensive downstream processing remain as bottlenecks. Aspergillus niger is a prolific citrate producer and a remarkably acid tolerant fungus. Neither a functional lactate dehydrogenase (LDH) from nor lactate production by A. niger is reported. Its genome was also investigated for the presence of a functional ldh. The endogenous A. niger citrate synthase promoter relevant to A. niger acidogenic metabolism was employed to drive constitutive expression of mouse lactate dehydrogenase (mldhA). An appraisal of different branches of the A. niger pyruvate node guided the choice of mldhA for heterologous expression. A high copy number transformant C12 strain, displaying highest LDH specific activity, was analyzed under different growth conditions. The C12 strain produced 7.7 g/l of extracellular L-lactate from 60 g/l of glucose, in non-neutralizing minimal media. Significantly, lactate and citrate accumulated under two different growth conditions. Already an established acidogenic platform, A. niger now promises to be a valuable host for lactate production. PMID:26683313

  16. Expression of Lactate Dehydrogenase in Aspergillus niger for L-Lactic Acid Production.

    PubMed

    Dave, Khyati K; Punekar, Narayan S

    2015-01-01

    Different engineered organisms have been used to produce L-lactate. Poor yields of lactate at low pH and expensive downstream processing remain as bottlenecks. Aspergillus niger is a prolific citrate producer and a remarkably acid tolerant fungus. Neither a functional lactate dehydrogenase (LDH) from nor lactate production by A. niger is reported. Its genome was also investigated for the presence of a functional ldh. The endogenous A. niger citrate synthase promoter relevant to A. niger acidogenic metabolism was employed to drive constitutive expression of mouse lactate dehydrogenase (mldhA). An appraisal of different branches of the A. niger pyruvate node guided the choice of mldhA for heterologous expression. A high copy number transformant C12 strain, displaying highest LDH specific activity, was analyzed under different growth conditions. The C12 strain produced 7.7 g/l of extracellular L-lactate from 60 g/l of glucose, in non-neutralizing minimal media. Significantly, lactate and citrate accumulated under two different growth conditions. Already an established acidogenic platform, A. niger now promises to be a valuable host for lactate production.

  17. [Role of metabolic lipases and lipotoxicity in the development of non-alcoholic steatosis and non-alcoholic steatohepatitis].

    PubMed

    Berlanga, Alba; Guiu-Jurado, Esther; Porras, José Antonio; Aragonès, Gemma; Auguet, Teresa

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in developed countries, covering a spectrum of pathological conditions ranging from single steatosis to non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. Its pathogenesis has been often interpreted by the "double-hit" hypothesis, where the lipid accumulation in the liver is followed by proinflammatory mediators inducing inflammation, hepatocellular injury and fibrosis. Nowadays, a more complex model suggests that free fatty acids and their metabolites could be the true lipotoxic agents that contribute to the development of NAFLD and hepatic insulin resistance, suggesting a central role for metabolic lipases in that process.

  18. Nuclear receptors and nonalcoholic fatty liver disease.

    PubMed

    Cave, Matthew C; Clair, Heather B; Hardesty, Josiah E; Falkner, K Cameron; Feng, Wenke; Clark, Barbara J; Sidey, Jennifer; Shi, Hongxue; Aqel, Bashar A; McClain, Craig J; Prough, Russell A

    2016-09-01

    Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic

  19. Nuclear receptors and nonalcoholic fatty liver disease.

    PubMed

    Cave, Matthew C; Clair, Heather B; Hardesty, Josiah E; Falkner, K Cameron; Feng, Wenke; Clark, Barbara J; Sidey, Jennifer; Shi, Hongxue; Aqel, Bashar A; McClain, Craig J; Prough, Russell A

    2016-09-01

    Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic

  20. Innate immune signaling and gut-liver interactions in non-alcoholic fatty liver disease

    PubMed Central

    Trautwein, Christian

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and covers a disease spectrum ranging from steatosis to inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The innate immune response in the liver plays an important role during NAFLD progression. In addition, changes in the intestinal microbial balance and bacterial translocation can further affect disease progression. Immune cells in the liver recognize cell damage or pathogen invasion with intracellular or surface-expressed pattern recognition receptors (PRRs), subsequently initiating signaling cascades that trigger the release of factors promoting the inflammatory response during NAFLD progression. Therefore, mechanisms by which cells of the immune system are activated and recruited into the liver and how these cells cause injury and stress are important for understanding the inflammatory response during NAFLD. PMID:25568861

  1. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease

    PubMed Central

    Miura, Kouichi; Ohnishi, Hirohide

    2014-01-01

    Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease (NAFLD). The change in gut microbiota may alter nutritional absorption and storage. In addition, gut microbiota are a source of Toll-like receptor (TLR) ligands, and their compositional change can also increase the amount of TLR ligands delivered to the liver. TLR ligands can stimulate liver cells to produce proinflammatory cytokines. Therefore, the gut-liver axis has attracted much interest, particularly regarding the pathogenesis of NAFLD. The abundance of the major gut microbiota, including Firmicutes and Bacteroidetes, has been considered a potential underlying mechanism of obesity and NAFLD, but the role of these microbiota in NAFLD remains unknown. Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD. For instance, a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability, which allows the leakage of bacterial components. Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD. In children, the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis (NASH) compared with those in obese control. Escherichia can produce ethanol, which promotes gut permeability. Thus, normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD. In addition, TLR signaling in the liver is activated, and its downstream molecules, such as proinflammatory cytokines, are increased in NAFLD. To data, TLR2, TLR4, TLR5, and TLR9 have been shown to be associated with the pathogenesis of NAFLD. Therefore, gut microbiota and TLRs are targets for NAFLD treatment. PMID:24966608

  2. Inflammatory mediators in mastitis and lactation insufficiency.

    PubMed

    Ingman, Wendy V; Glynn, Danielle J; Hutchinson, Mark R

    2014-07-01

    Mastitis is a common inflammatory disease during lactation that causes reduced milk supply. A growing body of evidence challenges the central role of pathogenic bacteria in mastitis, with disease severity associated with markers of inflammation rather than infection. Inflammation in the mammary gland may be triggered by microbe-associated molecular patterns (MAMPs) as well as danger-associated molecular patterns (DAMPs) binding to pattern recognition receptors such as the toll-like receptors (TLRs) on the surface of mammary epithelial cells and local immune cell populations. Activation of the TLR4 signalling pathway and downstream nuclear factor kappa B (NFkB) is critical to mediating local mammary gland inflammation and systemic immune responses in mouse models of mastitis. However, activation of NFkB also induces epithelial cell apoptosis and reduced milk protein synthesis, suggesting that inflammatory mediators activated during mastitis promote partial involution. Perturbed milk flow, maternal stress and genetic predisposition are significant risk factors for mastitis, and could lead to a heightened TLR4-mediated inflammatory response, resulting in increased susceptibility and severity of mastitis disease in the context of low MAMP abundance. Therefore, heightened host inflammatory signalling may act in concert with pathogenic or commensal bacterial species to cause both the inflammation associated with mastitis and lactation insufficiency. Here, we present an alternate paradigm to the widely held notion that breast inflammation is driven principally by infectious bacterial pathogens, and suggest there may be other therapeutic strategies, apart from the currently utilised antimicrobial agents, that could be employed to prevent and treat mastitis in women.

  3. 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

  4. Lactate metabolism by pediococci isolated from cheese.

    PubMed

    Thomas, T D; McKay, L L; Morris, H A

    1985-04-01

    Pediococcus pentosaceus is commonly found among the adventitious microflora of Cheddar cheese. When this organism was incubated with L-(+)-lactate under anaerobic conditions, L-(+)-lactate was rapidly converted to D-(-)-lactate until racemic (DL) lactate was present. Under aerobic conditions this initial reaction was followed by a slower reaction resulting in the use of both lactate isomers and in the production of acetate and CO2. With intact cells the lactate oxidation system had an optimum pH of 5 to 6, depending on the initial lactate concentration. Cells grown anaerobically possessed lactate-oxidizing activity which increased two- to fourfold as sugar was exhausted from the medium. Aerobic growth further increased specific activities. Cheddar cheese was made with the deliberate addition of P. pentosaceus. When the resulting cheese was grated to expose a large surface area to O2, lactate was converted to acetate at a rate which depended on the density of pediococci in the cheese. The lactate oxidation system remained active in cheese which had been ripened for 6 months.

  5. Lactate metabolism in the fetal rabbit lung

    SciTech Connect

    Engle, M.J.; Brown, D.J.; Dooley, M.

    1986-05-01

    Lactate is frequently overlooked as a potential substrate for the fetal lung, even though it is present in the fetal circulation in concentrations as high as 8 mM. These high concentrations, coupled with the relatively low levels of glucose in the fetal blood, may indicate that lactate can substitute for glucose in pulmonary energy generation and phospholipid synthesis. A series of experiments was therefore undertaken in order to investigate the role of lactate in perinatal pulmonary development. Explants from 30 day gestation fetal rabbit lungs were incubated in Krebs-Ringer bicarbonate buffer supplemented with 3 mM (U-/sup 14/C)-glucose and varying levels of lactate. In the absence of medium lactate, fetal rabbit lung explants were capable of producing lactate at a rate of approximately 200 etamoles/mg protein/hour. The addition of lactate to the bathing medium immediately reduced net lactate production and above 4 mM, fetal rabbit lung explants became net utilizers of lactate. Media lactate concentrations of 2.5 mM, 5 mM and 10 mM also decreased glucose incorporation into total tissue disaturated phosphatidylcholine by approximately 20%, 35%, and 45%, respectively. Glucose incorporation into surfactant phosphatidylcholine was also reduced by approximately 50%, when lactate was present in the incubation medium at a concentration of 5 mM. Additional experiments also revealed that fetal lung lactate dehydrogenase activity was almost twice that found in the adult rabbit lung. These data indicate that lactate may be an important carbon source for the developing lung and could be a significant component in the manufacture of surfactant phosphatidylcholine during late gestation.

  6. Lactate induced HIF-1α-PRMT1 cross talk affects MHC I expression in monocytes.

    PubMed

    Gupta, Piyushi; Singh, Ankita; Gowda, Pruthvi; Ghosh, Sadashib; Chatterjee, Arpita; Sen, Ellora

    2016-10-01

    Tumor infiltrating monocytes play a crucial role in tumor immune surveillance. As lactate is an important component of the tumor milieu, we investigated its role in the transcriptional regulation of MHC I which is crucial for mounting effective immune responses against tumors. Lactate elevated MHC class I expression in monocytes. Increase in HLAB expression was concomitant with increase in HIF-1α and decrease in PRMT1 levels. Interestingly, a reciprocal relationship was observed between PRMT1 and HIF-1α. While HIF-1α inhibition decreased lactate induced MHC I, both pharmacological inhibition and siRNA mediated knockdown of PRMT1 upregulated HLAB levels. PRMT1 over-expression rescued lactate mediated increase in MHC I expression. Lactate mediated changes in nucleosomal occupancy on HLAB promoter facilitated a chromatin landscape that favoured decreased recruitment of CREB and PRMT1 on CRE site of HLAB locus. The effect of lactate on the chromatin landscape of HLAB was completely mimicked by PRMT1 inhibitor AMI-1 in terms of nucleosomal occupancy and CREB recruitment. Besides demonstrating the importance of lactate in the transcriptional regulation of HLAB, this study highlights for the first time the (i) existence of HIF-1α-PRMT1 regulatory loop and (ii) role of PRMT1 in modulating chromatin landscape crucial for facilitating HLAB gene expression. PMID:27521225

  7. Lactate administration reproduces specific brain and liver exercise-related changes.

    PubMed

    E, Lezi; Lu, Jianghua; Selfridge, J Eva; Burns, Jeffrey M; Swerdlow, Russell H

    2013-10-01

    The effects of exercise are not limited to muscle, and its ability to mitigate some chronic diseases is under study. A more complete understanding of how exercise impacts non-muscle tissues might facilitate design of clinical trials and exercise mimetics. Here, we focused on lactate's ability to mediate changes in liver and brain bioenergetic-associated parameters. In one group of experiments, C57BL/6 mice underwent 7 weeks of treadmill exercise sessions at intensities intended to exceed the lactate threshold. Over time, the mice dramatically increased their lactate threshold. To ensure that plasma lactate accumulated during the final week, the mice were run to exhaustion. In the liver, mRNA levels of gluconeogenesis-promoting genes increased. While peroxisome proliferator-activated receptor-gamma co-activator 1 alpha (PGC-1α) expression increased, there was a decrease in PGC-1β expression, and overall gene expression changes favored respiratory chain down-regulation. In the brain, PGC-1α and PGC-1β were unchanged, but PGC-1-related co-activator expression and mitochondrial DNA copy number increased. Brain tumor necrosis factor alpha expression fell, whereas vascular endothelial growth factor A expression rose. In another group of experiments, exogenously administered lactate was found to reproduce some but not all of these observed liver and brain changes. Our data suggest that lactate, an exercise byproduct, could mediate some of the effects exercise has on the liver and the brain, and that lactate itself can act as a partial exercise mimetic.

  8. Lactation amenorrhea in Saudi women.

    PubMed Central

    Madani, K A; Khashoggi, R H; al-Nowaisser, A A; Nasrat, H A; Khalil, M H

    1994-01-01

    STUDY OBJECTIVE--The study aimed to investigate some aspects of breast feeding, namely-lactation amenorrhea, the average interval between pregnancies, and the extent of knowledge that an average Saudi woman has about breast feeding. DESIGN--This was a cross sectional study in which a pretested questionnaire was used to collect the information. SETTING--The study was conducted in the Taif area between January and April of 1990. Seventy nine primary health care centres participated. PARTICIPANTS--Altogether 1019 of 2400 women contacted who agreed to participate and met the criteria were studied. Eligible subjects were defined as Saudi women, between 16 and 40 years old, who came with their infants for vaccination, and had delivered between one week and 12 months previously. Each mother had at least one other child. MEASUREMENT AND MAIN RESULT--At birth, the percentage of infants who were initially breast fed was 98% but within three days of delivery over two thirds (68.9%) of the mothers gave other supplementary liquids to their infants. At the time of interview more than half (55.1%) of mothers had lactation amenorrhea. The mean (SD) lactation amenorrhea period and birth interval were 5.95 (5) and 26.8 (14.1) months, respectively. Mothers obtained information on breast feeding mainly from their doctors and television. Within families, husbands had the primary role in encouraging their wives to breast feed, followed by the mother and then by the mother in law. It was found that a high percentage (94.2%) of women had breast fed their previous child. CONCLUSION--The lack of adequate information on breast feeding and the short interval between births are local problems which should be considered by the health authorities. PMID:8051529

  9. Discrimination of Nonalcoholic Steatohepatitis Using Transient Elastography in Patients with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Kim, Seung Up; Jang, Jae Young; Park, Hana; Kim, Ja Kyung; Lee, Chun Kyon; Chon, Young Eun; Han, Kwang-Hyub

    2016-01-01

    Background/aims The accuracy of noninvasive markers to discriminate nonalcoholic steatohepatitis (NASH) is unsatisfactory. We investigated whether transient elastography (TE) could discriminate patients with NASH from those with nonalcoholic fatty liver disease (NAFLD). Methods The patients suspected of NAFLD who underwent liver biopsy and concomitant TE were recruited from five tertiary centers between November 2011 and December 2013. Results The study population (n = 183) exhibited a mean age of 40.6 years and male predominance (n = 111, 60.7%). Of the study participants, 89 (48.6%) had non-NASH and 94 (51.4%) had NASH. The controlled attenuation parameter (CAP) and liver stiffness (LS) were significantly correlated with the degrees of steatosis (r = 0.656, P<0.001) and fibrosis (r = 0.714, P<0.001), respectively. The optimal cut-off values for steatosis were 247 dB/m for S1, 280 dB/m for S2, and 300 dB/m for S3. Based on the independent predictors derived from multivariate analysis [P = 0.044, odds ratio (OR) 4.133, 95% confidence interval (CI) 1.037–16.470 for CAP>250 dB/m; P = 0.013, OR 3.399, 95% CI 1.295–8.291 for LS>7.0 kPa; and P<0.001, OR 7.557, 95% CI 2.997–19.059 for Alanine aminotransferase>60 IU/L], we developed a novel CLA model for discriminating patients with NASH. The CLA model showed good discriminatory capability, with an area under the receiver operating characteristic curve (AUROC) of 0.812 (95% CI 0.724–0.880). To assess discriminatory power, the AUROCs, as determined by the bootstrap method, remained largely unchanged between iterations, with an average value of 0.833 (95% CI 0.740–0.893). Conclusion This novel TE-based CLA model showed acceptable accuracy in discriminating NASH from simple steatosis. However, further studies are required for external validation. PMID:27284700

  10. [Resumption of menstruation during lactation after delivery].

    PubMed

    Baszak, E; Radomański, T; Sikorski, R

    2000-09-01

    Twenty-three women in the menstruation resumption during lactation were evaluated. Average period of lactational amenorrhoea was 7 months after delivery. Ovulation before the first menstruation has occurred in 7 breastfeeding women (39%), but only in one case it took place earlier than 6 months after labour. The correlation was established between the resumption of menstruation and entirely period of breastfeeding per day. The Lactational Amenorrhoea Method (LAM) as the family planning procedure was discussed. PMID:11082964

  11. 21 CFR 184.1639 - Potassium lactate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Potassium lactate. 184.1639 Section 184.1639 Food... Specific Substances Affirmed as GRAS § 184.1639 Potassium lactate. (a) Potassium lactate (C3H5O3K, CAS Reg. No. 996-31-6) is the potassium salt of lactic acid. It is a hydroscopic, white, odorless solid and...

  12. 21 CFR 184.1639 - Potassium lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Potassium lactate. 184.1639 Section 184.1639 Food... Specific Substances Affirmed as GRAS § 184.1639 Potassium lactate. (a) Potassium lactate (C3H5O3K, CAS Reg. No. 996-31-6) is the potassium salt of lactic acid. It is a hydroscopic, white, odorless solid and...

  13. 21 CFR 184.1639 - Potassium lactate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Potassium lactate. 184.1639 Section 184.1639 Food... Specific Substances Affirmed as GRAS § 184.1639 Potassium lactate. (a) Potassium lactate (C3H5O3K, CAS Reg. No. 996-31-6) is the potassium salt of lactic acid. It is a hydroscopic, white, odorless solid and...

  14. 21 CFR 184.1639 - Potassium lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Potassium lactate. 184.1639 Section 184.1639 Food... GRAS § 184.1639 Potassium lactate. (a) Potassium lactate (C3H5O3K, CAS Reg. No. 996-31-6) is the potassium salt of lactic acid. It is a hydroscopic, white, odorless solid and is prepared commercially...

  15. 21 CFR 184.1207 - Calcium lactate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Calcium lactate. 184.1207 Section 184.1207 Food... Specific Substances Affirmed as GRAS § 184.1207 Calcium lactate. (a) Calcium lactate (C6H10CaO6.xH2O, where... lactic acid with calcium carbonate or calcium hydroxide. (b) The ingredient meets the specifications...

  16. 21 CFR 184.1207 - Calcium lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Calcium lactate. 184.1207 Section 184.1207 Food and... Substances Affirmed as GRAS § 184.1207 Calcium lactate. (a) Calcium lactate (C6H10CaO6.xH2O, where x is any... calcium carbonate or calcium hydroxide. (b) The ingredient meets the specifications of the Food...

  17. 21 CFR 184.1207 - Calcium lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Calcium lactate. 184.1207 Section 184.1207 Food... GRAS § 184.1207 Calcium lactate. (a) Calcium lactate (C6H10CaO6.xH2O, where x is any integer up to 5, CAS Reg. No. 814-80-2) is prepared commercially by the neutralization of lactic acid with...

  18. 21 CFR 184.1207 - Calcium lactate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Calcium lactate. 184.1207 Section 184.1207 Food... Specific Substances Affirmed as GRAS § 184.1207 Calcium lactate. (a) Calcium lactate (C6H10CaO6.xH2O, where... lactic acid with calcium carbonate or calcium hydroxide. (b) The ingredient meets the specifications...

  19. 21 CFR 184.1207 - Calcium lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Calcium lactate. 184.1207 Section 184.1207 Food... Specific Substances Affirmed as GRAS § 184.1207 Calcium lactate. (a) Calcium lactate (C6H10CaO6.xH2O, where... lactic acid with calcium carbonate or calcium hydroxide. (b) The ingredient meets the specifications...

  20. 21 CFR 184.1639 - Potassium lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Potassium lactate. 184.1639 Section 184.1639 Food... Specific Substances Affirmed as GRAS § 184.1639 Potassium lactate. (a) Potassium lactate (C3H5O3K, CAS Reg. No. 996-31-6) is the potassium salt of lactic acid. It is a hydroscopic, white, odorless solid and...

  1. 21 CFR 184.1768 - Sodium lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... sodium hydroxide. (b) The ingredient must be of a purity suitable for its intended use. (c) In accordance... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Sodium lactate. 184.1768 Section 184.1768 Food and... Substances Affirmed as GRAS § 184.1768 Sodium lactate. (a) Sodium lactate (C3H5O3Na, CAS Reg. No. 72-17-3)...

  2. 21 CFR 184.1768 - Sodium lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... sodium hydroxide. (b) The ingredient must be of a purity suitable for its intended use. (c) In accordance... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Sodium lactate. 184.1768 Section 184.1768 Food and... Substances Affirmed as GRAS § 184.1768 Sodium lactate. (a) Sodium lactate (C3H5O3Na, CAS Reg. No. 72-17-3)...

  3. 21 CFR 184.1768 - Sodium lactate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... sodium hydroxide. (b) The ingredient must be of a purity suitable for its intended use. (c) In accordance... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Sodium lactate. 184.1768 Section 184.1768 Food and... Substances Affirmed as GRAS § 184.1768 Sodium lactate. (a) Sodium lactate (C3H5O3Na, CAS Reg. No. 72-17-3)...

  4. 21 CFR 184.1768 - Sodium lactate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... sodium hydroxide. (b) The ingredient must be of a purity suitable for its intended use. (c) In accordance... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Sodium lactate. 184.1768 Section 184.1768 Food and... Substances Affirmed as GRAS § 184.1768 Sodium lactate. (a) Sodium lactate (C3H5O3Na, CAS Reg. No. 72-17-3)...

  5. 21 CFR 184.1768 - Sodium lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ....1768 Sodium lactate. (a) Sodium lactate (C3H5O3Na, CAS Reg. No. 72-17-3) is the sodium salt of lactic acid. It is prepared commercially by the neutralization of lactic acid with sodium hydroxide. (b) The... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Sodium lactate. 184.1768 Section 184.1768 Food...

  6. Cerebral Lactate Metabolism After Traumatic Brain Injury.

    PubMed

    Patet, Camille; Suys, Tamarah; Carteron, Laurent; Oddo, Mauro

    2016-04-01

    Cerebral energy dysfunction has emerged as an important determinant of prognosis following traumatic brain injury (TBI). A number of studies using cerebral microdialysis, positron emission tomography, and jugular bulb oximetry to explore cerebral metabolism in patients with TBI have demonstrated a critical decrease in the availability of the main energy substrate of brain cells (i.e., glucose). Energy dysfunction induces adaptations of cerebral metabolism that include the utilization of alternative energy resources that the brain constitutively has, such as lactate. Two decades of experimental and human investigations have convincingly shown that lactate stands as a major actor of cerebral metabolism. Glutamate-induced activation of glycolysis stimulates lactate production from glucose in astrocytes, with subsequent lactate transfer to neurons (astrocyte-neuron lactate shuttle). Lactate is not only used as an extra energy substrate but also acts as a signaling molecule and regulator of systemic and brain glucose use in the cerebral circulation. In animal models of brain injury (e.g., TBI, stroke), supplementation with exogenous lactate exerts significant neuroprotection. Here, we summarize the main clinical studies showing the pivotal role of lactate and cerebral lactate metabolism after TBI. We also review pilot interventional studies that examined exogenous lactate supplementation in patients with TBI and found hypertonic lactate infusions had several beneficial properties on the injured brain, including decrease of brain edema, improvement of neuroenergetics via a "cerebral glucose-sparing effect," and increase of cerebral blood flow. Hypertonic lactate represents a promising area of therapeutic investigation; however, larger studies are needed to further examine mechanisms of action and impact on outcome. PMID:26898683

  7. Hemichannel-mediated release of lactate

    PubMed Central

    Karagiannis, Anastassios; Sylantyev, Sergiy; Hadjihambi, Anna; Hosford, Patrick S; Kasparov, Sergey

    2015-01-01

    In the central nervous system lactate contributes to the extracellular pool of readily available energy substrates and may also function as a signaling molecule which mediates communication between glial cells and neurons. Monocarboxylate transporters are believed to provide the main pathway for lactate transport across the membranes. Here we tested the hypothesis that lactate could also be released via opening of pannexin and/or functional connexin hemichannels. In acute slices prepared from the brainstem, hippocampus, hypothalamus and cortex of adult rats, enzymatic amperometric biosensors detected significant tonic lactate release inhibited by compounds, which block pannexin/connexin hemichannels and facilitated by lowering extracellular [Ca2+] or increased PCO2. Enhanced lactate release triggered by hypoxia was reduced by ∼50% by either connexin or monocarboxylate transporter blockers. Stimulation of Schaffer collateral fibers triggered lactate release in CA1 area of the hippocampus, which was facilitated in conditions of low extracellular [Ca2+], markedly reduced by blockade of connexin hemichannels and abolished by lactate dehydrogenase inhibitor oxamate. These results indicate that lactate transport across the membranes may occur via mechanisms other than monocarboxylate transporters. In the central nervous system, hemichannels may function as a conduit of lactate release, and this mechanism is recruited during hypoxia and periods of enhanced neuronal activity. PMID:26661210

  8. Social stress during lactation, depressed maternal care, and neuropeptidergic gene expression.

    PubMed

    Murgatroyd, Christopher A; Taliefar, Mohammad; Bradburn, Steven; Carini, Lindsay M; Babb, Jessica A; Nephew, Benjamin C

    2015-10-01

    Depression and anxiety can be severely detrimental to the health of both the affected woman and her offspring. In a rodent model of postpartum depression and anxiety, chronic social stress exposure during lactation induces deficits in maternal care and increases anxiety. Here, we extend previous findings by expanding the behavioral analyses, assessing lactation, and examining several neural systems within amygdalar and hypothalamic regions involved in the control of the stress response and expression of maternal care that may be mediating the behavioral changes in stressed dams. Compared with control dams, those exposed to chronic social stress beginning on day 2 of lactation show impaired maternal care and lactation and increased maternal anxiety on day 9 of lactation. Saccharin-based anhedonia and maternal aggression were increased and lactation was also impaired on day 16 of lactation. These behavioral changes were correlated with a decrease in oxytocin mRNA expression in the medial amygdala, and increases in the expressions of corticotrophin-releasing hormone mRNA in the central nucleus of the amygdala, glucocorticoid receptor mRNA in the paraventricular nucleus, and orexin 2 receptor mRNA in the supraoptic nucleus of stressed compared with control dams. The increase in glucocorticoid receptor mRNA in the paraventricular nucleus was negatively correlated with methylation of a CpG site in the promoter region. In conclusion, the data support the hypothesis that social stress during lactation can have profound effects on maternal care, lactation, and anxiety, and that these behavioral effects are mediated by central changes in stress and maternally relevant neuropeptide systems. PMID:26061353

  9. Non-alcoholic fatty liver disease and obesity: Biochemical, metabolic and clinical presentations

    PubMed Central

    Milić, Sandra; Lulić, Davorka; Štimac, Davor

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is a hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components. Up to 80% of patients with NAFLD are obese, defined as a body mass index (BMI) > 30 kg/m2. However, the distribution of fat tissue plays a greater role in insulin resistance than the BMI. The large amount of visceral adipose tissue (VAT) in morbidly obese (BMI > 40 kg/m2) individuals contributes to a high prevalence of NAFLD. Free fatty acids derived from VAT tissue, as well as from dietary sources and de novo lipogenesis, are released to the portal venous system. Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD. In addition, secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways, which are also activated by free fatty acids, and contribute to insulin resistance. Most NAFLD patients are asymptomatic on clinical presentation, even though some may present with fatigue, dyspepsia, dull pain in the liver and hepatosplenomegaly. Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications, anti-obesity medication and bariatric surgery. This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease. The relative contribution of visceral and liver fat to insulin resistance is discussed, and recommendations for clinical evaluation of affected individuals is provided. PMID:25071327

  10. Pediatric non-alcoholic fatty liver disease: Preventive and therapeutic value of lifestyle intervention

    PubMed Central

    Nobili, Valerio; Alisi, Anna; Raponi, Massimiliano

    2009-01-01

    Nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), and eventually cirrhosis and liver failure, is seen to be increasing amongst Western children. NAFLD rates are rising in parallel with the epidemic of childhood obesity, and in particular, fatty liver evolves more easily in NASH when poor dietary habits and sedentary lifestyle are combined. In fact, its general prevalence in the child population varies between 2.6% and 10%, but increases up to 80% in obese children. Since NASH is expected to become the most common cause of pediatric chronic liver disease in the near future, there is broad interest amongst clinical researchers to move forward, both in diagnosis and treatment. Unfortunately, to date, the expensive and invasive procedure of liver biopsy is seen as the gold standard for NASH diagnosis and few noninvasive diagnostic methods can be applied successfully. Moreover, there are still no approved pharmacological interventions for NAFLD/NASH. Therefore, current management paradigms are based upon the presence of associated risk factors and aims to improve an individual’s quality of life, thus reducing NAFLD-associated morbidity and mortality. Today, lifestyle intervention (diet and exercise) is the treatment of choice for NAFLD/NASH. Thus far, no study has evaluated the potential preventive effect of lifestyle intervention on children at risk of NAFLD/NASH. Future studies will be required in this area with the perspective of developing a national program to promote nutrition education and increase physical activity as means of preventing the disease in individuals at risk. Here, we outline the clinical course, pathogenesis and management of NAFLD in children, highlighting the preventive and therapeutic value of lifestyle intervention. PMID:20027672

  11. 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

  12. A20 Attenuates FFAs-induced Lipid Accumulation in Nonalcoholic Steatohepatitis

    PubMed Central

    Ai, Luoyan; Xu, Qingqing; Wu, Changwei; Wang, Xiaohan; Chen, Zhiwei; Su, Dazhi; Jiang, Xiaoke; Xu, Antao; Lin, Qing; Fan, Zhuping

    2015-01-01

    A20 is a ubiquitin-editing enzyme that attenuates the activity of proximal signaling complexes at pro-inflammatory receptors. It has been well documented that A20 protein plays an important role in response to liver injury and hepatocytes apoptosis in pro-inflammatory pathways. However, there was little evidence showing that A20 protein was involving in fatty-acid homeostasis except the up-regulation of two fatty acid metabolism regulatory genes at mRNA level (PPARa and CPT1a) by adenovirus-mediated A20 protein overexpression. In this study we found that: 1) the expression level of A20 protein was significantly higher in the steatotic liver from MCD-fed mice than the controls; 2) Overexpression of A20 protein suppressed FFAs-stimulated triglyceride deposition in HepG2 cells while under expression of A20 protein increased FFAs-stimulated triglyceride deposition; 3) Overexpression of A20 protein in HepG2 cells upregulated genes that promote β-oxidation and decreased the mRNA levels of key lipogenic genes such as fatty acid synthase (FAS), indicating A20 function as anti-steatotic factor by the activation of mitochondrial β-oxidation and attenuation of de novo lipogenesis; 4) Nonalcoholic steatohepatitis (NASH) patients showed significantly higher A20 expression level in liver compared with control individuals. Our results demonstrated that A20 protein plays an important role in fatty-acid homeostasis in human as well as animals. In addition, our data suggested that the pathological function of A20 protein in hepatocyte from lipotoxicity to NASH is by the alleviation of triglyceride accumulation in hepatocytes. Elevated expression of A20 protein could be a potential therapeutic strategy for preventing the progression of nonalcoholic steatohepatitis. PMID:26681923

  13. Medical and Surgical Treatment Options for Nonalcoholic Steatohepatitis.

    PubMed

    Corey, Kathleen E; Rinella, Mary E

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in the USA with a growing prevalence worldwide. Nonalcoholic steatohepatitis (NASH), progressive form of NAFLD, can lead to the development of cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. Treatment of NASH may decrease the risk of progressive disease. Treatment for NAFLD should center around weight loss and exercise. Pharmacotherapy with vitamin E and pioglitazone should be considered for those with NASH, especially those with fibrosis. Weight loss surgery is also an effective treatment for NASH in individuals with other indications for surgery. In this review, we will discuss the currently available therapies for NASH including lifestyle, pharmacologic, and surgical options.

  14. Dietary recommendations for patients with nonalcoholic fatty liver disease

    PubMed Central

    Stankowiak-Kulpa, Hanna; Grzymisławski, Marian

    2014-01-01

    Changes to patients’ lifestyle, especially a modified dietary approach, play a key role in the treatment of nonalcoholic fatty liver disease (NAFLD). A balanced, limiting and individually tailored nutritional scheme enables weight loss and an improvement in the clinical picture of NAFLD. According to nutritional recommendations for patients with NAFLD, carbohydrates should comprise 40–50% of total dietary energy. It is advisable to increase the amount of complex carbohydrates rich in dietary fibre. A major role in the aetiology of NAFLD is played by excessive intake of fructose, which is related to the rise in consumption of nonalcoholic beverages among subjects in developed countries. Fat intake should comprise < 30% of daily calories. It is essential to increase consumption of food products rich in mono- and polyunsaturated fatty acids. Ingestion of protein should constitute 15–20% of total energy. PMID:24868294

  15. Treatment of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Scherer, Antonia; Dufour, Jean-François

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions from steatosis to cirrhosis and hepatocellular carcinoma. Steatosis is a benign reversible condition, which does not need treatment. Cirrhosis and hepatocellular carcinoma are the end stages of any chronic liver disease and do not have etiology-specific treatments. In this chapter, we will review treatment options for non-alcoholic steatohepatitis, which is the progressive form of NAFLD. Basically there are 2 strategies, the first of which is to address lifestyle and the second to use medication. The first approach is the most physiologic, the least expensive, but is also the most difficult to implement. The second approach, which should help patients who failed the first approach, is at the advanced clinical research stage. PMID:27548081

  16. Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame

    PubMed Central

    Ibrahim, Samar H.; Hirsova, Petra; Malhi, Harmeet; Gores, Gregory J.

    2016-01-01

    With the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become a public health problem with increasing prevalence. The mechanism of disease progression remains obscure and effective therapy is lacking. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary, especially, since causative mechanistic studies of NAFLD are more difficult or unethical to perform in humans. A large number of studies regarding the pathophysiology and treatment of NASH have been undertaken in mice to model human NAFLD and nonalcoholic steatohepatitis (NASH). This review discusses the known dietary, genetic and inflammation based animal models of NASH described in recent years, with a focus on the major advances made in this field. PMID:26626909

  17. Lactate Sensors on Flexible Substrates

    PubMed Central

    Yang, Xuesong; Fu, Timothy; Kota, Pavan Kumar; Tjia, Maggie; Nguyen, Cuong Manh; Chiao, Jung-Chih

    2016-01-01

    Lactate detection by an in situ sensor is of great need in clinical medicine, food processing, and athletic performance monitoring. In this paper, a flexible, easy to fabricate, and low-cost biosensor base on lactate oxidase is presented. The fabrication processes, including metal deposition, sol-gel IrOx deposition, and drop-dry enzyme loading method, are described in detail. The loaded enzyme was examined by scanning electron microscopy. Cyclic voltammetry was used to characterize the sensors. Durability, sensibility, and selectivity of the biosensors were examined. The comparison for different electrode sizes and different sensing film materials was conducted. The sensor could last for four weeks with an average surface area normalized sensitivity of 950 nA/(cm2 mM) and 9250 nA/(cm2 mM) for Au-based electrodes, and IrOx-modified electrodes respectively, both with an electrode size of 100 × 50 μm. The self-referencing method to record noises simultaneously with the working electrode greatly improved sensor sensitivity and selectivity. The sensor showed little response to interference chemicals, such as glutamate and dopamine. PMID:27657147

  18. Nonalcoholic fatty liver disease: molecular pathways and therapeutic strategies

    PubMed Central

    2013-01-01

    Along with rising numbers of patients with metabolic syndrome, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased in proportion with the obesity epidemic. While there are no established treatments for NAFLD, current research is targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications for the treatment of NAFLD. The basic research that has identified potential molecular targets for pharmacotherapy will be outlined. PMID:24209497

  19. Role of the Gut Microbiome in Nonalcoholic Fatty Liver Disease.

    PubMed

    Aqel, Bashar; DiBaise, John K

    2015-12-01

    The incidence of nonalcoholic fatty liver disease (NAFLD) continues to increase with prevalence estimates ranging from 17%-33%, making it is the most common cause of chronic liver disease in North America. Its importance is due to not only its prevalence but also its association with increased cardiovascular morbidity and progression to cirrhosis in a subset of patients. NAFLD encompasses a pathologic spectrum of disease, from relatively benign accumulation of lipid (steatosis) to progressive nonalcoholic steatohepatitis associated with inflammation, fibrosis, and necrosis. Nonalcoholic steatohepatitis remains an important phenotypic state because this subgroup of patients is deemed at high risk for developing cirrhosis and progressing to liver failure requiring transplantation or to death. Gut microbiota has recently been identified as regulators of energy homeostasis and fat deposition, thereby implicating them in the development of obesity and associated metabolic diseases. The growing evidence that alteration in gut microbiota (dysbiosis) may affect liver pathology may allow for a better understanding of its role in the pathogenesis of NAFLD, help to identify patients at risk of progression, and expose a microbial target for prevention and therapeutic intervention. In this review, we discuss the growing evidence that highlights the relationship between gut microbiota and its association with NAFLD. PMID:26449892

  20. Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis

    PubMed Central

    Le, Thuy-Anh; Loomba, Rohit

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver enzymes and chronic liver disease in the US with expected rise in incidence paralleling the epidemic of obesity. A subset of patients with NAFLD have the progressive form of NAFLD that is termed non-alcoholic steatohepatitis (NASH), which is characterized by specific features on liver histology including hepatocellular ballooning degeneration, lobular inflammation, and zone-3 steatosis with or without peri-sinusoidal fibrosis. Non-alcoholic steatohepatitis can progress to cirrhosis and result in liver-related death. Insulin resistance is commonly seen in patients with NASH and often co-exists with other features of the metabolic syndrome including hypertension, hyperlipidemia, and obesity. Although weight loss through lifestyle modifications including dietary changes and increased physical exercise remains the backbone of management of NASH, it has proved challenging for patients to achieve and maintain weight loss goals. Thus, it is often necessary to couple lifestyle changes with another pharmacologic treatment for NASH. Insulin sensitizers including the biguanides (metformin), thiazolidinediones (pioglitazone and rosiglitazone), and glucagon-like peptide-1 receptor agonists (exenatide) are large groups of medications that have been studied for the treatment of NASH. Other agents with anti-inflammatory, anti-apoptotic, or anti-fibrotic properties which have been studied in NASH include vitamin E, pentoxifylline, betaine, and ursodeoxycholic acid. This review will provide a detailed summary on the clinical data behind the full spectrum of treatments that exist for NASH and suggest management recommendations. PMID:25755424

  1. Management of non-alcoholic fatty liver disease in 2015.

    PubMed

    Malhotra, Neel; Beaton, Melanie D

    2015-12-28

    There is no single pharmacologic therapy that has been approved to treat nonalcoholic fatty liver disease in the general population. The backbone of therapy currently includes intensive lifestyle modification with established targets for diet and weight loss. The use of unsweetened, unfiltered coffee along with limiting high fructose corn syrup have emerged as beneficial dietary recommendations. The use of empiric oral hypoglycemic agents and vitamin E, however, has not been widely accepted. Developing bariatric surgical techniques are promising, but additional studies with long-term follow up are needed before it can be widely recommended. Finally, liver transplantation is an increasingly frequent consideration once complications of end-stage disease have developed. The future treatment of those with nonalcoholic fatty liver disease will likely involve a personalized approach. The importance of the gut microbiome in mediating hepatocyte inflammation and intestinal permeability is emerging and may offer avenues for novel treatment. The study of anti-fibrotic agents such as pentoxifylline and FXR agonists hold promise and new pathways, such as hepatocyte cannabinoid receptor antagonists are being studied. With the incidence of obesity and the metabolic syndrome increasing throughout the developed world, the future will continue to focus on finding novel agents and new applications of existing therapies to help prevent and to mediate the progression of nonalcoholic fatty liver disease. PMID:26730275

  2. Mechanisms of disease progression in nonalcoholic fatty liver disease.

    PubMed

    Jou, Janice; Choi, Steve S; Diehl, Anna Mae

    2008-11-01

    Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic pathology, ranging from simple steatosis (also called nonalcoholic fatty liver or NAFL) in its most benign form, to cirrhosis in its most advanced form. Nonalcoholic steatohepatitis (NASH) is an intermediate level of hepatic pathology. Hepatocyte accumulation of triglyceride is a hallmark of NAFL and NASH, but this sometimes subsides once cirrhosis has developed. Triglyceride storage per se is not hepatotoxic. Rather, it is a marker of increased exposure of hepatocytes to potentially toxic fatty acids. NAFL progresses to NASH when adaptive mechanisms that protect hepatocytes from fatty acid-mediated lipotoxicity become overwhelmed and rates of hepatocyte death begin to outstrip mechanisms that normally regenerate dead hepatocytes. This triggers repair responses that involve activation of hepatic stellate cells to myofibroblasts. The myofibroblasts generate excessive matrix and produce factors that stimulate expansion of liver progenitor populations. The progenitor cells produce chemokines to attract various kinds of inflammatory cells to the liver. They also differentiate to replace the dead hepatocytes. The intensity of these repair responses generally parallel the degree of hepatocyte death, resulting in variable distortion of the hepatic architecture with fibrosis, infiltrating immune cells, and regenerating epithelial nodules. As in other types of chronic liver injury, cirrhosis ensues in patients with NAFLD when repair is extreme and sustained, but ultimately unsuccessful, at reconstituting healthy hepatic epithelia. PMID:18956293

  3. Metabolomic analysis of human cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis diseases

    PubMed Central

    Safaei, Akram; Arefi Oskouie, Afsaneh; Mohebbi, Seyed Reza; Rezaei-Tavirani, Mostafa; Mahboubi, Mohammad; Peyvandi, Maryam; Okhovatian, Farshad; Zamanian-Azodi, Mona

    2016-01-01

    Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies. PMID:27458508

  4. Metabolomic analysis of human cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis diseases.

    PubMed

    Safaei, Akram; Arefi Oskouie, Afsaneh; Mohebbi, Seyed Reza; Rezaei-Tavirani, Mostafa; Mahboubi, Mohammad; Peyvandi, Maryam; Okhovatian, Farshad; Zamanian-Azodi, Mona

    2016-01-01

    Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies. PMID:27458508

  5. Evolution of lactation: ancient origin and extreme adaptations of the lactation system.

    PubMed

    Lefèvre, Christophe M; Sharp, Julie A; Nicholas, Kevin R

    2010-01-01

    Lactation, an important characteristic of mammalian reproduction, has evolved by exploiting a diversity of strategies across mammals. Comparative genomics and transcriptomics experiments have now allowed a more in-depth analysis of the molecular evolution of lactation. Milk cell and mammary gland genomic studies have started to reveal conserved milk proteins and other components of the lactation system of monotreme, marsupial, and eutherian lineages. These analyses confirm the ancient origin of the lactation system and provide useful insight into the function of specific milk proteins in the control of lactation. These studies also illuminate the role of milk in the regulation of growth and development of the young beyond simple nutritive aspects.

  6. Enantioselective Regulation of Lactate Racemization by LarR in Lactobacillus plantarum

    PubMed Central

    Desguin, Benoît; Goffin, Philippe; Bakouche, Nordine; Diman, Aurélie; Viaene, Eric; Dandoy, Damien; Fontaine, Laetitia; Hallet, Bernard

    2014-01-01

    Lactobacillus plantarum is a lactic acid bacterium that produces a racemic mixture of l- and d-lactate from sugar fermentation. The interconversion of lactate isomers is performed by a lactate racemase (Lar) that is transcriptionally controlled by the l-/d-lactate ratio and maximally induced in the presence of l-lactate. We previously reported that the Lar activity depends on the expression of two divergently oriented operons: (i) the larABCDE operon encodes the nickel-dependent lactate racemase (LarA), its maturases (LarBCE), and a lactic acid channel (LarD), and (ii) the larR(MN)QO operon encodes a transcriptional regulator (LarR) and a four-component ABC-type nickel transporter [Lar(MN), in which the M and N components are fused, LarQ, and LarO]. LarR is a novel regulator of the Crp-Fnr family (PrfA group). Here, the role of LarR was further characterized in vivo and in vitro. We show that LarR is a positive regulator that is absolutely required for the expression of Lar activity. Using gel retardation experiments, we demonstrate that LarR binds to a 16-bp palindromic sequence (Lar box motif) that is present in the larR-larA intergenic region. Mutations in the Lar box strongly affect LarR binding and completely abolish transcription from the larA promoter (PlarA). Two half-Lar boxes located between the Lar box and the −35 box of PlarA promote LarR multimerization on DNA, and point mutations within one or both half-Lar boxes inhibit PlarA induction by l-lactate. Gel retardation and footprinting experiments indicate that l-lactate has a positive effect on the binding and multimerization of LarR, while d-lactate antagonizes the positive effect of l-lactate. A possible mechanism of LarR regulation by lactate enantiomers is proposed. PMID:25349156

  7. Relationship between non-alcoholic fatty liver disease and inflammation in patients with non-alcoholic fatty liver

    PubMed Central

    Foroughi, Mehdi; Maghsoudi, Zahra; Khayyatzadeh, Saeid; Ghiasvand, Reza; Askari, Gholamreza; Iraj, Bijan

    2016-01-01

    Background: Non-alcoholic fatty liver is the most chronic liver disease that eventually can become cirrhosis. One of the underlying assumptions for the fatty liver created by inflammation of the hepatocytes. We aimed to assess the association between non-alcoholic fatty liver disease (NAFLD) and sub-clinical inflammation. Materials and Methods: This is a cross-sectional study which was conducted on 55 patients over 30 years, with NAFLD. Fatty liver grade was assessed using liver ultrasound. Liver enzymes (alanine aminotransferase, aspartate aminotransferase), anthropometric characteristics and inflammatory marker C-reactive protein (CRP) were measured. Qualitative variables (sex and fatty liver grade) and quantitative variables such as were compared with independent t-test and Chi-square test. Relationship between fatty liver grade and inflammatory index was assessed with SPSS software (version 20; SPSS, Inc. Chicago, IL, USA). Results: Non-alcoholic fatty liver grades were associated with CRP level and this relationship remains in statistically significant level even after adjusting the effects of confounding variables such as age, sex and body mass index of participants (P = 0.016). Conclusion: In this cross-sectional study, presentation of NAFLD showed a significant correlation with sub-clinical systemic inflammation and CRP level. PMID:27014655

  8. Lactation curves of commercial ewes rearing lambs.

    PubMed

    Cardellino, R A; Benson, M E

    2002-01-01

    Three-hour milk production measurements determined by machine milking at 3-d intervals throughout a 63-d lactation period were used to describe lactation curves for crossbred ewes lambing at 1 and 2 yr of age and rearing single and twin lambs. Age of ewe, type of rearing, and day of lactation affected (P < 0.05) milk production. Over the 63-d lactation, average daily milk production was 2.56 and 2.63 kg, respectively, for 1- and 2-yr-old ewes rearing single lambs and 2.73 and 3.47 kg, respectively, for 1- and 2-yr-old ewes rearing twins. Milk production of 2-yr-old ewes rearing twin lambs peaked at 21 d of lactation, and that of 1- and 2-yr-old ewes rearing singles peaked between 27 and 30 d of lactation. The largest differences in the lactation curves among age and rearing ewe classes were found in early lactation. These differences were reduced by midlactation, and by late lactation, milk production for all ewes was similar. Diurnal variation in milk production by ewes was evaluated in an 8 x 8 Latin square design. Diurnal variation in milk yield measurements of eight mature ewes, each bearing and rearing twin lambs, was similar between d 21 and 24 of lactation. Time of milk production measurements within a day did not affect yield determinations. Extrapolation from 3-h production estimates to daily milk production is valid in determining a ewe's milk contribution in support of lamb growth.

  9. CEUS and Fibroscan in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

    PubMed Central

    Cocciolillo, Sila; Parruti, Giustino; Marzio, Leonardo

    2014-01-01

    AIM: To determine intra-hepatic blood flow and liver stiffness in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) using contrast-enhanced ultrasound and fibroscan. METHODS: This prospective study included 15 patients with NAFLD, 17 patients with NASH and 16 healthy controls. In each patient, real-time ultrasound was used to locate the portal vein (PV) and the right liver lobe, and 5 mL of SonoVue® was then injected intravenous in a peripheral vein of the left arm over a 4-s span. Digital recording was performed for 3 min thereafter. The recording was subsequently retrieved to identify an area of interest in the PV area and in the right liver parenchyma (LP) to assess the blood flow by processing the data using dedicated software (Qontrast®, Bracco, Italy). The following parameters were evaluated: percentage of maximal contrast activity (Peak%), time to peak (TTP, s), regional blood volume (RBV, cm3), regional blood flow (RBF, cm3/s) and mean transit time (MTT, s). At 24-48 h post-injection, liver stiffness was evaluated using Fibroscan and measured in kPa. The statistical evaluation was performed using Student’s t test. RESULTS: In the PV, the Peak%, RBV and RBF were significantly reduced in the NAFLD and NASH patients compared with the controls (Peak%: NAFLD 26.3 ± 6.6, NASH 28.1 ± 7.3 vs controls 55.8 ± 9.9, P < 0.001; RBV: NAFLD 4202.3 ± 3519.7, NASH 3929.8 ± 1941.3 vs controls 7473 ± 3281, P < 0.01; RBF: NAFLD 32.5 ± 10.8, NASH 32.7 ± 12.1 vs controls 73.1 ± 13.9, P < 0.001). The TTP in the PV was longer in both patient groups but reached statistical significance only in the NASH patients compared with the controls (NASH 79.5 ± 37.8 vs controls 43.2 ± 30, P < 0.01). In the LP, the Peak%, RBV and RBF were significantly reduced in the NAFLD and NASH patients compared with the controls (Peak%: NAFLD 43.2 ± 7.3, NASH 41.7 ± 7.7 vs controls 56.6 ± 6.3, P < 0.001; RBV: NAFLD 4851.5 ± 2009, NASH 5069

  10. L-Lactate Protects Skin Fibroblasts against Aging-Associated Mitochondrial Dysfunction via Mitohormesis.

    PubMed

    Zelenka, Jaroslav; Dvořák, Aleš; Alán, Lukáš

    2015-01-01

    A moderate elevation of reactive oxygen species (ROS) production and a mild inhibition of mitochondrial respiratory chain have been associated with a health promotion and a lifespan extension in several animal models of aging. Here, we tested whether this phenomenon called mitohormesis could be mediated by L-lactate. The treatment with 5 mM L-lactate significantly increased H2O2 production and slightly inhibited the respiration in cultured skin fibroblasts and in isolated mitochondria. The L-lactate exposure was associated with oxidation of intracellular glutathione, phosphorylation of 5'AMP-activated protein kinase (AMPK), and induction of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) transcription. A replicative aging of fibroblasts (L0) with a constant (LC), or intermittent 5 mM L-lactate (LI) in media showed that the high-passage LI fibroblasts have higher respiration, lower H2O2 release, and lower secretion of L-lactate compared to L0 and LC. This protection against mitochondrial dysfunction in LI cells was associated with lower activity of mechanistic target of rapamycin complex 1 (mTORC1), less signs of cellular senescence, and increased autophagy compared to L0 and LC. In conclusion, we demonstrated that intermittent but not constant exposure to L-lactate triggers mitohormesis, prevents aging-associated mitochondrial dysfunction, and improves other markers of aging. PMID:26171114

  11. L-Lactate Protects Skin Fibroblasts against Aging-Associated Mitochondrial Dysfunction via Mitohormesis

    PubMed Central

    Zelenka, Jaroslav; Dvořák, Aleš; Alán, Lukáš

    2015-01-01

    A moderate elevation of reactive oxygen species (ROS) production and a mild inhibition of mitochondrial respiratory chain have been associated with a health promotion and a lifespan extension in several animal models of aging. Here, we tested whether this phenomenon called mitohormesis could be mediated by L-lactate. The treatment with 5 mM L-lactate significantly increased H2O2 production and slightly inhibited the respiration in cultured skin fibroblasts and in isolated mitochondria. The L-lactate exposure was associated with oxidation of intracellular glutathione, phosphorylation of 5′AMP-activated protein kinase (AMPK), and induction of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) transcription. A replicative aging of fibroblasts (L0) with a constant (LC), or intermittent 5 mM L-lactate (LI) in media showed that the high-passage LI fibroblasts have higher respiration, lower H2O2 release, and lower secretion of L-lactate compared to L0 and LC. This protection against mitochondrial dysfunction in LI cells was associated with lower activity of mechanistic target of rapamycin complex 1 (mTORC1), less signs of cellular senescence, and increased autophagy compared to L0 and LC. In conclusion, we demonstrated that intermittent but not constant exposure to L-lactate triggers mitohormesis, prevents aging-associated mitochondrial dysfunction, and improves other markers of aging. PMID:26171114

  12. Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

    PubMed Central

    Civini, Sara; Pacelli, Consiglia; Dieng, Mame Massar; Lemieux, William; Jin, Ping; Bazin, Renée; Patey, Natacha; Marincola, Francesco M.; Moldovan, Florina; Zaouter, Charlotte; Trudeau, Louis-Eric; Benabdhalla, Basma; Louis, Isabelle; Beauséjour, Christian; Stroncek, David; Le Deist, Françoise; Haddad, Elie

    2016-01-01

    Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-macrophage features in terms of morphology, surface markers, migratory properties and antigen presentation capacity. Microarray expression profiling indicates that UC-MSC modify the expression of metabolic-related genes and induce a M2-macrophage expression signature. Importantly, monocyte-derived DC obtained in presence of UC-MSC, polarize naïve allogeneic CD4+ T-cells into Th2 cells. Treatment of UC-MSC with an inhibitor of lactate dehydrogenase strongly decreases lactate concentration in culture supernatant and abrogates the effect on monocyte-to-DC differentiation. Metabolic analysis further revealed that UC-MSC decrease oxidative phosphorylation in differentiating monocytes while strongly increasing the spare respiratory capacity proportional to the amount of secreted lactate. Because both MSC and monocytes are recruited in vivo at the site of tissue damage and inflammation, we propose the local increase of lactate concentration induced by UC-MSC and the consequent enrichment in M2-macrophage generation as a mechanism to achieve immunomodulation. PMID:27070086

  13. Accumulation of duct cells with activated YAP parallels fibrosis progression in NonAlcoholic Fatty Liver Disease

    PubMed Central

    Machado, Mariana Verdelho; Michelotti, Gregory Alexander; de Almeida, Thiago Pereira; Xie, Guanhua; Premont, Richard; Cortez-Pinto, Helena; Diehl, Anna Mae

    2015-01-01

    Background & Aims Mechanisms that regulate regeneration of injured livers are complex. YAP, a stem-cell associated factor, controls liver growth in healthy adult mice. Increasing nuclear localization of YAP triggers accumulation of reactive-appearing ductular cells (YAP+RDC) with liver progenitor capabilities. The significance of YAP activation, and mechanisms involved, are unknown in diseased livers. We evaluated the hypothesis that YAP is more activated in injured livers that are scarring than in those that are regenerating effectively. Methods Immunohistochemistry and qRT-PCR analysis were used to localize and quantify changes in YAP and RDC in 52 patients with nonalcoholic fatty liver disease (NAFLD) and two mouse models of diet-induced nonalcoholic steatohepatitis (NASH). Results were correlated with liver disease severity, metabolic risk factors, and factors proven to control NAFLD progression. Results YAP increased in NAFLD where it mainly localized in nuclei of RDC that expressed progenitor markers. Accumulation of YAP+RDC paralleled the severity of hepatocyte injury and accumulation of Sonic hedgehog (Shh), but not steatosis or metabolic risk factors. YAP+RDC expressed osteopontin, a Shh-regulated fibrogenic factor. Myofibroblast accumulation, fibrosis, and numbers of YAP+RDC strongly correlated. In murine NASH models, atrophic fibrotic livers contained significantly more YAP+RDC than livers with less severe NASH. Conclusion YAP+RDC promote scarring, rather than effective regeneration, during NASH. PMID:26070409

  14. Genome-based nutrition: An intervention strategy for the prevention and treatment of obesity and nonalcoholic steatohepatitis

    PubMed Central

    Roman, Sonia; Ojeda-Granados, Claudia; Ramos-Lopez, Omar; Panduro, Arturo

    2015-01-01

    Obesity and nonalcoholic steatohepatitis are increasing in westernized countries, regardless of their geographic location. In Latin America, most countries, including Mexico, have a heterogeneous admixture genome with Amerindian, European and African ancestries. However, certain high allelic frequencies of several nutrient-related polymorphisms may have been achieved by past gene-nutrient interactions. Such interactions may have promoted the positive selection of variants adapted to regional food sources. At present, the unbalanced diet composition of the Mexicans has led the country to a 70% prevalence rate of overweightness and obesity due to substantial changes in food habits, among other factors. International guidelines and intervention strategies may not be adequate for all populations worldwide because they do not consider disparities in genetic and environmental factors, and thus there is a need for differential prevention and management strategies. Here, we provide the rationale for an intervention strategy for the prevention and management of obesity-related diseases such as non-alcoholic steatohepatitis based on a regionalized genome-based diet. The components required to design such a diet should focus on the specific ancestry of each population around the world and the convenience of consuming traditional ethnic food. PMID:25834309

  15. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease.

    PubMed

    Kawano, Yuki; Cohen, David E

    2013-04-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation in the absence of excess alcohol intake. NAFLD is the most common chronic liver disease, and ongoing research efforts are focused on understanding the underlying pathobiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. Under physiological conditions, the low steady-state triglyceride concentrations in the liver are attributable to a precise balance between acquisition by uptake of non-esterified fatty acids from the plasma and by de novo lipogenesis, versus triglyceride disposal by fatty acid oxidation and by the secretion of triglyceride-rich lipoproteins. In NAFLD patients, insulin resistance leads to hepatic steatosis by multiple mechanisms. Greater uptake rates of plasma non-esterified fatty acids are attributable to increased release from an expanded mass of adipose tissue as a consequence of diminished insulin responsiveness. Hyperinsulinemia promotes the transcriptional upregulation of genes that promote de novo lipogenesis in the liver. Increased hepatic lipid accumulation is not offset by fatty acid oxidation or by increased secretion rates of triglyceride-rich lipoproteins. This review discusses the molecular mechanisms by which hepatic triglyceride homeostasis is achieved under normal conditions, as well as the metabolic alterations that occur in the setting of insulin resistance and contribute to the pathogenesis of NAFLD. PMID:23397118

  16. OSAS-related inflammatory mechanisms of liver injury in nonalcoholic fatty liver disease.

    PubMed

    Paschetta, Elena; Belci, Paola; Alisi, Anna; Liccardo, Daniela; Cutrera, Renato; Musso, Giovanni; Nobili, Valerio

    2015-01-01

    Obstructive sleep apnoea syndrome (OSAS) is a common sleep disorder, affecting over 4% of the general population, and is associated with metabolic syndrome and cardiovascular disease, independent of obesity and traditional risk factors. OSAS has been recently connected to nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the world, which can be found in 30% of the general adult population. Several studies suggest that the chronic intermittent hypoxia (CIH) of OSAS patients may per se trigger liver injury, inflammation, and fibrogenesis, promoting NAFLD development and the progression from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In NAFLD patients, liver disease may be caused by hypoxia both indirectly by promoting inflammation and insulin resistance and directly by enhancing proinflammatory cytokine production and metabolic dysregulation in liver cells. In this review, we focus on molecular mechanisms linking OSAS to NAFLD, including hypoxia inducible factor (HIF), nuclear factor kappa B (NF-κB), YKL-40, unfolded protein response, and hypoxic adipose tissue inflammation, which all could provide novel potential therapeutic approaches for the management of NAFLD patients with OSAS. PMID:25873773

  17. Simultaneous measurements of lactate turnover rate and umbilical lactate uptake in the fetal lamb.

    PubMed Central

    Sparks, J W; Hay, W W; Bonds, D; Meschia, G; Battaglia, F C

    1982-01-01

    Lactic acid represents a major exogenous nutrient for the developing fetal lamb in utero. Our study was undertaken (a) to quantitate the net consumption of lactate by the fetus, (b) to quantitate the net lactate production and metabolism by the placenta, and (c) to compare the net fetal lactate consumption with fetal lactate use, measured simultaneously with radioactive tracers. 14 pregnant sheep were prepared with catheters in the maternal femoral artery and uterine vein and in the fetal aorta and umbilical vein. By simultaneous application of the Fick principle to the uterine and umbilical circulations, placental glucose consumption and placental lactate production were rapid, averaging 39.8 +/- 5.1 and 11.8 +/- 0.7 mg.min-1. Net lactate umbilical uptake averaged 1.95 +/- 0.16 mg-1.kg.min-1. During infusion of L-[14C(U)]lactate, fetal lactate turnover was much more rapid, averaging 6.5 +/- 0.8 mg.kg-1.min-1, and lactate utilization within the anatomic fetus was 5.9 +/- 0.7 mg.kg-1.min-1. During infusion of tracer glucose, endogenous fetal lactate production from glucose and nonglucose substrates averaged 3.0 and 1.5 mg.kg-1.min-1, respectively. The present studies have quantitated under well oxygenated, steady-state conditions, the rapid placental metabolism and production of lactate, the net fetal consumption of lactate, and the rapid endogenous fetal lactate production from glucose and nonglucose substrates. PMID:7085882

  18. Lactate as a Biomarker for Sleep

    PubMed Central

    Naylor, Erik; Aillon, Daniel V.; Barrett, Brian S.; Wilson, George S.; Johnson, David A.; Johnson, Donna A.; Harmon, Hans P.; Gabbert, Seth; Petillo, Peter A.

    2012-01-01

    Study Objectives: An ideal biomarker for sleep should change rapidly with sleep onset, remain at a detectably differential level throughout the sleep period, and exhibit a rapid change with waking. Currently, no molecular marker has been identified that exhibits all three properties. This study examined three substances (lactate, glucose, and glutamate) for suitability as a sleep biomarker. Design: Using amperometric biosensor technology in conjunction with electroencephalograph (EEG) and electromyograph (EMG) monitoring, extracellular concentrations of lactate and glucose (Cohort 1) as well as lactate and glutamate (Cohort 2) were recorded over multiple sleep/wake cycles. Patients or Participants: There were 12 C57Bl/6J male mice (3-5 mo old). Interventions: Sleep and waking transitions were identified using EEG recordings. Extracellular concentrations of lactate, glucose, and glutamate were evaluated before and during transition events as well as during extended sleep and during a 6-h sleep deprivation period. Measurements and Results: Rapid and sustained increases in cortical lactate concentration (approximately 15 μM/min) were immediately observed upon waking and during rapid eye movement sleep. Elevated lactate concentration was also maintained throughout a 6-h period of continuous waking. A persistent and sustained decline in lactate concentration was measured during nonrapid eye movement sleep. Glutamate exhibited similar patterns, but with a much slower rise and decline (approximately 0.03 μM/min). Glucose concentration changes did not demonstrate a clear correlation with either sleep or wake. Conclusions: These findings indicate that extracellular lactate concentration is a reliable sleep/wake biomarker and can be used independently of the EEG signal. Citation: Naylor E; Aillon DV; Barrett BS; Wilson GS; Johnson DA; Johnson DA; Harmon HP; Gabbert S; Petillo PA. Lactate as a biomarker for sleep. SLEEP 2012;35(9):1209-1222. PMID:22942499

  19. Murine Models of Nonalcoholic Fatty Liver Disease and Steatohepatitis

    PubMed Central

    Ninomiya, Masashi; Kondo, Yasuteru; Shimosegawa, Tooru

    2013-01-01

    In 1980, Ludwig et al. first reported patients of steatohepatitis who lacked a history of excessive alcohol consumption but showed liver histology resembling alcoholic hepatitis and progression to cirrhosis of the liver accompanied by inflammation and fibrosis. The development of nonalcoholic steatohepatitis (NASH) is associated with obesity, diabetes mellitus, insulin resistance, and hyperlipidemia. However, the pathogenesis of NASH remains incomplete. A “multiple-hit” hypothesis for the pathogenesis of NASH based on an animal model has been proposed and remains a foundation for research in this field. We review the important dietary and genetic animal models and discuss the pathogenesis of NASH. PMID:27335818

  20. Murine Models of Nonalcoholic Fatty Liver Disease and Steatohepatitis.

    PubMed

    Ninomiya, Masashi; Kondo, Yasuteru; Shimosegawa, Tooru

    2013-01-01

    In 1980, Ludwig et al. first reported patients of steatohepatitis who lacked a history of excessive alcohol consumption but showed liver histology resembling alcoholic hepatitis and progression to cirrhosis of the liver accompanied by inflammation and fibrosis. The development of nonalcoholic steatohepatitis (NASH) is associated with obesity, diabetes mellitus, insulin resistance, and hyperlipidemia. However, the pathogenesis of NASH remains incomplete. A "multiple-hit" hypothesis for the pathogenesis of NASH based on an animal model has been proposed and remains a foundation for research in this field. We review the important dietary and genetic animal models and discuss the pathogenesis of NASH. PMID:27335818

  1. Perspective: nonalcoholic fatty liver disease and cardiovascular risk.

    PubMed

    Nestel, Paul J; Mensink, Ronald P

    2013-02-01

    Nonalcoholic fatty liver disease (NAFLD) has emerged as a clear risk factor for cardiovascular risk. Through its association with metabolic syndrome including insulin resistance and type 2 diabetes, NAFLD certainly has strong indirect associations with cardiovascular risk. Recent population studies have strengthened the association with prevalent coronary heart disease. Investigative cardiology has shown that NAFLD is also associated with markers of subclinical atherosclerosis, such as diminished endothelial function and carotid artery intima-media thickening. Though causality between NAFLD and cardiovascular disease can only be tested in a clinical trial, these recent findings do emphasize the need to develop strategies including nutritional that may prevent NAFLD. PMID:23298957

  2. Nonalcoholic Fatty Liver Disease and the Gut Microbiome.

    PubMed

    Boursier, Jerome; Diehl, Anna Mae

    2016-05-01

    Recent progress has allowed a more comprehensive study of the gut microbiota. Gut microbiota helps in health maintenance and gut dysbiosis associates with chronic metabolic diseases. Modulation of short-chain fatty acids and choline bioavailability, lipoprotein lipase induction, alteration of bile acid profile, endogenous alcohol production, or liver inflammation secondary to endotoxemia result from gut dysbiosis. Modulation of the gut microbiota by pre/probiotics gives promising results in animal, but needs to be evaluated in human before use in clinical practice. Gut microbiota adds complexity to the pathophysiology of nonalcoholic fatty liver disease but represents an opportunity to discover new therapeutic targets.

  3. Genetics Home Reference: lactate dehydrogenase deficiency

    MedlinePlus

    ... dehydrogenase-B pieces (subunits) of the lactate dehydrogenase enzyme. This enzyme is found throughout the body and is important ... cells. There are five different forms of this enzyme, each made up of four protein subunits. Various ...

  4. Affinity chromatography of bacterial lactate dehydrogenases.

    PubMed Central

    Kelly, N; Delaney, M; O'Carra, P

    1978-01-01

    The affinity system used was the immobilized oxamate derivative previously used to purify mammalian lactate dehydrogenases. The bacterial dehydrogenases specific for the L-stereoisomer of lactate behaved in the same way as the mammalian enzymes, binding strongly in the presence of NADH. The D-lactate-specific enzymes, however, did not show any biospecific affinity for this gel. The L-specific enzymes could be purified to homogeneity in one affinity-chromatographic step. The D-specific enzymes could be efficiently separated from the L-specific ones and could then be further purified on an immobilized NAD derivative. The mechanism of activation of the lactate dehydrogenase from Streptococcus faecalis by fructose 1,6-bisphosphate was investigated by using the immobilized oxamate gel. PMID:666726

  5. Affinity chromatography of bacterial lactate dehydrogenases.

    PubMed

    Kelly, N; Delaney, M; O'Carra, P

    1978-06-01

    The affinity system used was the immobilized oxamate derivative previously used to purify mammalian lactate dehydrogenases. The bacterial dehydrogenases specific for the L-stereoisomer of lactate behaved in the same way as the mammalian enzymes, binding strongly in the presence of NADH. The D-lactate-specific enzymes, however, did not show any biospecific affinity for this gel. The L-specific enzymes could be purified to homogeneity in one affinity-chromatographic step. The D-specific enzymes could be efficiently separated from the L-specific ones and could then be further purified on an immobilized NAD derivative. The mechanism of activation of the lactate dehydrogenase from Streptococcus faecalis by fructose 1,6-bisphosphate was investigated by using the immobilized oxamate gel. PMID:666726

  6. Regulation of bone mineral loss during lactation

    NASA Technical Reports Server (NTRS)

    Brommage, R.; Deluca, H. F.

    1985-01-01

    The effects of varyng dietary calcium and phosphorous levels, vitamin D deficiency, oophorectomy, adrenalectomy, and simultaneous pregnancy on bone mineral loss during lactation in rats are studied. The experimental procedures and evaluations are described. The femur ash weight of lactating and nonlactating rats are calculated. The data reveals that a decrease in dietary calcium of 0.02 percent results in an increased loss of bone mineral, an increase in calcium to 1.4 percent does not lessen bone mineral loss, and bone mineral loss in vitamin D deficient rats is independent of calcium levels. It is observed that changes in dietary phosphorous level, oophorectomy, adrenalectomy, and simultaneous pragnancy do not reduce bone mineral loss during lactation. The analysis of various hormones to determine the mechanism that triggers bone mineral loss during lactation is presented.

  7. [Natural remedies during pregnancy and lactation].

    PubMed

    Gut, E; Melzer, J; von Mandach, U; Saller, R

    2004-10-01

    Up to date there is a lack of systematically gathered data on the use of natural remedies (phytotherapeutic, homeopathic, anthroposophic, spagyric, Bach and Schussler remedies) during pregnancy and lactation. The aim of this non-representative pilot study on 139 women, who came for delivery to three institutions between mid-1997 and the beginning of 1998, was to receive data about how often and within which spectrum natural remedies are used during pregnancy and lactation. During pregnancy 96% and within the lactation period 84% of the women consumed at least 1 natural remedy. Phytotherapeutic drugs were used most frequently. In contrast to the widespread use of natural remedies by pregnant women and nursing mothers in this study, little information on the effectiveness and possible risks is available. Therefore it seems necessary to examine and evaluate natural remedies used during pregnancy and lactation.

  8. Phyllodes Tumor in a Lactating Breast.

    PubMed

    Murthy, Sudha S; Raju, K V V N; Nair, Haripreetha G

    2016-01-01

    Phyllodes tumor is attributed to a small fraction of primary tumors of the breast. Such tumors occur rarely in pregnancy and lactation. We report a case of a 25-year-old lactating mother presenting with a lump in the left breast. Core needle biopsy was opined as phyllodes tumor with lactational changes, and subsequent wide local excision confirmed the diagnosis of benign phyllodes tumor with lactational changes. The characteristic gross and microscopic findings of a well-circumscribed lesion with leaf-like fibroepithelial growth pattern and typical nonuniform or diffuse stromal proliferation with periductal accentuation even in the absence of mitotic figures can help clinch the diagnosis. Benign phyllodes is known for its recurrence and requires wide excision and close follow-up. It is vital to identify these lesions even on limited biopsies as therapeutic options differ. This case is presented for its rarity and the diagnostic challenge it poses in limited biopsy. PMID:27081326

  9. Phyllodes Tumor in a Lactating Breast

    PubMed Central

    Murthy, Sudha S.; Raju, K. V. V. N.; Nair, Haripreetha G.

    2016-01-01

    Phyllodes tumor is attributed to a small fraction of primary tumors of the breast. Such tumors occur rarely in pregnancy and lactation. We report a case of a 25-year-old lactating mother presenting with a lump in the left breast. Core needle biopsy was opined as phyllodes tumor with lactational changes, and subsequent wide local excision confirmed the diagnosis of benign phyllodes tumor with lactational changes. The characteristic gross and microscopic findings of a well-circumscribed lesion with leaf-like fibroepithelial growth pattern and typical nonuniform or diffuse stromal proliferation with periductal accentuation even in the absence of mitotic figures can help clinch the diagnosis. Benign phyllodes is known for its recurrence and requires wide excision and close follow-up. It is vital to identify these lesions even on limited biopsies as therapeutic options differ. This case is presented for its rarity and the diagnostic challenge it poses in limited biopsy. PMID:27081326

  10. Lactate oxidation at the mitochondria: a lactate-malate-aspartate shuttle at work

    PubMed Central

    Kane, Daniel A.

    2014-01-01

    Lactate, the conjugate base of lactic acid occurring in aqueous biological fluids, has been derided as a “dead-end” waste product of anaerobic metabolism. Catalyzed by the near-equilibrium enzyme lactate dehydrogenase (LDH), the reduction of pyruvate to lactate is thought to serve to regenerate the NAD+ necessary for continued glycolytic flux. Reaction kinetics for LDH imply that lactate oxidation is rarely favored in the tissues of its own production. However, a substantial body of research directly contradicts any notion that LDH invariably operates unidirectionally in vivo. In the current Perspective, a model is forwarded in which the continuous formation and oxidation of lactate serves as a mitochondrial electron shuttle, whereby lactate generated in the cytosol of the cell is oxidized at the mitochondria of the same cell. From this perspective, an intracellular lactate shuttle operates much like the malate-aspartate shuttle (MAS); it is also proposed that the two shuttles are necessarily interconnected in a lactate-MAS. Among the requisite features of such a model, significant compartmentalization of LDH, much like the creatine kinase of the phosphocreatine shuttle, would facilitate net cellular lactate oxidation in a variety of cell types. PMID:25505376

  11. Australian midwives: leaders in lactation consultancy.

    PubMed

    Drew, D; Escott, R

    1997-09-01

    Midwives all over Australia are furthering their breastfeeding knowledge and skills, to lead the world in lactation support. The certification exam conducted by the International Board of Lactation Consultant Examiners has played a central role in this extraordinary revolution by setting competency standards, motivating the acquisition of specialist skills, and opening up career opportunities. However, it is the consumers, the mothers and babies, who are the principal beneficiaries.

  12. Lactation and the risk of breast cancer.

    PubMed

    Purwanto, H; Sadjimin, T; Dwiprahasto, I

    2000-05-01

    Some factors are suggested to have an association with an increased risk of breast cancer, which are called risk factors. Lactation is one of the risk factors that still needs to be studied because of conflicting findings in epidemiological studies and also uncertainty regarding biologic plausibility. Our objective was to study the relationship between lactation and the risk of breast cancer. A pair of unmatched case control studies was held among parous women at Dr. Soetomo Hospital (general hospital) and some private hospitals in the Surabaya municipality. There are 219 (51.9%) cases and 203 (48.1%) controls analyzed in this study. Age, age at menarche, regular menstruation and number of parity between both groups are not statistical different. When we divided the age at menarche (below 13), it was statistically different. The cases consisted of more women with menarche below 13 (p = 0.00038). Other factors showing statistical differences in the risk of breast cancer between case and control are age at first delivery, family history of breast cancer and age at menopause. Women who have lactated (more than 4-month duration of breast feeding) show a "protective effect" against breast cancer, OR 0.57 (95% CI 0.33-0.99). However, there was no clear duration of lactation and the risk of breast cancer. Logistic regression analysis showed that lactation was not any independent factor. Lactation exerts a "protective effect" against breast cancer. However, the duration of lactation did not show an influence in reducing the risk of breast cancer, and logistic regression analysis did not show that lactation was an independent factor in the risk of breast cancer.

  13. Lactation: historical patterns and potential for manipulation.

    PubMed

    Blackburn, D G

    1993-10-01

    The advent of biotechnology has made data on undomesticated mammals relevant to dairy science. Such data indicate the potential of lactation for modification, reveal genetic material available for use through bioengineering, help distinguish adaptive features from historical artifacts, and clarify limits on lactational diversity that date from early evolution. Evolutionary analysis indicates that a complex degree of lactation preceded divergence of the extant mammalian lineages during the Mesozoic Era. Although aspects of monotreme lactation appear to be ancestral for extant mammals, the marsupials and eutherians exhibit divergent specializations. Evidence is consistent with the idea that protolacteal glands evolved by combining features of skin gland populations into a new functional complex. Secretions of these ancestral glands may have had antimicrobial properties that protected the eggs or hatchlings and organic components that supplemented offspring nutrition. Following development of highly nutritious milks, evolution produced diversity in milk composition and function, milk output, length of lactation, mammary gland anatomy, and contributions of lactation to offspring nutrition. Certain marsupials are specialized in terms of functional independence and temporal plasticity of mammary tissues. Mammalian diversity indicates that artificial selection and physiological manipulation of domestic artiodactyls has only modestly exploited the potential of mammary glands as a nutritional source for humans. PMID:8227641

  14. Intracellular Shuttle: The Lactate Aerobic Metabolism

    PubMed Central

    Cruz, Rogério Santos de Oliveira; de Aguiar, Rafael Alves; Turnes, Tiago; Penteado Dos Santos, Rafael; Fernandes Mendes de Oliveira, Mariana; Caputo, Fabrizio

    2012-01-01

    Lactate is a highly dynamic metabolite that can be used as a fuel by several cells of the human body, particularly during physical exercise. Traditionally, it has been believed that the first step of lactate oxidation occurs in cytosol; however, this idea was recently challenged. A new hypothesis has been presented based on the fact that lactate-to-pyruvate conversion cannot occur in cytosol, because the LDH enzyme characteristics and cytosolic environment do not allow the reaction in this way. Instead, the Intracellular Lactate Shuttle hypothesis states that lactate first enters in mitochondria and only then is metabolized. In several tissues of the human body this idea is well accepted but is quite resistant in skeletal muscle. In this paper, we will present not only the studies which are protagonists in this discussion, but the potential mechanism by which this oxidation occurs and also a link between lactate and mitochondrial proliferation. This new perspective brings some implications and comes to change our understanding of the interaction between the energy systems, because the product of one serves as a substrate for the other. PMID:22593684

  15. Lactation: historical patterns and potential for manipulation.

    PubMed

    Blackburn, D G

    1993-10-01

    The advent of biotechnology has made data on undomesticated mammals relevant to dairy science. Such data indicate the potential of lactation for modification, reveal genetic material available for use through bioengineering, help distinguish adaptive features from historical artifacts, and clarify limits on lactational diversity that date from early evolution. Evolutionary analysis indicates that a complex degree of lactation preceded divergence of the extant mammalian lineages during the Mesozoic Era. Although aspects of monotreme lactation appear to be ancestral for extant mammals, the marsupials and eutherians exhibit divergent specializations. Evidence is consistent with the idea that protolacteal glands evolved by combining features of skin gland populations into a new functional complex. Secretions of these ancestral glands may have had antimicrobial properties that protected the eggs or hatchlings and organic components that supplemented offspring nutrition. Following development of highly nutritious milks, evolution produced diversity in milk composition and function, milk output, length of lactation, mammary gland anatomy, and contributions of lactation to offspring nutrition. Certain marsupials are specialized in terms of functional independence and temporal plasticity of mammary tissues. Mammalian diversity indicates that artificial selection and physiological manipulation of domestic artiodactyls has only modestly exploited the potential of mammary glands as a nutritional source for humans.

  16. [Non-alcoholic fatty liver disease: age peculiarities, breakthrough in pathogenetic therapy].

    PubMed

    Pal'tsev, A I; Sharapov, I V; Gorbunova, E N; Khomchenko, T N; Kurganova, I V; Soldatova, G S; Eremina, A A; Nikolaev, Iu A

    2009-01-01

    Non-alcoholic fatty liver disease, including non-alcoholic steatohepatosis (NSH) and non-alcoholic steatohepatitis (NASH) is considered to be a wide spread disease. Such reasons as metabolic, toxic, infections, alimentary and cryptogenic cause this disease. Pathogenesis of the disease is complex. If the necessary medical preventive measures are absent the disease develops as follows, first steatosis, then steatohepatitis, fibrosis, liver cirrhosis, hepatocarcinoma. The aim of the investigation was to study influence of Metadoxil in patients with NSH and NASH. The conducted investigation have shown high efficiency of the drug at combined treatment of a patient. PMID:20469674

  17. Ethanol-induced hyperlacticacidemia: inhibition of lactate utilization

    PubMed Central

    Kreisberg, Robert A.; Owen, W. Crawford; Siegal, Alan M.

    1971-01-01

    The effects of oral ethanol administration on blood glucose and lactate concentrations, lactate inflow and outflow rates, and lactate incorporation into glucose were investigated in eight human volunteers. Lactate incorporation into glucose, lactate turnover, and lactate inflow and outflow rates were determined during an 8 hr constant infusion of 100 μCi of lactate-U-14C. Ethanol was administered by mouth at hourly intervals, 60 ml of bonded whiskey initially and 30 ml/hr thereafter. Blood lactate concentrations increased precipitously after the administration of ethanol, reached a plateau within 120-180 min, and remained constant thereafter despite the continued administration of ethanol. Before ethanol, the lactate turnover rate was 0.76 mmoles/kg per hr ±0.05 (SEM) and lactate inflow and outflow rates were closely balanced. During the administration of ethanol, the lactate inflow rate was unchanged, but the lactate outflow rate was significantly inhibited, decreasing to 50% of the inflow rate. Despite the continued administration of ethanol, equilibrium between lactate inflow and outflow was restored within 120-180 min and coincided temporally with establishment of a constant blood lactate concentration. Lactate oxidation was unaltered by ethanol, but lactate incorporation into glucose was significantly inhibited. Lactate incorporation into glucose was reduced within 30 min of the administration of ethanol, and nadir values were reached within 120-180 min. Lactate incorporation into glucose remained constant thereafter at rates that were only 30% of those observed in the absence of ethanol. The results of these studies indicate that ethanol-induced hyperlacticacidemia is due to decreased lactate disposal rather than increased lactate production. PMID:5101293

  18. Continuous lactation effects on mammary remodeling during late gestation and lactation in dairy goats.

    PubMed

    Safayi, S; Theil, P K; Hou, L; Engbaek, M; Nørgaard, J V; Sejrsen, K; Nielsen, M O

    2010-01-01

    The present study aimed to 1) elucidate whether continuous milking during late gestation in dairy goats negatively affects mammary remodeling and hence milk production in the subsequent lactation, and 2) identify the regulatory factors responsible for changes in cell turnover and angiogenesis in the continuously lactating mammary gland. Nine multiparous dairy goats were used. One udder half was dried off approximately 9 wk prepartum (normal lactation; NL), and the other udder half of the same goat was milked continuously (continuous lactation; CL) until parturition or until the half-udder milk yields had dropped to below 50 g/d. Mammary biopsies were obtained from each udder half just before the NL gland was dried off (before dry period), within the first 2 wk after drying-off (early dry period, samples available only for NL glands), in the mid dry period, within the last 2 wk before parturition (late dry period), and at d 1 (the day of parturition), 3, 10, 60, and 180 of lactation. Mammary morphology was characterized in biopsies by quantitative histology, and cell turnover was determined by immunohistochemistry (terminal deoxynucleotidyl transferase dUTP nick end labeling and Ki-67). Transcription of genes encoding factors involved in mammary epithelial cell (MEC) turnover and vascular function was quantified by quantitative reverse transcription PCR. Results demonstrated that omitting the dry period was possible in goats but was not as easy as claimed before. Renewal of MEC was suppressed in CL glands, which resulted in a smaller MEC population in the subsequent lactation. At the time of parturition (and throughout lactation), the mammary glands subjected to CL had smaller alveoli, more fully differentiated MEC, and a substantially larger capillary fraction compared with NL glands. The continuously lactating gland thus resembled a normally lactating gland in an advanced stage of lactation. None of the studied genomic factors could account for these treatment

  19. Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain.

    PubMed

    Overgaard, Morten; Rasmussen, Peter; Bohm, Aske M; Seifert, Thomas; Brassard, Patrice; Zaar, Morten; Homann, Pernille; Evans, Kevin A; Nielsen, Henning B; Secher, Niels H

    2012-07-01

    Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions were combined. We measured cerebral lactate turnover via a tracer dilution method ([1-(13)C]lactate), using arterial to right internal jugular venous differences in 9 healthy individuals (5 males and 4 females), at rest and during 30 min of submaximal exercise in normoxia and hypoxia (F(i)o(2) 10%, arterial oxygen saturation 72 ± 10%, mean ± sd). Whole-body lactate turnover increased 3.5-fold and 9-fold at two workloads in normoxia and 18-fold during exercise in hypoxia. Although middle cerebral artery mean flow velocity increased during exercise in hypoxia, calculated cerebral mitochondrial oxygen tension decreased by 13 mmHg (P<0.001). At the same time, cerebral lactate release increased from 0.15 ± 0.1 to 0.8 ± 0.6 mmol min(-1) (P<0.05), corresponding to ∼10% of cerebral energy consumption. Concurrently, cerebral lactate uptake was 1.0 ± 0.9 mmol min(-1) (P<0.05), of which 57 ± 9% was oxidized, demonstrating that lactate oxidation may account for up to ∼33% of the energy substrate used by the brain. These results support the existence of a cell-cell lactate shuttle that may involve neurons and astrocytes.

  20. Translational approaches: From fatty liver to non-alcoholic steatohepatitis

    PubMed Central

    Rosso, Natalia; Chavez-Tapia, Norberto C; Tiribelli, Claudio; Bellentani, Stefano

    2014-01-01

    Over the past few decades, non-alcoholic fatty liver disease (NAFLD) has become one, if not the most common, cause of chronic liver disease affecting both adults and children. The increasing number of cases at an early age is the most worrying aspect of this pathology, since it provides more time for its evolution. The spectrum of this disease ranges from liver steatosis to steatohepatitis, fibrosis and in some cases, hepatocellular carcinoma. NAFLD may not always be considered a benign disease and hepatologists must be cautious in the presence of fatty liver. This should prompt the use of the available experimental models to understand better the pathogenesis and to develop a rational treatment of a disease that is dangerously increasing. In spite of the growing efforts, the pathogenesis of NAFLD is still poorly understood. In the present article we review the most relevant hypotheses and evidence that account for the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis. The available in vitro and in vivo experimental models of NASH are discussed and revised in terms of their validity in translational studies. These studies must be aimed at the discovery of the still unknown triggers or mediators that induce the progression of hepatic inflammation, apoptosis and fibrosis. PMID:25083077

  1. Nonalcoholic fatty liver disease: a challenge for pediatricians.

    PubMed

    Nobili, Valerio; Alkhouri, Naim; Alisi, Anna; Della Corte, Claudia; Fitzpatrick, Emer; Raponi, Massimiliano; Dhawan, Anil

    2015-02-01

    Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is considered the most common form of chronic liver disease in children. Several factors contribute to NAFLD development, including race/ethnicity, genetic factors, environmental exposures, and alterations in the gut microbiome. The histologic spectrum of NAFLD ranges from simple steatosis to the more aggressive nonalcoholic steatohepatitis (NASH). Fibrosis and eventually cirrhosis can develop from NAFLD during childhood. Diagnosing advanced disease is challenging and may require a liver biopsy, highlighting the urgent need for reliable, noninvasive markers of disease severity. The mainstay of treatment for NAFLD remains lifestyle modifications and weight loss. Probiotics and ω-3 fatty acids may ameliorate disease progression. Recent data have suggested that vitamin E may be considered as a NASH-specific therapy in children, and there are several ongoing human studies evaluating different therapeutic targets for NAFLD. We provide an up-to-date review of the risk factors, diagnosis, and treatment to manage this common disease in children.

  2. Nonalcoholic steatohepatitis: emerging targeted therapies to optimize treatment options

    PubMed Central

    Milic, Sandra; Mikolasevic, Ivana; Krznaric-Zrnic, Irena; Stanic, Marija; Poropat, Goran; Stimac, Davor; Vlahovic-Palcevski, Vera; Orlic, Lidija

    2015-01-01

    Diet and lifestyle changes have led to worldwide increases in the prevalences of obesity and metabolic syndrome, resulting in substantially greater incidence of nonalcoholic fatty liver disease (NAFLD). NAFLD is considered a hepatic manifestation of metabolic syndrome and is related to diabetes, insulin resistance, central obesity, hyperlipidemia, and hypertension. Nonalcoholic steatohepatitis (NASH) is an entity that describes liver inflammation due to NAFLD. Growing evidence suggests that NAFLD is a multisystem disease with a clinical burden that is not only confined to liver-related morbidity and mortality, but that also affects several extra-hepatic organs and regulatory pathways. Thus, NAFLD is considered an important public health issue, but there is currently no effective therapy for all NAFLD patients in the general population. Studies seeking optimal therapy for NAFLD and NASH have not yet led to development of a universal protocol for treating this growing problem. Several pharmacological agents have been studied in an effort to improve insulin resistance and the proinflammatory mediators that may be responsible for NASH progression. Cardiovascular risk factors are highly prevalent among NASH patients, and the backbone of treatment regimens for these patients still comprises general lifestyle interventions, including dietary changes and increased physical activity. Vitamin E and thiazolidinedione derivatives are currently the most evidence-based therapeutic options, but only limited clinical evidence is available regarding their long-term efficacy and safety. Vitamin D and renin–angiotensin–aldosterone system blockers are promising drugs that are currently being intensively investigated for use in NAFLD/NASH patients. PMID:26316717

  3. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease

    PubMed Central

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-01-01

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as “fatty infiltration” or “nonalcoholic fatty pancreas disease” (NAFPD). The term “fatty replacement” describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of “ectopic fat deposition”, which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula. PMID:27678349

  4. Non-alcoholic fatty liver disease in 2015

    PubMed Central

    Ahmed, Monjur

    2015-01-01

    There is worldwide epidemic of non-alcoholic fatty liver disease (NAFLD). NAFLD is a clinical entity related to metabolic syndrome. Majority of the patients are obese but the disease can affect non-obese individuals as well. Metabolic factors and genetics play important roles in the pathogenesis of this disorder. The spectrum of disorders included in NAFLD are benign macrovesicular hepatic steatosis, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis of liver and hepatocellular carcinoma. Although the disease remains asymptomatic most of the time, it can slowly progress to end stage liver disease. It will be the most common indication of liver transplantation in the future. It is diagnosed by abnormal liver chemistry, imaging studies and liver biopsy. As there are risks of potential complications during liver biopsy, many patients do not opt for liver biopsy. There are some noninvasive scoring systems to find out whether patients have advanced hepatic fibrosis. At the present time, there are limited treatment options which include lifestyle modification to loose weight, vitamin E and thioglitazones. Different therapeutic agents are being investigated for optimal management of this entity. There are some studies done on incretin based therapies in patients with NAFLD. Other potential agents will be silent information regulator protein Sirtuin and antifibrotic monoclonal antibody Simtuzumab against lysyl oxidase like molecule 2. But they are still in the investigational phase. PMID:26085906

  5. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease.

    PubMed

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-09-14

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as "fatty infiltration" or "nonalcoholic fatty pancreas disease" (NAFPD). The term "fatty replacement" describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of "ectopic fat deposition", which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula.

  6. Non-alcoholic fatty liver disease and liver transplantation.

    PubMed

    Khan, Reenam S; Newsome, Philip N

    2016-08-01

    Cirrhosis secondary to non-alcoholic steatohepatitis (NASH) is a common indication for liver transplant. In comparison to other cirrhotic patients, patients with NASH cirrhosis are more likely to be older and have the metabolic syndrome. Pre-transplant, patients require careful evaluation of cardiovascular risk. As the incidence of non-alcoholic fatty liver disease (NAFLD) is rising, a greater proportion of donor grafts have steatosis greater than 30%, which is associated with poor outcomes. Grafts with steatosis greater than 60% are unsuitable for transplant. Overall, post-transplant survival outcomes for patients with NASH cirrhosis are similar to those with cirrhosis without NASH. However, NASH cirrhosis is associated with a higher 30-day mortality, predominantly from an increase in cardiovascular events and infections. Following liver transplant, there is a significant risk of NASH recurrence, although this seldom results in allograft loss. Furthermore, a significant number of patients who had a liver transplant for other reasons develop NASH de novo. When patients with NASH cirrhosis are considered for transplant, one of the major challenges lies in identifying which patients are too high risk for surgery. This review aims to provide information to aid this decision making process, and to provide guidance on the peri-operative care strategies that can modify risk. PMID:26997540

  7. Dietary approach in the treatment of nonalcoholic fatty liver disease

    PubMed Central

    Ferolla, Silvia Marinho; Silva, Luciana Costa; Ferrari, Maria de Lourdes Abreu; da Cunha, Aloísio Sales; Martins, Flaviano dos Santos; Couto, Cláudia Alves; Ferrari, Teresa Cristina Abreu

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) has been identified as one of the most prevalent chronic liver disease in adults and children populations. NAFLD is usually associated with the metabolic syndrome (MS), which is chiefly related to insulin resistance and its consequences. Insulin resistance has a crucial role in the pathogenesis of hepatic steatosis and potentially nonalcoholic steatohepatitis (NASH). Because of the contemporary epidemics of MS and obesity, the burden of NAFLD is also expected to rise. Unhealthy diets, such as the so-called western diet, are enriched in fructose, trans-fatty acids and saturated fat and seem to be associated with the development of NAFLD. In human studies, certain dietary sugars, particularly fructose, are used as a substrate for lipogenesis leading to hepatic fatty infiltration, inflammation, and possibly fibrosis. Other investigations have shown that fat consumption especially cholesterol and trans/saturated fatty acids are also steatogenic and seem to increase visceral adiposity. The identification of specific dietary components that favor the development of NASH could be important for the management of this disorder. This review focuses on the effects of different dietary approaches to prevent and treat NAFLD emphasizing the macronutrients and energy composition. PMID:26523205

  8. The Natural Course of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Calzadilla Bertot, Luis; Adams, Leon Anton

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from "bland steatosis" to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death.

  9. The Natural Course of Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Calzadilla Bertot, Luis; Adams, Leon Anton

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death. PMID:27213358

  10. Nonalcoholic Steatohepatitis in a Patient with Ataxia-Telangiectasia

    PubMed Central

    Caballero, Trinidad; Caba-Molina, Mercedes; Salmerón, Javier; Gómez-Morales, Mercedes

    2014-01-01

    Ataxia-telangiectasia (A-T) is a rare disease characterized by neurodegenerative alterations, telangiectasia, primary immunodeficiency, extreme sensitivity to radiation, and susceptibility to neoplasms. A-T patients have inactivation of ataxia-telangiectasia-mutated (ATM) protein, which controls DNA double-strand break repair and is involved in oxidative stress response, among other functions; dysfunctional control of reactive oxygen species may be responsible for many of the clinical manifestations of this disease. To the best of our knowledge, hepatic lesions of steatohepatitis have not previously been reported in A-T patients. The present study reports the case of a 22-year-old man diagnosed with A-T at the age of 6 years who was referred to our Digestive Disease Unit with a three-year history of hyperlipidemia and liver test alterations. Core liver biopsy showed similar lesions to those observed in nonalcoholic steatohepatitis. Immunohistochemical staining disclosed the absence of ATM protein in hepatocyte nuclei. We suggest that the liver injury may be mainly attributable to the oxidative stress associated with ATM protein deficiency, although other factors may have made a contribution. We propose the inclusion of A-T among the causes of nonalcoholic steatohepatitis, which may respond to antioxidant therapy. PMID:25374730

  11. Non-alcoholic fatty liver disease, diet and gut microbiota.

    PubMed

    Finelli, Carmine; Tarantino, Giovanni

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may advantageously affect host metabolism. Large-scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high-risk populations, are fervently awaited.

  12. Clinical approaches to non-alcoholic fatty liver disease

    PubMed Central

    Schwenger, Katherine JP; Allard, Johane P

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients. PMID:24587650

  13. Non-alcoholic fatty liver disease, diet and gut microbiota

    PubMed Central

    Finelli, Carmine; Tarantino, Giovanni

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may advantageously affect host metabolism. Large-scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high-risk populations, are fervently awaited. PMID:26417275

  14. Role of Alcohol Metabolism in Non-Alcoholic Steatohepatitis

    PubMed Central

    Baker, Susan S.; Baker, Robert D.; Liu, Wensheng; Nowak, Norma J.; Zhu, Lixin

    2010-01-01

    Background Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD), associated with obesity and insulin resistance. Previous studies suggested that intestinal bacteria produced more alcohol in obese mice than lean animals. Methodology/Principal Findings To investigate whether alcohol is involved in the pathogenesis of NASH, the expression of inflammation, fibrosis and alcohol metabolism related genes in the liver tissues of NASH patients and normal controls (NCs) were examined by microarray (NASH, n = 7; NC, n = 4) and quantitative real-time PCR (NASH, n = 6; NC, n = 6). Genes related to liver inflammation and fibrosis were found to be elevated in NASH livers compared to normal livers. The most striking finding is the increased gene transcription of alcohol dehydrogenase (ADH) genes, genes for catalase and cytochrome P450 2E1, and aldehyde dehydrogenase genes. Immunoblot analysis confirmed the increased expression of ADH1 and ADH4 in NASH livers (NASH, n = 9; NC, n = 4). Conclusions/Significance The augmented activity of all the available genes of the pathways for alcohol catabolism suggest that 1) alcohol concentration was elevated in the circulation of NASH patients; 2) there was a high priority for the NASH livers to scavenge alcohol from the circulation. Our data is the first human evidence that suggests alcohol may contribute to the development of NAFLD. PMID:20221393

  15. A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats

    PubMed Central

    Svegliati-Baroni, Gianluca; Candelaresi, Cinzia; Saccomanno, Stefania; Ferretti, Gianna; Bachetti, Tiziana; Marzioni, Marco; De Minicis, Samuele; Nobili, Liliana; Salzano, Renata; Omenetti, Alessia; Pacetti, Deborah; Sigmund, Soeren; Benedetti, Antonio; Casini, Alessandro

    2006-01-01

    Insulin resistance induces nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). We used a high-fat, high-calorie solid diet (HFD) to create a model of insulin resistance and NASH in nongenetically modified rats and to study the relationship between visceral adipose tissue and liver. Obesity and insulin resistance occurred in HFD rats, accompanied by a progressive increase in visceral adipose tissue tumor necrosis factor (TNF)-α mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-α expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-α-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor substrate-1Ser307 phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinflammation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis at 6 months. Supplementation of n-3 polyunsaturated fatty acid, a PPARα ligand, to HFD-treated animals restored hepatic adiponectin and PPARα expression, reduced TNF-α hepatic levels, and ameliorated fatty liver and the degree of liver injury. Thus, our model mimics the most common features of NASH in humans and provides an ideal tool to study the role of individual pathogenetic events (as for PPARα down-regulation) and to define any future experimental therapy, such as n-3 polyunsaturated fatty acid, which ameliorated the degree of liver injury. PMID:16936261

  16. Development of a Representative Mouse Model with Nonalcoholic Steatohepatitis.

    PubMed

    Verbeek, Jef; Jacobs, Ans; Spincemaille, Pieter; Cassiman, David

    2016-06-01

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the Western world. It represents a disease spectrum ranging from isolated steatosis to non-alcoholic steatohepatitis (NASH). In particular, NASH can evolve to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The development of novel treatment strategies is hampered by the lack of representative NASH mouse models. Here, we describe a NASH mouse model, which is based on feeding non-genetically manipulated C57BL6/J mice a 'Western style' high-fat/high-sucrose diet (HF-HSD). HF-HSD leads to early obesity, insulin resistance, and hypercholesterolemia. After 12 weeks of HF-HSD, all mice exhibit the complete spectrum of features of NASH, including steatosis, hepatocyte ballooning, and lobular inflammation, together with fibrosis in the majority of mice. Hence, this model closely mimics the human disease. Implementation of this mouse model will lead to a standardized setup for the evaluation of (i) underlying mechanisms that contribute to the progression of NAFLD to NASH, and (ii) therapeutic interventions for NASH. © 2016 by John Wiley & Sons, Inc.

  17. The Natural Course of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Calzadilla Bertot, Luis; Adams, Leon Anton

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from "bland steatosis" to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death. PMID:27213358

  18. [Non-alcoholic steatohepatitis - from NAFLD to MAFLD].

    PubMed

    Balmer, Maria Luisa; Dufour, Jean-François

    2011-04-01

    Non-alcoholic steatohepatitis (NASH) as one entity of non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and accompanies the rise in the prevalence of obesity, diabetes mellitus, hypertension and hyperlipidemia in the western world. It is not known why some patients progress in the disease and develop inflammation in the liver, whereas others remain in the stage of simple steatosis, which generally has a benign course. However, NASH can progress to fibrosis and cirrhosis as well as hepatocellular carcinoma. Therefore, it is important to determine the stage of the disease in patients presenting with the metabolic syndrome and abnormal liver function tests, suggesting NAFLD. Liver biopsy is the only tool that allows for reliable detection, grading and staging of liver disease. The main strategies in the treatment of NASH are correction of risk factors (lifestyle modifications, insuline sensitizer) and anti-oxidants (ursodeoxycholic acid, vitamin E) which both have been shown to improve liver histology as well as liver enzymes. Patients wih alcoholic fatty liver disease (AFLD) present the same liver histology and often also metabolic alterations similar to metabolic syndrome. Therefore, MAFLD (metabolic syndrome-associated fatty liver disease) might describe both patient populations more accurately and also describes the pathophysiological characteristics. PMID:21452138

  19. Non-alcoholic Fatty Liver Disease (NAFLD)--A Review.

    PubMed

    Karim, M F; Al-Mahtab, M; Rahman, S; Debnath, C R

    2015-10-01

    Non-alcoholic fatty liver disease (NAFLD) is an emerging problem in Hepatology clinics. It is closely related to the increased frequency of overweight or obesity. It has recognised association with metabolic syndrome. Central obesity, diabetes mellitus, dyslipidemia are commonest risk factors. Association with hepatitis C genotype 3 is also recognised. NAFLD is an important cause of cyptogenic cirrhosis of liver. It affects all populations and all age groups. Most patients with NAFLD are asymptomatic or vague upper abdominal pain. Liver function tests are mostly normal or mild elevation of aminotranferases. Histological features almost identical to those of alcohol-induced liver damage and can range from mild steatosis to cirrhosis. Two hit hypothesis is prevailing theory for the development of NAFLD. Diagnosis is usually made by imaging tools like ultrasonogram which reveal a bright liver while liver biopsy is gold standard for diagnosis as well as differentiating simple fatty liver and non-alcoholic steatohepatitis (NASH). Prognosis is variable. Simple hepatic steatosis generally has a benign long-term prognosis. However, one to two third of NASH progress to fibrosis or cirrhosis and may have a similar prognosis as cirrhosis from other liver diseases. Treatment is mostly control of underlying disorders and dietary advice, exercise, insulin sensitizers, antioxidants, or cytoprotective agents. The prevalence of NAFLD is increasing. So it needs more research to address this problem. PMID:26620035

  20. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease.

    PubMed

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-09-14

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as "fatty infiltration" or "nonalcoholic fatty pancreas disease" (NAFPD). The term "fatty replacement" describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of "ectopic fat deposition", which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula. PMID:27678349

  1. Bile acid receptors and nonalcoholic fatty liver disease

    PubMed Central

    Yuan, Liyun; Bambha, Kiran

    2015-01-01

    With the high prevalence of obesity, diabetes, and other features of the metabolic syndrome in United States, nonalcoholic fatty liver disease (NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis (NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor (TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH. PMID:26668692

  2. Non-alcoholic fatty liver disease: The diagnosis and management

    PubMed Central

    Abd El-Kader, Shehab M; El-Den Ashmawy, Eman M Salah

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease that occurs across all age groups and is recognized to occur in 14%-30% of the general population, representing a serious and growing clinical problem due to the growing prevalence of obesity and overweight. Histologically, it resembles alcoholic liver injury but occurs in patients who deny significant alcohol consumption. NAFLD encompasses a spectrum of conditions, ranging from benign hepatocellular steatosis to inflammatory nonalcoholic steatohepatitis, fibrosis, and cirrhosis. The majority of hepatocellular lipids are stored as triglycerides, but other lipid metabolites, such as free fatty acids, cholesterol, and phospholipids, may also be present and play a role in disease progression. NAFLD is associated with obesity and insulin resistance and is considered the hepatic manifestation of the metabolic syndrome, a combination of medical conditions including type 2 diabetes mellitus, hypertension, hyperlipidemia, and visceral adiposity. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies; however, staging the disease requires a liver biopsy. Current treatment relies on weight loss and exercise, although various insulin-sensitizing agents, antioxidants and medications appear promising. The aim of this review is to highlight the current information regarding epidemiology, diagnosis, and management of NAFLD as well as new information about pathogenesis, diagnosis and management of this disease. PMID:25937862

  3. Nonalcoholic fatty liver disease and aging: epidemiology to management.

    PubMed

    Bertolotti, Marco; Lonardo, Amedeo; Mussi, Chiara; Baldelli, Enrica; Pellegrini, Elisa; Ballestri, Stefano; Romagnoli, Dante; Loria, Paola

    2014-10-21

    Nonalcoholic fatty liver disease (NAFLD) is common in the elderly, in whom it carries a more substantial burden of hepatic (nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma) and extra-hepatic manifestations and complications (cardiovascular disease, extrahepatic neoplasms) than in younger age groups. Therefore, proper identification and management of this condition is a major task for clinical geriatricians and geriatric hepatologists. In this paper, the epidemiology and pathophysiology of this condition are reviewed, and a full discussion of the link between NAFLD and the aspects that are peculiar to elderly individuals is provided; these aspects include frailty, multimorbidity, polypharmacy and dementia. The proper treatment strategy will have to consider the peculiarities of geriatric patients, so a multidisciplinary approach is mandatory. Non-pharmacological treatment (diet and physical exercise) has to be tailored individually considering the physical limitations of most elderly people and the need for an adequate caloric supply. Similarly, the choice of drug treatment must carefully balance the benefits and risks in terms of adverse events and pharmacological interactions in the common context of both multiple health conditions and polypharmacy. In conclusion, further epidemiological and pathophysiological insight is warranted. More accurate understanding of the molecular mechanisms of geriatric NAFLD will help in identifying the most appropriate diagnostic and therapeutic approach for individual elderly patients. PMID:25339806

  4. Nonalcoholic fatty liver disease and aging: Epidemiology to management

    PubMed Central

    Bertolotti, Marco; Lonardo, Amedeo; Mussi, Chiara; Baldelli, Enrica; Pellegrini, Elisa; Ballestri, Stefano; Romagnoli, Dante; Loria, Paola

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is common in the elderly, in whom it carries a more substantial burden of hepatic (nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma) and extra-hepatic manifestations and complications (cardiovascular disease, extrahepatic neoplasms) than in younger age groups. Therefore, proper identification and management of this condition is a major task for clinical geriatricians and geriatric hepatologists. In this paper, the epidemiology and pathophysiology of this condition are reviewed, and a full discussion of the link between NAFLD and the aspects that are peculiar to elderly individuals is provided; these aspects include frailty, multimorbidity, polypharmacy and dementia. The proper treatment strategy will have to consider the peculiarities of geriatric patients, so a multidisciplinary approach is mandatory. Non-pharmacological treatment (diet and physical exercise) has to be tailored individually considering the physical limitations of most elderly people and the need for an adequate caloric supply. Similarly, the choice of drug treatment must carefully balance the benefits and risks in terms of adverse events and pharmacological interactions in the common context of both multiple health conditions and polypharmacy. In conclusion, further epidemiological and pathophysiological insight is warranted. More accurate understanding of the molecular mechanisms of geriatric NAFLD will help in identifying the most appropriate diagnostic and therapeutic approach for individual elderly patients. PMID:25339806

  5. Cost-Utility Analysis of Nonalcoholic Steatohepatitis Screening

    PubMed Central

    Zhang, Eric; Wartelle-Bladou, Claire; Lepanto, Luigi; Lachaine, Jean; Cloutier, Guy; Tang, An

    2016-01-01

    OBJECTIVES Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. No studies have examined the cost-effectiveness of screening for nonalcoholic steatohepatitis (NASH), its advanced form. METHODS We performed a cost-utility analysis of annual non-invasive screening strategies using third-party payer perspective in a general population and compared it to screening in a high-risk obese or diabetic population. Screening algorithms involved well-studied techniques including NAFLD fibrosis score, transient elastography (TE), and acoustic radiation force impulse (ARFI) imaging for detecting advanced fibrosis (≥ F3); and plasma cytokeratin (CK)-18 for NASH detection. Liver biopsy and magnetic resonance elastography (MRE) were compared as confirmation methods. Canadian dollar costs were adjusted for inflation and discounted at 5%. Incremental cost-effectiveness ratio (ICER) of ≤$C50,000 was considered cost-effective. RESULTS Compared with no screening, screening with NAFLD fibrosis score/TE/CK-18 algorithm with MRE as confirmation for advanced fibrosis had an ICER of $C26,143 per quality-adjusted life year (QALY) gained. Screening in high-risk obese or diabetic populations was more cost-effective, with an ICER of $C9,051 and $C7,991 per QALY gained respectively. Liver biopsy confirmation was not found to be cost-effective. CONCLUSIONS Our model suggests that annual NASH screening in high-risk obese or diabetic populations can be cost-effective. PMID:25994191

  6. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease

    PubMed Central

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-01-01

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as “fatty infiltration” or “nonalcoholic fatty pancreas disease” (NAFPD). The term “fatty replacement” describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of “ectopic fat deposition”, which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula.

  7. Glycolysis and the significance of lactate in traumatic brain injury.

    PubMed

    Carpenter, Keri L H; Jalloh, Ibrahim; Hutchinson, Peter J

    2015-01-01

    In traumatic brain injury (TBI) patients, elevation of the brain extracellular lactate concentration and the lactate/pyruvate ratio are well-recognized, and are associated statistically with unfavorable clinical outcome. Brain extracellular lactate was conventionally regarded as a waste product of glucose, when glucose is metabolized via glycolysis (Embden-Meyerhof-Parnas pathway) to pyruvate, followed by conversion to lactate by the action of lactate dehydrogenase, and export of lactate into the extracellular fluid. In TBI, glycolytic lactate is ascribed to hypoxia or mitochondrial dysfunction, although the precise nature of the latter is incompletely understood. Seemingly in contrast to lactate's association with unfavorable outcome is a growing body of evidence that lactate can be beneficial. The idea that the brain can utilize lactate by feeding into the tricarboxylic acid (TCA) cycle of neurons, first published two decades ago, has become known as the astrocyte-neuron lactate shuttle hypothesis. Direct evidence of brain utilization of lactate was first obtained 5 years ago in a cerebral microdialysis study in TBI patients, where administration of (13)C-labeled lactate via the microdialysis catheter and simultaneous collection of the emerging microdialysates, with (13)C NMR analysis, revealed (13)C labeling in glutamine consistent with lactate utilization via the TCA cycle. This suggests that where neurons are too damaged to utilize the lactate produced from glucose by astrocytes, i.e., uncoupling of neuronal and glial metabolism, high extracellular levels of lactate would accumulate, explaining the association between high lactate and poor outcome. Recently, an intravenous exogenous lactate supplementation study in TBI patients revealed evidence for a beneficial effect judged by surrogate endpoints. Here we review the current state of knowledge about glycolysis and lactate in TBI, how it can be measured in patients, and whether it can be modulated to achieve

  8. Kinetics of lactate transport into rat liver in vivo

    SciTech Connect

    Lupo, M.A.; Cefalu, W.T.; Pardridge, W.M.

    1990-04-01

    Lactate clearance by liver plays an important role in lactate homeostasis and in the development of lactic acidosis. The role of lactate delivery to liver as a limiting factor in hepatic uptake of lactate is unclear. Lactate delivery of mechanisms could be important if rates of lactate transport approximate rates of lactate metabolism by liver. The rates of lactate transport into liver have been determined in vitro with isolated liver cells and the results have been conflicting. Therefore, the present studies measure the rate of transport of (14C)-L-lactate, and its poorly metabolizeable stereoisomer, (14C)-D-lactate, into rat liver in vivo using a portal vein injection technique. The transport of (3H)-water and of (14C)-sucrose, an extracellular reference compound, were also studied. Portal blood flow was determined from the kinetics of (3H)-water efflux in liver and was 1.93 +/- 0.22 mL/min/g. The volumes of distribution of (14C)-L-lactate, and (14C)-sucrose were 1.31 +/- 0.22, 0.71 +/- 0.07, and 0.22 +/- 0.07 mL/g, respectively. The extraction of unidirectional influx of (14C)-L-lactate and (14C)-D-lactate by rat liver was 93% +/- 10% and 91% +/- 9%, respectively. The rate of lactate transport into rat liver in vivo, 1.8 mumols.min-1.g-1, is approximately twofold greater than the rate of lactate metabolism by rat liver reported in the literature. Therefore, lactate uptake by liver may not be limited by transport under normal conditions. However, conditions such as decreased portal blood flow, which slow lactate delivery to liver by 50% or more, could cause lactate uptake by liver to be limited by transport of circulating lactate.

  9. Gut-liver axis and probiotics: Their role in non-alcoholic fatty liver disease

    PubMed Central

    Paolella, Giulia; Mandato, Claudia; Pierri, Luca; Poeta, Marco; Di Stasi, Martina; Vajro, Pietro

    2014-01-01

    The incidence of obesity and its related conditions, including non-alcoholic fatty liver disease (NAFLD), has dramatically increased in all age groups worldwide. Given the health consequences of these conditions, and the subsequent economic burden on healthcare systems, their prevention and treatment have become major priorities. Because standard dietary and lifestyle changes and pathogenically-oriented therapies (e.g., antioxidants, oral hypoglycemic agents, and lipid-lowering agents) often fail due to poor compliance and/or lack of efficacy, novel approaches directed toward other pathomechanisms are needed. Here we present several lines of evidence indicating that, by increasing energy extraction in some dysbiosis conditions or small intestinal bacterial overgrowth, specific gut microbiota and/or a “low bacterial richness” may play a role in obesity, metabolic syndrome, and fatty liver. Under conditions involving a damaged intestinal barrier (“leaky gut”), the gut-liver axis may enhance the natural interactions between intestinal bacteria/bacterial products and hepatic receptors (e.g., toll-like receptors), thus promoting the following cascade of events: oxidative stress, insulin-resistance, hepatic inflammation, and fibrosis. We also discuss the possible modulation of gut microbiota by probiotics, as attempted in NAFLD animal model studies and in several pilot pediatric and adult human studies. Globally, this approach appears to be a promising and innovative add-on therapeutic tool for NAFLD in the context of multi-target therapy. PMID:25400436

  10. Recent advances in mouse models of obesity- and nonalcoholic steatohepatitis-associated hepatocarcinogenesis

    PubMed Central

    Nakagawa, Hayato

    2015-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer, and obesity has been established as a risk factor for HCC development. Nonalcoholic steatohepatitis (NASH) is apparently the key link between obesity and hepatocarcinogenesis, and obesity also accelerates HCC development synergistically with other risk factors, such as hepatitis virus infection and alcohol consumption. As an explanation for the pathogenesis of NASH, the so-called “two-hit” theory has been widely accepted, but recently, a better model, the so-called “multiple-hits hypothesis” was proposed, which states that many disease-promoting factors may occur in parallel, rather than consecutively. However, the overall mechanism remains largely unknown. Various cell-cell and organ-organ interactions are involved in the pathogenesis of NASH, and thus appropriate in vivo disease models are essential for a deeper understanding. However, replicating the full spectrum of human NASH has been difficult, as NASH involves obesity, insulin resistance, steatohepatitis, fibrosis, and ultimately HCC, and the lack of an appropriate mouse model has been a considerable barrier to determining the missing links among obesity, NASH, and HCC. In recent years, several innovative mouse models presenting obesity- and NASH-associated HCC have been established by modified diets, chemotoxic agents, genetic manipulation, or a combination of these factors, shedding some light on this complex network and providing new therapeutic strategies. Thus, in this paper, I review the mouse models of obesity- and NASH-associated HCC, especially focusing on recent advances and their clinical relevance. PMID:26301053

  11. Gut-liver axis and probiotics: their role in non-alcoholic fatty liver disease.

    PubMed

    Paolella, Giulia; Mandato, Claudia; Pierri, Luca; Poeta, Marco; Di Stasi, Martina; Vajro, Pietro

    2014-11-14

    The incidence of obesity and its related conditions, including non-alcoholic fatty liver disease (NAFLD), has dramatically increased in all age groups worldwide. Given the health consequences of these conditions, and the subsequent economic burden on healthcare systems, their prevention and treatment have become major priorities. Because standard dietary and lifestyle changes and pathogenically-oriented therapies (e.g., antioxidants, oral hypoglycemic agents, and lipid-lowering agents) often fail due to poor compliance and/or lack of efficacy, novel approaches directed toward other pathomechanisms are needed. Here we present several lines of evidence indicating that, by increasing energy extraction in some dysbiosis conditions or small intestinal bacterial overgrowth, specific gut microbiota and/or a "low bacterial richness" may play a role in obesity, metabolic syndrome, and fatty liver. Under conditions involving a damaged intestinal barrier ("leaky gut"), the gut-liver axis may enhance the natural interactions between intestinal bacteria/bacterial products and hepatic receptors (e.g., toll-like receptors), thus promoting the following cascade of events: oxidative stress, insulin-resistance, hepatic inflammation, and fibrosis. We also discuss the possible modulation of gut microbiota by probiotics, as attempted in NAFLD animal model studies and in several pilot pediatric and adult human studies. Globally, this approach appears to be a promising and innovative add-on therapeutic tool for NAFLD in the context of multi-target therapy. PMID:25400436

  12. Insulin resistance in development and progression of nonalcoholic fatty liver disease

    PubMed Central

    Alam, Shahinul; Mustafa, Golam; Alam, Mahabubul; Ahmad, Nooruddin

    2016-01-01

    Although insulin resistance (IR) is strongly associated with nonalcoholic fatty liver disease (NAFLD), the association of IR and NAFLD is not universal and correlation between IR and severity of NAFLD is still controversial. In this review, we summarize recent evidence that partially dissociates insulin resistance from NAFLD. It has also been reported that single-nucleotide polymorphisms in the diacylglycerol acyltransferase gene, rather than IR, account for the variability in liver fat content. Polymorphisms of the patatin-like phospholipase 3 gene have also been reported to be associated with NAFLD without metabolic syndrome, which suggests that genetic conditions that promote the development of fatty changes in the liver may occur independently of IR. Moreover, environmental factors such as nutrition and physical activity as well as small intestinal bacterial overgrowth have been linked to the pathogenesis of NAFLD, although some of the data are conflicting. Therefore, findings from both genetically engineered animal models and humans with genetic conditions, as well as recent studies that have explored the role of environmental factors, have confirmed the view that NAFLD is a polygenic disease process caused by both genetic and environmental factors. Therefore, IR is not the sole predictor of the pathogenesis of NAFLD. PMID:27190693

  13. 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

  14. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism.

    PubMed

    Lauritzen, Knut H; Morland, Cecilie; Puchades, Maja; Holm-Hansen, Signe; Hagelin, Else Marie; Lauritzen, Fredrik; Attramadal, Håvard; Storm-Mathisen, Jon; Gjedde, Albert; Bergersen, Linda H

    2014-10-01

    The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiological concentrations of lactate and by the specific GPR81 agonist 3,5-dihydroxybenzoate to reduce cAMP. Cerebral GPR81 is concentrated on the synaptic membranes of excitatory synapses, with a postsynaptic predominance. GPR81 is also enriched at the blood-brain-barrier: the GPR81 densities at endothelial cell membranes are about twice the GPR81 density at membranes of perivascular astrocytic processes, but about one-seventh of that on synaptic membranes. There is only a slight signal in perisynaptic processes of astrocytes. In synaptic spines, as well as in adipocytes, GPR81 immunoreactivity is located on subplasmalemmal vesicular organelles, suggesting trafficking of the protein to and from the plasma membrane. The results indicate roles of lactate in brain signaling, including a neuronal glucose and glycogen saving response to the supply of lactate. We propose that lactate, through activation of GPR81 receptors, can act as a volume transmitter that links neuronal activity, cerebral energy metabolism and energy substrate availability.

  15. [Retinal and carotid changes in non-alcoholic fatty liver disease].

    PubMed

    Baloşeanu, Cristina; Rogoveanu, I; Mocanu, Carmen

    2013-01-01

    This article presents the results of a study on 85 patients with non-alcoholic fatty liver disease (NAFLD). We evaluate the retinal vascular changes using retinal photography and carotid vascular changes, by ultrasounds, occured in this group of patients.

  16. Marital Interaction in Alcoholic and Nonalcoholic Couples: Alcoholic Subtype Variations and Wives’ Alcoholism Status

    PubMed Central

    Floyd, Frank J.; Daugherty, Michelle Klotz; Fitzgerald, Hiram H.; Cranford, James A.; Zucker, Robert A.

    2008-01-01

    The authors examined problem-solving marital interactions of alcoholic and nonalcoholic couples (N = 132). Four alcoholic groups (husband alcoholic with antisocial personality disorder or not, paired with alcoholic or nonalcoholic wives) were compared with each other and with a both-spouses-nonalcoholic group. Consistent with the alcoholic subtypes hypothesis, couples with an antisocial alcoholic husband had higher levels of hostile behavior regardless of wives’ alcoholism status. In contrast, rates of positive behaviors and the ratio of positive to negative behaviors were greatest among couples in which either both or neither of the spouses had alcoholic diagnoses and were lowest among alcoholic husbands with nonalcoholic wives. Discussion focuses on possible mechanisms linking antisocial alcoholism and discrepant alcoholic diagnoses to poorer marital outcomes. PMID:16492103

  17. The genetic epidemiology of nonalcoholic fatty liver disease: toward a personalized medicine.

    PubMed

    Sookoian, Silvia; Pirola, Carlos J

    2012-08-01

    The understanding of the genetic bases of complex diseases such as nonalcoholic fatty liver disease opens new opportunities and challenges. This article explores new tools designed toward moving genomic data into clinical medicine, providing putative answers to more practical questions.

  18. Conversion of oral glucose to lactate in dogs. Primary site and relative contribution to blood lactate

    SciTech Connect

    Youn, J.H.; Bergman, R.N. )

    1991-06-01

    The authors evaluated the relative contribution of oral glucose to arterial lactate and the relative role of the splanchnic bed in converting glucose to lactate in dogs. After an oral glucose load (1.2 g/kg) spiked with (U-14C)glucose (16.9 muCi/kg; protocol 1, n = 7), arterial blood lactate increased from 0.43 {plus minus} 0.03 mM at basal to a peak of 1.04 {plus minus} 0.07 mM at 45 min and then slowly decreased to 0.47 {plus minus} 0.07 mM at 240 min. Arterial blood {sup 14}Clactate peaked at 60 min and then decreased to {approximately} 35% of the peak at 4 h. When arterial blood lactate peaked at 45 min, the proportion of arterial lactate that was derived from oral glucose was 34 {plus minus} 3%. The integrated area under the curve of lactate derived from exogenous glucose was 40 {plus minus} 2% of that of total lactate. The splanchnic bed released lactate and {sup 14}Clactate during the initial 2 h after oral {sup 14}Cglucose. Thus, the splanchnic bed apparently contributed to the conversion of exogenous glucose to lactate. In the matched experiments (protocol 2, n = 5), dogs were given the same amount of oral glucose but no {sup 14}Cglucose, and (U-14C)lactate was infused into the right atrium to match the splanchnic {sup 14}Clactate release from the first experiment. Despite a well-matched splanchnic {sup 14}Clactate contribution, arterial concentrations of {sup 14}Clactate were markedly lower in protocol 2 compared with protocol 1. The integrated area under the {sup 14}Clactate profile in protocol 2 was only 11 {plus minus} 1% of that in protocol 1. These results indicate that the splanchnic bed is responsible for only 11% of arterial blood lactate that was derived from oral glucose. They concluded that (1) after oral glucose loading, a major portion of circulating lactate has its origin not in exogenous glucose but in endogenous sources, and (2) the splanchnic bed is not the major site of oral glucose conversion to lactate after glucose ingestion.

  19. Systematic review of genetic association studies involving histologically confirmed non-alcoholic fatty liver disease

    PubMed Central

    Wood, Kayleigh L; Miller, Michael H; Dillon, John F

    2015-01-01

    Non-alcoholic fatty liver disease has an increasing prevalence in Western countries, affecting up to 20% of the population. Objective The aim of this project was to systematically review and summarise the genetic association studies that investigate possible genetic influences that confer susceptibility to non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Design The MEDLINE and SCOPUS databases were searched to identify candidate gene studies on histologically diagnosed non-alcoholic fatty liver disease. Results A total of 85 articles have been summarised and categorised on the basis of the general pathway each candidate gene is involved in, including lipid metabolism, lipoprotein processing, cholesterol synthesis, glucose homoeostasis, inflammatory response, protection against oxidative stress and whole body metabolism. Conclusions The main findings demonstrate a small but consistent association of PNPLA3 with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Genetic association studies have investigated general disease susceptibility, histological characteristics, severity and progression. However, further study is required to better elucidate the genetic factors influencing fatty liver disease. PMID:26462272

  20. Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research

    PubMed Central

    Willebrords, Joost; Pereira, Isabel Veloso Alves; Maes, Michaël; Yanguas, Sara Crespo; Colle, Isabelle; Van Den Bossche, Bert; Da silva, Tereza Cristina; Oliveira, Cláudia P; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Cogliati, Bruno; Vinken, Mathieu

    2015-01-01

    Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and ‘-omics’-based read-outs are still in their infancy, but show great promise. . In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed. PMID:26073454

  1. The Effectiveness of Lactation Consultants and Lactation Counselors on Breastfeeding Outcomes.

    PubMed

    Patel, Sanjay; Patel, Shveta

    2016-08-01

    Breastfeeding for all infants starting at birth and continuing until at least 6 months of age has been recommended by the World Health Organization and the American Academy of Pediatrics. The health benefits to infants and mothers have been demonstrated in many studies. Dedicated lactation specialists may play a role in providing education and support to pregnant women and new mothers wishing to breastfeed to improve breastfeeding outcomes. The objective of this review was to assess if lactation education or support programs using lactation consultants or lactation counselors would improve rates of initiation and duration of any breastfeeding and exclusive breastfeeding compared with usual practice. A systematic literature review of the evidence was conducted using electronic databases. The review was limited to randomized trials and yielded 16 studies with 5084 participants. It was found that breastfeeding interventions using lactation consultants and counselors increase the number of women initiating breastfeeding (odds ratio [OR] for any initiation vs not initiating breastfeeding = 1.35; 95% confidence interval [CI], 1.10-1.67). The interventions improve any breastfeeding rates (OR for any breastfeeding up to 1 month vs not breastfeeding = 1.49; 95% CI, 1.09-2.04). In addition, there were beneficial effects on exclusive breastfeeding rates (OR for exclusive breastfeeding up to 1 month vs not exclusive breastfeeding = 1.71; 95% CI, 1.20-2.44). Most of the evidence would suggest developing and improving postpartum support programs incorporating lactation consultants and lactation counselors.

  2. Metabolic Imaging: A link between Lactate Dehydrogenase A, Lactate and Tumor Phenotype

    PubMed Central

    Thakur, Sunitha B.; Vider, Jelena; Russell, James; Blasberg, Ronald; Koutcher, Jason A.

    2014-01-01

    Purpose We compared the metabolic profiles and the association between LDH-A expression and lactate production in two isogenic murine breast cancer cell lines and tumors (67NR and 4T1). These cell lines were derived from a single mammary tumor and have different growth and metabolic phenotypes. Experimental Design LDH-A expression, lactate concentration, glucose utilization and oxygen consumption were measured in cells, and the potential relationship between tumor lactate levels (measured by magnetic resonance spectroscopic imaging (MRSI)) and tumor glucose utilization (measured by [18F] 2-deoxy-2-fluoro-D-glucose positron emission tomography ([18F]FDG-PET)) was assessed in orthotopic breast tumors derived from these cell lines. Results We show a substantial difference in LDH-A expression between 67NR and 4T1 cells under normoxia and hypoxia. We also show that small orthotopic 4T1 tumors generate tenfold more lactate than corresponding 67NR tumors. The high lactate levels in small primary 4T1 tumors are associated with intense pimonidazole staining (a hypoxia indicator). Less intense hypoxia staining was observed in the larger 67NR tumors, and is consistent with the gradual increase and plateau of lactate concentration in enlarging 67NR tumors. Conclusions Lactate-MRSI has a greater dynamic range than [18F]FDG-PET and may be a more sensitive measure with which to evaluate the aggressive and metastatic potential of primary breast tumors. PMID:21844011

  3. The Effectiveness of Lactation Consultants and Lactation Counselors on Breastfeeding Outcomes.

    PubMed

    Patel, Sanjay; Patel, Shveta

    2016-08-01

    Breastfeeding for all infants starting at birth and continuing until at least 6 months of age has been recommended by the World Health Organization and the American Academy of Pediatrics. The health benefits to infants and mothers have been demonstrated in many studies. Dedicated lactation specialists may play a role in providing education and support to pregnant women and new mothers wishing to breastfeed to improve breastfeeding outcomes. The objective of this review was to assess if lactation education or support programs using lactation consultants or lactation counselors would improve rates of initiation and duration of any breastfeeding and exclusive breastfeeding compared with usual practice. A systematic literature review of the evidence was conducted using electronic databases. The review was limited to randomized trials and yielded 16 studies with 5084 participants. It was found that breastfeeding interventions using lactation consultants and counselors increase the number of women initiating breastfeeding (odds ratio [OR] for any initiation vs not initiating breastfeeding = 1.35; 95% confidence interval [CI], 1.10-1.67). The interventions improve any breastfeeding rates (OR for any breastfeeding up to 1 month vs not breastfeeding = 1.49; 95% CI, 1.09-2.04). In addition, there were beneficial effects on exclusive breastfeeding rates (OR for exclusive breastfeeding up to 1 month vs not exclusive breastfeeding = 1.71; 95% CI, 1.20-2.44). Most of the evidence would suggest developing and improving postpartum support programs incorporating lactation consultants and lactation counselors. PMID:26644419

  4. Diet for a Healthy Lactating Woman.

    PubMed

    Kolasa, Kathryn M; Firnhaber, Gina; Haven, Kelley

    2015-12-01

    The nutrient and caloric requirements for lactation are set by the Institute of Medicine. The dietary pattern to meet those needs is found in the Dietary Guidelines for Americans. Only deficiency states for selected nutrients and/or prolonged inadequate caloric intake appear to affect the volume and quality of breast milk. Other dietary concerns of lactating women include "dieting" to return to prepregnancy weight; low maternal intake of selected nutrients due to health conditions or food choices; need for supplementation of calcium, vitamin D, and fatty acids; and use of non-nutritive sweeteners, caffeine, herbal supplements, and alcohol. PMID:26398295

  5. Non-alcoholic Fatty Liver Disease: East Versus West

    PubMed Central

    Agrawal, Swastik; Duseja, Ajay K

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease worldwide with prevalence ranging from 10% to 30% in various countries. It has become an important cause of unexplained rise in transaminases, cryptogenic cirrhosis, and cryptogenic hepatocellular carcinoma. Pathogenesis is related to obesity, insulin resistance, oxidative stress, lipotoxicity, and resultant inflammation in the liver progressing to fibrosis. Pharmacological treatment in patients with NAFLD is still evolving and the treatment of these patients rests upon lifestyle modification with diet and exercise being the cornerstones of therapy. While there are many similarities between patients with NAFLD from Asia and the West, there are certain features which make the patients with NAFLD from Asia stand apart. This review highlights the data on NAFLD from Asia comparing it with the data from the West. PMID:25755421

  6. Nutrition and Physical Activity in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Oliveira, Claudia P.; de Lima Sanches, Priscila; de Abreu-Silva, Erlon Oliveira; Marcadenti, Aline

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and it is associated with other medical conditions such as diabetes mellitus, metabolic syndrome, and obesity. The mechanisms of the underlying disease development and progression are not completely established and there is no consensus concerning the pharmacological treatment. In the gold standard treatment for NAFLD weight loss, dietary therapy, and physical activity are included. However, little scientific evidence is available on diet and/or physical activity and NAFLD specifically. Many dietary approaches such as Mediterranean and DASH diet are used for treatment of other cardiometabolic risk factors such as insulin resistance and type-2 diabetes mellitus (T2DM), but on the basis of its components their role in NAFLD has been discussed. In this review, the implications of current dietary and exercise approaches, including Brazilian and other guidelines, are discussed, with a focus on determining the optimal nonpharmacological treatment to prescribe for NAFLD. PMID:26770987

  7. Current complications and challenges in nonalcoholic steatohepatitis screening and diagnosis.

    PubMed

    Golabi, Pegah; Sayiner, Mehmet; Fazel, Yousef; Koenig, Aaron; Henry, Linda; Younossi, Zobair M

    2016-01-01

    Nonalcoholic steatohepatitis (NASH) can lead to complications such as liver failure, cirrhosis and hepatocellular carcinoma. The diagnostic gold standard for NASH is liver biopsy; however, other noninvasive methods have been developed. In this article, the authors evaluate current methods in NASH screening and diagnosis. Routine radiologic modalities were found to detect hepatic steatosis accurately, but were unable to establish the diagnosis of NASH or stage of fibrosis. Newly developed elastography based techniques seem promising to estimate liver fibrosis. Other noninvasive tests such as FibroTest, ELF, Hepascore, FIB-4, NFS, FLI and ION (biochemical panels) have AUROCs ranging between 0.80-0.98 for detecting advanced fibrosis but lack specificity for detecting mild fibrosis. Noninvasive tools, especially elastography, identify NASH associated advanced fibrosis potentially reducing liver biopsies. More research is needed to validate the clinical utility of these tests.

  8. [Research advances in pediatric nonalcoholic fatty liver disease].

    PubMed

    Dai, Dong-Ling

    2015-01-01

    In recent years, nonalcoholic fatty liver disease (NAFLD) has increased because of the growing prevalence of obesity and overweight in the pediatric population. It has become the most common form of chronic liver diseases in children and the related research on NAFLD is expanded. The "two-hit" and "multiple hit" hypothesis have been widely accepted, and some research has shown that genetic, diet structure and environmental factors appear to play a crucial role in the development of pediatric NAFLD. Though it is expected by researchers, there is not an available satisfactory noninvasive marker for the diagnosis of this disease. Fortunately, some new non-invasive prediction scores for pediatric NAFLD have been developed. There is currently no established special therapy, and lifestyle intervention should be adequate for most cases of NAFLD in children. This article reviews the advances in the current knowledge and ideas concerning pediatric NAFLD, and discusses the diagnosis, perspective therapies and scoring methods for this disease.

  9. Carotenoids and non-alcoholic fatty liver disease

    PubMed Central

    Yilmaz, Bahiddin; Sahin, Kazim; Bilen, Hande; Bahcecioglu, Ibrahim H.; Bilir, Birdal; Ashraf, Sara; Halazun, Karim J.

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a growing health problem around the world, especially in developed countries. NAFLD includes all cases of fatty liver disease from simple steatosis to cirrhosis, without excessive alcohol intake, use of steatogenic medication or hereditary disorders. Pathogenesis is associated with dietary high fat intake, decreased free fatty acid (FFA) oxidation, increased hepatic lipogenesis and lipolysis from the adipose tissue. These metabolic alterations contribute to the hepatic fat accumulation. Consequently, stimulated oxidative stress and inflammation play a major role in hepatocellular damage. Therefore, antioxidant and anti-inflammatory agents may have a role in the prevention of this disease. Carotenoids are potent antioxidant and anti-inflammatory micronutrients, which have been investigated in the prevention and treatment of NAFLD. The main sources of the carotenoids are fruits and vegetables. In this article we review the potential role and possible molecular mechanism of carotenoids in NAFLD. PMID:26151056

  10. Glycosyltransferases and non-alcoholic fatty liver disease

    PubMed Central

    Zhan, Yu-Tao; Su, Hai-Ying; An, Wei

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and its incidence is increasing worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. Glycosyltransferases (GTs) are a diverse class of enzymes involved in catalyzing the transfer of one or multiple sugar residues to a wide range of acceptor molecules. GTs mediate a wide range of functions from structure and storage to signaling, and play a key role in many fundamental biological processes. Therefore, it is anticipated that GTs have a role in the pathogenesis of NAFLD. In this article, we present an overview of the basic information on NAFLD, particularly GTs and glycosylation modification of certain molecules and their association with NAFLD pathogenesis. In addition, the effects and mechanisms of some GTs in the development of NAFLD are summarized. PMID:26937136

  11. Serum proteomics for biomarker discovery in nonalcoholic fatty liver disease.

    PubMed

    Yilmaz, Yusuf

    2012-08-16

    Proteomic platforms have gained increasing attention in the clinical spectrum of nonalcoholic fatty liver disease (NAFLD). This approach allows for the unbiased discovery of circulating biochemical markers, i.e., it is not limited to known molecules of presumed importance. This manuscript provides an overview of proteomic serum biomarker discovery in NAFLD. Hemoglobin is currently the most widely replicated proteomic circulating biomarker of NAFLD; it was identified as a biomarker of fatty liver in two distinct proteomic studies and subsequently validated using distinct analytical methods by independent research groups in large replication cohorts. Given the increasing availability of numerous serum samples and the refinement of the technological platforms available to scrutinize the blood proteome, large collaborative studies between academia and industry are warmly encouraged to identify novel, unbiased circulating biomarkers of NAFLD.

  12. Non-alcoholic Fatty Liver Disease: East Versus West.

    PubMed

    Agrawal, Swastik; Duseja, Ajay K

    2012-06-01

    Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease worldwide with prevalence ranging from 10% to 30% in various countries. It has become an important cause of unexplained rise in transaminases, cryptogenic cirrhosis, and cryptogenic hepatocellular carcinoma. Pathogenesis is related to obesity, insulin resistance, oxidative stress, lipotoxicity, and resultant inflammation in the liver progressing to fibrosis. Pharmacological treatment in patients with NAFLD is still evolving and the treatment of these patients rests upon lifestyle modification with diet and exercise being the cornerstones of therapy. While there are many similarities between patients with NAFLD from Asia and the West, there are certain features which make the patients with NAFLD from Asia stand apart. This review highlights the data on NAFLD from Asia comparing it with the data from the West. PMID:25755421

  13. NASH (Nonalcoholic steatohepatitis): A case of multiorganelle failure.

    PubMed

    Caldwell, Stephen

    2014-10-01

    The clinical term 'multiorgan failure' lends itself, modified to 'multiorganelle failure', to the cascading events in cellular systems leading to hepatocyte injury, cell death, inflammation and fibrosis and ultimately to cirrhosis in NASH (non-alcoholic steatohepatitis). NASH is one of the most common forms of liver disease and constitutes the severe form of NAFLD (non-alcoholic fatty liver disease). The key features that distinguish potentially progressive NASH from relatively stable non-NASH fatty liver (NNFL, often referred to as simple steatosis) are cellular ballooning, inflammation and fibrosis. These findings, together with steatosis or accumulation of greater than normal hepatic lipid, usually constitute histological NASH seen on liver biopsy or in laboratory samples. Cellular ballooning is not specific to NASH but it is perhaps the most emblematic finding on histological samples. The ballooned hepatocyte has evidence of cytoskeletal injury (depletion and condensation as Mallory-Denk bodies), accumulation of partially oxidized small fat droplets, mitochondrial morphological changes presumably related to organelle dysfunction, dilated endoplasmic reticulum and autophagosomes - an attempt at cellular repair. Ballooning itself likely results from a combination of cytoskeletal injury resulting in loss of normal cell shape and from accumulation of injured and somewhat derelict small fat droplets and dilated endoplasmic reticulum. Cellular injury in NASH and especially cellular ballooning can be viewed as a process of 'multi-organelle failure' beginning with generation of super oxide and failure to contain the subsequent oxidative injury and by-products in an environment rich in lipid fuel. These events lead to activation of imunologic pathways. Dysfunction of the small fat droplet appears to be a central mechanism and the oxidative injury can be viewed as the process of rancidification - the chemical decomposition of oils, lipids and fats. PMID:26461413

  14. Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability

    PubMed Central

    Luther, Jay; Garber, John J.; Khalili, Hamed; Dave, Maneesh; Bale, Shyam Sundhar; Jindal, Rohit; Motola, Daniel L.; Luther, Sanjana; Bohr, Stefan; Jeoung, Soung Won; Deshpande, Vikram; Singh, Gurminder; Turner, Jerrold R.; Yarmush, Martin L.; Chung, Raymond T.; Patel, Suraj J.

    2015-01-01

    BACKGROUND & AIMS Emerging data suggest that changes in intestinal permeability and increased gut microbial translocation contribute to the inflammatory pathway involved in nonalcoholic steatohepatitis (NASH) development. Numerous studies have investigated the association between increased intestinal permeability and NASH. Our meta-analysis of this association investigates the underlying mechanism. METHODS A meta-analysis was performed to compare the rates of increased intestinal permeability in patients with NASH and healthy controls. To further address the underlying mechanism of action, we studied changes in intestinal permeability in a diet-induced (methionine-and-choline-deficient; MCD) murine model of NASH. In vitro studies were also performed to investigate the effect of MCD culture medium at the cellular level on hepatocytes, Kupffer cells, and intestinal epithelial cells. RESULTS Nonalcoholic fatty liver disease (NAFLD) patients, and in particular those with NASH, are more likely to have increased intestinal permeability compared with healthy controls. We correlate this clinical observation with in vivo data showing mice fed an MCD diet develop intestinal permeability changes after an initial phase of liver injury and tumor necrosis factor-α (TNFα) induction. In vitro studies reveal that MCD medium induces hepatic injury and TNFα production yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFα in altering intestinal permeability, we found that mice genetically resistant to TNFα-myosin light chain kinase (MLCK)–induced intestinal permeability changes fed an MCD diet still develop increased permeability and liver injury. CONCLUSIONS Our clinical and experimental results strengthen the association between intestinal permeability increases and NASH and also suggest that an early phase of hepatic injury and inflammation contributes to altered intestinal permeability in a fashion independent of TNF

  15. Differential Intrahepatic Phospholipid Zonation in Simple Steatosis and Nonalcoholic Steatohepatitis

    PubMed Central

    Wattacheril, Julia; Seeley, Erin H.; Angel, Peggi; Chen, Heidi; Bowen, Benjamin P.; Lanciault, Christian; M.Caprioli, Richard; Abumrad, Naji; Flynn, Charles Robb

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) occurs frequently in a setting of obesity, dyslipidemia and insulin resistance, but the etiology of the disease, particularly the events favoring progression to nonalcoholic steatohepatitis (NASH) as opposed to simple steatosis (SS), are not fully understood. Based on known zonation patterns in protein, glucose and lipid metabolism, coupled with evidence that phosphatidylcholine may play a role in NASH pathogenesis, we hypothesized that phospholipid zonation exists in liver and that specific phospholipid abundance and distribution may be associated with histologic disease. A survey of normal hepatic protein expression profiles in the Human Protein Atlas revealed pronounced zonation of enzymes involved in lipid utilization and storage, particularly those facilitating phosphatidylcholine (PC) metabolism. Immunohistochemistry of obese normal, SS and NASH liver specimens with anti-phosphatidylethanomine N-methyltransferase (PEMT) antibodies showed a progressive decrease in the zonal distribution of this PC biosynthetic enzyme. Phospholipid quantitation by liquid chromatography mass spectrometry (LC-MS) in hepatic extracts of Class III obese patients with increasing NAFLD severity revealed that most PC species with 32, 34 and 36 carbons as well as total PC abundance was decreased with SS and NASH. Matrix assisted laser desorption ionization - imaging mass spectrometry (MALDI-IMS) imaging revealed strong zonal distributions for 32, 34 and 36 carbon PCs in controls (minimal histologic findings) and SS that was lost in NASH specimens. Specific lipid species such as PC 34∶1 and PC 36∶2 best illustrated this phenomenon. These findings suggest that phospholipid zonation may be associated with the presence of an intrahepatic proinflammatory phenotype and thus have broad implications in the etiopathogenesis of NASH. PMID:23451176

  16. Expression of fatty acid synthase in nonalcoholic fatty liver disease.

    PubMed

    Dorn, Christoph; Riener, Marc-Oliver; Kirovski, Georgi; Saugspier, Michael; Steib, Kathrin; Weiss, Thomas S; Gäbele, Erwin; Kristiansen, Glen; Hartmann, Arndt; Hellerbrand, Claus

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which starts with simple hepatic steatosis and may progress toward inflammation (nonalcoholic steatohepatitis [NASH]). Fatty acid synthase (FASN) catalyzes the last step in fatty acid biosynthesis, and thus, it is believed to be a major determinant of the maximal hepatic capacity to generate fatty acids by de novo lipogenesis. The aim of this study was to analyze the correlation between hepatic steatosis and inflammation with FASN expression. In vitro incubation of primary human hepatocytes with fatty acids dose-dependently induced cellular lipid-accumulation and FASN expression, while stimulation with TNF did not affect FASN levels. Further, hepatic FASN expression was significantly increased in vivo in a murine model of hepatic steatosis without significant inflammation but not in a murine NASH model as compared to control mice. Also, FASN expression was not increased in mice subjected to bile duct ligation, an experimental model characterized by severe hepatocellular damage and inflammation. Furthermore, FASN expression was analyzed in 102 human control or NAFLD livers applying tissue micro array technology and immunohistochemistry, and correlated significantly with the degree of hepatic steatosis, but not with inflammation or ballooning of hepatocytes. Quantification of FASN mRNA expression in human liver samples confirmed significantly higher FASN levels in hepatic steatosis but not in NASH, and expression of SREBP1, which is the main transcriptional regulator of FASN, paralleled FASN expression levels in human and experimental NAFLD. In conclusion, the transcriptional induction of FASN expression in hepatic steatosis is impaired in NASH, while hepatic inflammation in the absence of steatosis does not affect FASN expression, suggesting that FASN may serve as a new diagnostic marker or therapeutic target for the progression of NAFLD. PMID:20606731

  17. Molecular pathways in non-alcoholic fatty liver disease

    PubMed Central

    Berlanga, Alba; Guiu-Jurado, Esther; Porras, José Antonio; Auguet, Teresa

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological change characterized by the accumulation of triglycerides in hepatocytes and has frequently been associated with obesity, type 2 diabetes mellitus, hyperlipidemia, and insulin resistance. It is an increasingly recognized condition that has become the most common liver disorder in developed countries, affecting over one-third of the population and is associated with increased cardiovascular- and liver-related mortality. NAFLD is a spectrum of disorders, beginning as simple steatosis. In about 15% of all NAFLD cases, simple steatosis can evolve into non-alcoholic steatohepatitis, a medley of inflammation, hepatocellular injury, and fibrosis, often resulting in cirrhosis and even hepatocellular cancer. However, the molecular mechanism underlying NAFLD progression is not completely understood. Its pathogenesis has often been interpreted by the “double-hit” hypothesis. The primary insult or the “first hit” includes lipid accumulation in the liver, followed by a “second hit” in which proinflammatory mediators induce inflammation, hepatocellular injury, and fibrosis. Nowadays, a more complex model suggests that fatty acids (FAs) and their metabolites may be the true lipotoxic agents that contribute to NAFLD progression; a multiple parallel hits hypothesis has also been suggested. In NAFLD patients, insulin resistance leads to hepatic steatosis via multiple mechanisms. Despite the excess hepatic accumulation of FAs in NAFLD, it has been described that not only de novo FA synthesis is increased, but FAs are also taken up from the serum. Furthermore, a decrease in mitochondrial FA oxidation and secretion of very-low-density lipoproteins has been reported. This review discusses the molecular mechanisms that underlie the pathophysiological changes of hepatic lipid metabolism that contribute to NAFLD. PMID:25045276

  18. Effect of chronic psychosocial stress on nonalcoholic steatohepatitis in mice.

    PubMed

    Czech, Barbara; Neumann, Inga D; Müller, Martina; Reber, Stefan O; Hellerbrand, Claus

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which may progress towards inflammation (nonalcoholic steatohepatitis (NASH)). NAFLD is regarded as a consequence of a sedentary, food-abundant lifestyle which, in the modern world, often coincides with chronically high levels of perceived psychosocial stress. Here, we aimed to characterize the effect of chronic psychosocial stress on the development of NAFLD/NASH in male mice either fed with standard chow or NASH-inducing high fat diet. Chronic psychosocial stress was induced by chronic subordinate colony housing (CSC), a pre-clinically validated paradigm relevant for human affective and somatic disorders. Single housed (SHC) mice served as controls. Under standard chow conditions CSC mice revealed lower hepatic triglyceride levels but higher hepatic TNFα, MCP-1 and HMOX mRNA expression, while serum transaminase levels did not significantly differ from SHC mice. Under the NASH-inducing high-fat diet CSC and SHC mice showed similar body weight-gain and serum levels of glucose and adiponectin. Moreover, liver histology as well as TNFα, MCP-1 and HMOX expression were similar in CSC and SHC mice fed with HFD. Surprisingly, CSC showed even significantly lower transaminase levels than SHC mice fed with the same NASH-inducing diet. Together, these data indicate that under normal dietary conditions the CSC model induces noticeable hepatic oxidative stress and inflammation without causing manifest hepatocellular injury. In contrast, CSC exhibited a protective effect on hepatocellular injury in a dietary NASH-model. Identification of the underlying mechanisms of this phenomenon may lead to novel therapeutic strategies to prevent progression of NAFLD.

  19. Effect of chronic psychosocial stress on nonalcoholic steatohepatitis in mice

    PubMed Central

    Czech, Barbara; Neumann, Inga D; Müller, Martina; Reber, Stefan O; Hellerbrand, Claus

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which may progress towards inflammation (nonalcoholic steatohepatitis (NASH)). NAFLD is regarded as a consequence of a sedentary, food-abundant lifestyle which, in the modern world, often coincides with chronically high levels of perceived psychosocial stress. Here, we aimed to characterize the effect of chronic psychosocial stress on the development of NAFLD/NASH in male mice either fed with standard chow or NASH-inducing high fat diet. Chronic psychosocial stress was induced by chronic subordinate colony housing (CSC), a pre-clinically validated paradigm relevant for human affective and somatic disorders. Single housed (SHC) mice served as controls. Under standard chow conditions CSC mice revealed lower hepatic triglyceride levels but higher hepatic TNFα, MCP-1 and HMOX mRNA expression, while serum transaminase levels did not significantly differ from SHC mice. Under the NASH-inducing high-fat diet CSC and SHC mice showed similar body weight-gain and serum levels of glucose and adiponectin. Moreover, liver histology as well as TNFα, MCP-1 and HMOX expression were similar in CSC and SHC mice fed with HFD. Surprisingly, CSC showed even significantly lower transaminase levels than SHC mice fed with the same NASH-inducing diet. Together, these data indicate that under normal dietary conditions the CSC model induces noticeable hepatic oxidative stress and inflammation without causing manifest hepatocellular injury. In contrast, CSC exhibited a protective effect on hepatocellular injury in a dietary NASH-model. Identification of the underlying mechanisms of this phenomenon may lead to novel therapeutic strategies to prevent progression of NAFLD. PMID:23923077

  20. Increased accumulation of 4-hydroxynonenal adducts in female GSTA4/PPAR alpha double knockout mice enhance steatosis and inflammation in a model of pediatric nonalcoholic fatty liver disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hepatocellular injury resulting from increased lipid peroxidation products and oxidative stress is considered a potential mechanism driving the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitsis (NASH). To test the significance of lipid peroxidation and protein...

  1. LactMed: New NLM Database on Drugs and Lactation

    MedlinePlus

    ... Issues Research News From NIH LactMed: New NLM Database on Drugs and Lactation Past Issues / Summer 2006 ... Javascript on. Photo: Comstock LactMed, a free online database with information on drugs and lactation, is one ...

  2. Protein Mediated Magnetic Coupling between Lactate and Water Protons

    NASA Astrophysics Data System (ADS)

    Swanson, Scott D.

    1998-11-01

    The magnetic coupling between methyl lactate protons and water protons in samples of cross-linked bovine serum albumin (BSA) is studied. Cross-relaxation spectroscopy shows efficient magnetization transfer from immobilized BSA to both water and methyl lactate protons. Transient and steady-state NOE experiments reveal a negative intermolecular NOE between methyl lactate and water protons. Lactate is indirectly detected by selectively saturating the methyl lactate protons and measuring the decrease in water proton magnetization. Indirect detection of methyl lactate protons is an order of magnitude more sensitive than direct detection in these model systems. Lactate was indirectly imaged, via the water proton resonance, with 1.1-μl voxels in 2 min. Immobilized BSA reduces the intermolecular correlation time between water and lactate protons into the spin-diffusion limit where the NOE is negative. Possible molecular mechanisms for this coupling and applications toin vivospectroscopy are discussed.

  3. Novel Membrane Based Process for Producing Lactate Esters

    SciTech Connect

    1999-02-01

    Lactate Esters from Renewable Carbohydrate Feedstocks can Replace Petroleum-Derived Solvents. Lactate esters are versatile solvents that are biodegradable, nontoxic, and applicable to a wide range of industrial and consumer uses.

  4. 21 CFR 73.165 - Ferrous lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Ferrous lactate. 73.165 Section 73.165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies...

  5. Microbial production of lactate-containing polyesters

    PubMed Central

    Yang, Jung Eun; Choi, So Young; Shin, Jae Ho; Park, Si Jae; Lee, Sang Yup

    2013-01-01

    Due to our increasing concerns on environmental problems and limited fossil resources, biobased production of chemicals and materials through biorefinery has been attracting much attention. Optimization of the metabolic performance of microorganisms, the key biocatalysts for the efficient production of the desired target bioproducts, has been achieved by metabolic engineering. Metabolic engineering allowed more efficient production of polyhydroxyalkanoates, a family of microbial polyesters. More recently, non-natural polyesters containing lactate as a monomer have also been produced by one-step fermentation of engineered bacteria. Systems metabolic engineering integrating traditional metabolic engineering with systems biology, synthetic biology, protein/enzyme engineering through directed evolution and structural design, and evolutionary engineering, enabled microorganisms to efficiently produce natural and non-natural products. Here, we review the strategies for the metabolic engineering of microorganisms for the in vivo biosynthesis of lactate-containing polyesters and for the optimization of whole cell metabolism to efficiently produce lactate-containing polyesters. Also, major problems to be solved to further enhance the production of lactate-containing polyesters are discussed. PMID:23718266

  6. 21 CFR 184.1311 - Ferrous lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Ferrous lactate. 184.1311 Section 184.1311 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) DIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED AS SAFE Listing...

  7. 21 CFR 184.1311 - Ferrous lactate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Ferrous lactate. 184.1311 Section 184.1311 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) DIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED AS SAFE Listing...

  8. 21 CFR 184.1311 - Ferrous lactate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Ferrous lactate. 184.1311 Section 184.1311 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) DIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED AS SAFE Listing...

  9. Studying Reliability Using Identical Handheld Lactate Analyzers

    ERIC Educational Resources Information Center

    Stewart, Mark T.; Stavrianeas, Stasinos

    2008-01-01

    Accusport analyzers were used to generate lactate performance curves in an investigative laboratory activity emphasizing the importance of reliable instrumentation. Both the calibration and testing phases of the exercise provided students with a hands-on opportunity to use laboratory-grade instrumentation while allowing for meaningful connections…

  10. Nutritional Guide for Pregnant and Lactating Adolescents.

    ERIC Educational Resources Information Center

    Gelbard, Nancy

    Designed to provide accurate and up-to-date information about nutrition and health, this booklet is centered on the nutritional needs of pregnant and lactating adolescents and on the role of schools and the California State Department of Education in meeting those needs. The first section presents information for pregnant adolescents regarding…

  11. IBFAN Africa training initiatives: code implementation and lactation management.

    PubMed

    Mbuli, A

    1994-01-01

    As part of an ongoing effort to halt the decline of breast feeding rates in Africa, 35 representatives of 12 different African countries met in Mangochi, Malawi, in February 1994. The Code of Marketing of Breastmilk Substitutes was scrutinized. National codes were drafted based on the "Model Law" of the IBFAN Code Documentation Centre (ICDC), Penang. Mechanisms of implementation, specific to each country, were developed. Strategies for the promotion, protection, and support of breast feeding, which is very important to child survival in Africa, were discussed. The training course was organized by ICDC, in conjunction with IBFAN Africa, and with the support of the United Nations Children's Fund (UNICEF) and the World Health Organization (WHO). Countries in eastern, central, and southern Africa were invited to send participants, who included professors, pediatricians, nutritionists, MCH personnel, nurses, and lawyers. IBFAN Africa has also been conducting lactation management workshops for a number of years in African countries. 26 health personnel (pediatricians, nutritionists, senior nursing personnel, and MCH workers), representing 7 countries in the southern African region, attended a training of trainers lactation management workshop in Swaziland in August, 1993 with the support of their UNICEF country offices. The workshop included lectures, working sessions, discussions, and slide and video presentations. Topics covered included national nutrition statuses, the importance of breast feeding, the anatomy and physiology of breast feeding, breast feeding problems, the International Code of Marketing, counseling skills, and training methods. The field trip to a training course covering primary health care that was run by the Traditional Healers Organization (THO) in Swaziland was of particular interest because of the strong traditional medicine sector in many African countries. IBFAN Africa encourages use of community workers (traditional healers, Rural Health

  12. Nonalcoholic Hepatic Steatosis Is a Strong Predictor of High-Risk Coronary-Artery Plaques as Determined by Multidetector CT

    PubMed Central

    Osawa, Kazuhiro; Miyoshi, Toru; Yamauchi, Kentarou; Koyama, Yasushi; Nakamura, Kazufumi; Sato, Shuhei; Kanazawa, Susumu; Ito, Hiroshi

    2015-01-01

    Background Nonalcoholic fatty liver disease is associated with a risk of coronary artery disease (e.g., diabetes mellitus, dyslipidemia, metabolic syndrome). We evaluated whether nonalcoholic hepatic steatosis is associated with high-risk plaques as assessed by multidetector computed tomography (CT). Methods This retrospective study involved 414 participants suspected of having coronary artery disease. Nonalcoholic hepatic steatosis was defined as a liver-to-spleen fat ratio of <1.0 and the presence and appropriate characteristics of coronary-artery plaques as assessed by coronary CT angiography. High-risk plaques were identified, as were low-density plaques, positive remodeling, and spotty calcification. Results Compared with patients who did not have nonalcoholic hepatic steatosis, patients with nonalcoholic hepatic steatosis had more low-density plaques (21% vs. 44%, p<0.01), positive remodeling (41% vs. 58%, p = 0.01), and spotty calcification (12% vs. 36%, p<0.01). The number of high-risk plaques in patients with nonalcoholic hepatic steatosis was greater than in those without nonalcoholic hepatic steatosis (p<0.01). Patients with nonalcoholic hepatic steatosis were more likely to have high-risk plaques than were those with only an elevated level of visceral adipose tissue (≥86 cm2; 35% vs. 16%, p<0.01). Multivariate analyses that included nonalcoholic hepatic steatosis, amount of visceral adipose tissue, and the presence/absence of traditional risk factors demonstrated that nonalcoholic hepatic steatosis was an independent predictor of high-risk plaques (odds ratio: 4.60; 95% confidence interval: 1.94–9.07, p<0.01). Conclusions Diagnosis of nonalcoholic hepatic steatosis may be of value when assessing the risk of coronary artery disease. PMID:26125952

  13. Comparison of the relationships of alcoholic and nonalcoholic fatty liver with hypertension, diabetes mellitus, and dyslipidemia

    PubMed Central

    Toshikuni, Nobuyuki; Fukumura, Atsushi; Hayashi, Nobuhiko; Nomura, Tomoe; Tsuchishima, Mutsumi; Arisawa, Tomiyasu; Tsutsumi, Mikihiro

    2013-01-01

    We compared the relationships of alcoholic fatty liver and nonalcoholic fatty liver with hypertension, diabetes mellitus, and dyslipidemia. Using a nationwide Japanese survey, we collected data on subjects with biopsy-proven alcoholic fatty liver or nonalcoholic fatty liver. Multiple logistic regression analysis was performed to determine whether alcoholic fatty liver and nonalcoholic fatty liver are associated factors for these diseases. Data on 191 subjects (65, alcoholic fatty liver; 126, nonalcoholic fatty liver) were analyzed. Alcoholic fatty liver (odds ratio, 2.54; 95% confidence interval, 1.06–6.32; p = 0.040), age ≥55 years, and body mass index ≥25 kg/m2 were correlated with hypertension, whereas nonalcoholic fatty liver (odds ratio, 2.32; 95% confidence interval, 1.08–5.20; p = 0.035) and serum γ-glutamyl transpeptidase levels ≥75 IU/l were correlated with dyslipidemia. Furthermore, we found that there were biological interactions between alcoholic fatty liver and body mass index ≥25 kg/m2 in ≥55-year-old subjects (attributable proportion due to interaction, 0.68; 95% confidence interval, 0.19–1.17), as well as between alcoholic fatty liver and age ≥55 years in subjects with body mass index ≥25 kg/m2 (attributable proportion due to interaction, 0.71; 95% confidence interval, 0.24–1.18). Alcoholic fatty liver was more strongly associated with hypertension than nonalcoholic fatty liver and nonalcoholic fatty liver was more strongly associated with dyslipidemia than alcoholic fatty liver. Moreover, alcoholic fatty liver, obesity, and older age may interact to influence hypertension status. PMID:23341703

  14. Sex Difference in the Association between Serum Homocysteine Level and Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Won, Bo-Youn; Lee, Soo-Hyun; Yun, Sung-Hwan; Kim, Moon-Jong; Park, Kye-Seon; Kim, Young-Sang; Haam, Ji-Hee; Kim, Hyung-Yuk; Kim, Hye-Jung; Park, Ki-Hyun

    2016-01-01

    Background The relationship between serum homocysteine levels and non-alcoholic fatty liver disease is poorly understood. This study aims to investigate the sex-specific relationship between serum homocysteine level and non-alcoholic fatty liver disease in the Korean population. Methods This cross-sectional study included 150 men and 132 women who participated in medical examination programs in Korea from January 2014 to December 2014. Patients were screened for fatty liver by abdominal ultrasound and patient blood samples were collected to measure homocysteine levels. Patients that consumed more than 20 grams of alcohol per day were excluded from this study. Results The homocysteine level (11.56 vs. 8.05 nmol/L) and the proportion of non-alcoholic fatty liver disease (60.7% vs. 19.7%) were significantly higher in men than in women. In men, elevated serum homocysteine levels were associated with a greater prevalence of non-alcoholic fatty liver disease (quartile 1, 43.6%; quartile 4, 80.6%; P=0.01); however, in females, there was no significant association between serum homocysteine levels and the prevalence of non-alcoholic fatty liver disease. In the logistic regression model adjusted for age and potential confounding parameters, the odds ratio for men was significantly higher in the uppermost quartile (model 3, quartile 4: odds ratio, 6.78; 95% confidential interval, 1.67 to 27.56); however, serum homocysteine levels in women were not associated with non-alcoholic fatty liver disease in the crude model or in models adjusted for confounders. Conclusion Serum homocysteine levels were associated with the prevalence of non-alcoholic fatty liver disease in men. PMID:27468343

  15. Risk of Depressive Disorder following Non-Alcoholic Cirrhosis: A Nationwide Population-Based Study

    PubMed Central

    Hu, Li-Yu; Yeh, Chiu-Mei; Chen, Mu-Hong; Tsai, Chia-Fen; Chiang, Huey-Ling; Hung, Yi-Ping; Su, Vincent Yi-Fong; Hu, Yu-Wen; Su, Tung-Ping; Chen, Pan-Ming; Hung, Jeng-Hsiu; Liu, Chia-Jen; Huang, Min-Wei

    2014-01-01

    Background & Aims To evaluate the risk of depressive disorders among non-alcoholic patients by using the Taiwan National Health Insurance Research Database (NHIRD). Methods We conducted a retrospective study of a matched cohort of 52 725 participants (10 545 non-alcoholic cirrhotic patients and 42 180 control patients) who were selected from the NHIRD. Patients were observed for a maximum of 11 years to determine the rates of newly onset depressive disorders, and Cox regression was used to identify the risk factors associated with depressive disorders in cirrhotic patients. Results During the 11-year follow-up period, 395 (3.75%) non-alcoholic cirrhotic patients and 1 183 (2.80%) control patients were diagnosed with depressive disorders. The incidence risk ratio of depressive disorders between non-alcoholic cirrhotic patients and control patients was 1.76 (95% CI, 1.57–1.98, P<.001). After adjusting for age, sex, and comorbidities, non-alcoholic cirrhotic patients were 1.75 times more likely to develop depressive disorders (95% CI, 1.56–1.96, P<.001) compared with the control patients. The hazard ratios for patients younger than 60 years old (1.31) and female (1.25) indicated that each is an independent risk factor for depressive disorders in non-alcoholic cirrhotic patients. Conclusions The likelihood of developing depressive disorders is greater among non-alcoholic cirrhotic patients than among patients without cirrhosis. Symptoms of depression should be sought in patients with cirrhosis. PMID:24533141

  16. Myocardial metabolism during hypoxia: Maintained lactate oxidation during increased glycolysis

    SciTech Connect

    Mazer, C.D.; Stanley, W.C.; Hickey, R.F.; Neese, R.A.; Cason, B.A.; Demas, K.A.; Wisneski, J.A.; Gertz, E.W. )

    1990-09-01

    In the intact animal, myocardial lactate utilization and oxidation during hypoxia are not well understood. Nine dogs were chronically instrumented with flow probes on the left anterior descending coronary artery and with a coronary sinus sampling catheter. ({sup 14}C)lactate and ({sup 13}C)glucose tracers, or ({sup 13}C)lactate and ({sup 14}C)glucose were administered to quantitate lactate and glucose oxidation, lactate conversion to glucose, and simultaneous lactate extraction and release. The animals were anesthetized and exposed to 90 minutes of severe hypoxia (PO2 = 25 +/- 4 torr). Hypoxia resulted in significant increases in heart rate, cardiac output and myocardial blood flow, but no significant change in myocardial oxygen consumption. The arterial/coronary sinus differences for glucose and lactate did not change from normoxia to hypoxia; however, the rate of glucose uptake increased significantly due to the increase in myocardial blood flow. Tracer-measured lactate extraction did not decrease with hypoxia, despite a 250% increase in lactate release. During hypoxia, 90% +/- 4% of the extracted {sup 14}C-lactate was accounted for by the appearance of {sup 14}CO{sub 2} in the coronary sinus, compared with 88% +/- 4% during normoxia. Thus, in addition to the expected increase in glucose uptake and lactate production, we observed an increase in lactate oxidation during hypoxia.

  17. D-Lactate transport and metabolism in rat liver mitochondria.

    PubMed Central

    de Bari, Lidia; Atlante, Anna; Guaragnella, Nicoletta; Principato, Giovanni; Passarella, Salvatore

    2002-01-01

    In the present study we investigated whether isolated rat liver mitochondria can take up and metabolize D-lactate. We found the following: (1) externally added D-lactate causes oxygen uptake by mitochondria [P/O ratio (the ratio of mol of ATP synthesized to mol of oxygen atoms reduced to water during oxidative phosphorylation)=2] and membrane potential (Delta(psi)) generation in processes that are rotenone-insensitive, but inhibited by antimycin A and cyanide, and proton release from coupled mitochondria inhibited by alpha-cyanocinnamate, but not by phenylsuccinate; (2) the activity of the putative flavoprotein (D-lactate dehydrogenase) was detected in inside-out submitochondrial particles, but not in mitochondria and mitoplasts, as it is localized in the matrix phase of the mitochondrial inner membrane; (3) three novel separate translocators exist to mediate D-lactate traffic across the mitochondrial inner membrane: the D-lactate/H(+) symporter, which was investigated by measuring fluorimetrically the rate of endogenous flavin reduction, the D-lactate/oxoacid antiporter (which mediates both the D-lactate/pyruvate and D-lactate/oxaloacetate exchanges) and D-lactate/malate antiporter studied by monitoring photometrically the appearance of the D-lactate counteranions outside mitochondria. The D-lactate translocators, in the light of their different inhibition profiles separate from the monocarboxylate carrier, were found to differ from each other in the V(max) values and in the inhibition and pH profiles and were shown to regulate mitochondrial D-lactate metabolism in vitro. The D-lactate translocators and the D-lactate dehydrogenase could account for the removal of the toxic methylglyoxal from cytosol, as well as for D-lactate-dependent gluconeogenesis. PMID:11955284

  18. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by nonalcoholic fatty liver disease (NAFLD) leading to nonalcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been show...

  19. The Effects of Varied Extinction Conditions Following Acquisition on a 100 Per Cent Rewarded Task in Alcoholics and Nonalcoholics.

    ERIC Educational Resources Information Center

    Okultich, Peter V.; Marlatt, G. Alan

    The purpose of this study was two-fold: (1) to determine whether alcoholics will show greater persistance in responding under punishment in a simple operant task as compared to nonalcoholics; and (2) with this task, under what conditions alcoholics will suppress their responses to the same extent as nonalcoholics. In the task, all subjects during…

  20. Mustard bran in lactating dairy cow diets.

    PubMed

    Maiga, H A; Bauer, M L; Dahlen, C R; Badaruddin, M; Scholljegerdes, E J

    2011-06-01

    Two trials using lactating Holstein cows were conducted to evaluate effects of a diet containing oriental mustard bran on dry matter intake (DMI), milk production, milk components, and organoleptic properties. In experiment 1, 34 lactating cows (24 multiparous and 10 primiparous; days in milk ≥ 50 d) were used in a switchback design to determine the lactational response and organoleptic quality of milk when the diet contained 8% oriental mustard bran (MB) versus a control diet (CON). Mustard bran replaced a portion of soybean meal and all the beet pulp in the CON diet. Milk yields were greater for cows fed the MB diet; however, no differences were found in DMI, 3.5% fat- (FCM) or solids-corrected milk. Milk components and components production were not affected by treatment. Milk organoleptic qualities were not affected by diet. In experiment 2, 22 lactating cows (16 multiparous and 6 primiparous; days in milk ≥ 21 d) were assigned randomly within parity to receive MB or CON from wk 4 to 19 postpartum in a randomized complete block design. Cows were fed CON wk 1 to 3 postpartum. The MB diet contained the same ingredients as the CON, except sunflower seed and a portion of soybean meal were replaced with mustard bran. Milk and components data were collected during wk 3 postpartum and used as covariates to adjust treatment means. Intake was greater for cows fed the MB diet; however, daily milk, 3.5% FCM, and solids-corrected milk yields were not different between diets. Milk components and component yields were not affected by treatment. Milk urea concentration was less for cows fed the MB diet. Although cows fed the MB diet had greater DMI, this was not translated into a higher milk 3.5% FCM/DMI production efficiency ratio. During experiment 2, many cows fed MB experienced minor to severe hemolysis with bloody urine. This hemolysis believed to be caused by the S-methyl-cysteine sulfoxide contained in mustard bran could have affected milk production efficiency

  1. Lactate Dehydrogenase B Controls Lysosome Activity and Autophagy in Cancer.

    PubMed

    Brisson, Lucie; Bański, Piotr; Sboarina, Martina; Dethier, Coralie; Danhier, Pierre; Fontenille, Marie-Joséphine; Van Hée, Vincent F; Vazeille, Thibaut; Tardy, Morgane; Falces, Jorge; Bouzin, Caroline; Porporato, Paolo E; Frédérick, Raphaël; Michiels, Carine; Copetti, Tamara; Sonveaux, Pierre

    2016-09-12

    Metabolic adaptability is essential for tumor progression and includes cooperation between cancer cells with different metabolic phenotypes. Optimal glucose supply to glycolytic cancer cells occurs when oxidative cancer cells use lactate preferentially to glucose. However, using lactate instead of glucose mimics glucose deprivation, and glucose starvation induces autophagy. We report that lactate sustains autophagy in cancer. In cancer cells preferentially to normal cells, lactate dehydrogenase B (LDHB), catalyzing the conversion of lactate and NAD(+) to pyruvate, NADH and H(+), controls lysosomal acidification, vesicle maturation, and intracellular proteolysis. LDHB activity is necessary for basal autophagy and cancer cell proliferation not only in oxidative cancer cells but also in glycolytic cancer cells. PMID:27622334

  2. Monocarboxylate Transporters and Lactate Metabolism in Equine Athletes: A Review

    PubMed Central

    Pösö, AR

    2002-01-01

    Lactate is known as the end product of anaerobic glycolysis, a pathway that is of key importance during high intensity exercise. Instead of being a waste product lactate is now regarded as a valuable substrate that significantly contributes to the energy production of heart, noncontracting muscles and even brain. The recent cloning of monocarboxylate transporters, a conserved protein family that transports lactate through biological membranes, has given a new insight into the role of lactate in whole body metabolism. This paper reviews current literature on lactate and monocarboxylate transporters with special reference to horses. PMID:12173504

  3. [Role of the endocrine system in the pathogenesis of non-alcoholic fatty liver disease].

    PubMed

    Hagymási, Krisztina; Reismann, Péter; Rácz, Károly; Tulassay, Zsolt

    2009-11-29

    The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future. PMID:19923096

  4. [Role of the endocrine system in the pathogenesis of non-alcoholic fatty liver disease].

    PubMed

    Hagymási, Krisztina; Reismann, Péter; Rácz, Károly; Tulassay, Zsolt

    2009-11-29

    The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.

  5. Insulin resistance and hypothyroidism: a complex relationship in non-alcoholic fatty liver disease.

    PubMed

    Misra, Sanjukta; Singh, Bratati

    2013-05-01

    An association of non-alcoholic fatty liver disease with insulin resistant metabolic syndrome and hypothyroidism has been suggested. Aim of the present study was to explore the above association and also to establish the correlation between hypothyroidism and insulin resistance in patients with nonalcoholic fatty liver disease. Study group comprised 40 cases of non-alcoholic fatty liver disease and 30 healthy controls. Serum samples were analysed for fasting glucose, insulin, lipid profile and thyroid hormones. Insulin resistance was assessed by homeostatic model of assessment calculation. Nonalcoholic fatty liver disease patients demonstrated significantly higher insulin resistance, TSH values and significantly lower FT4 values as compared to controls, which illustrates the prevalence of insulin resistance and hypothyroidism in patients. A significant positive correlation between TSH and Insulin resistance (r = 0.87, p < 0.001) and a significant negative correlation between FT4 and insulin resistance (r = -0.14, p < 0.001) were established in the cases. Moreover TSH was significantly related to low density lipoprotein cholesterol, independent of insulin resistance. There have been some doubts over the clinical correlation between insulin resistance and hypothyroidism to delineate increased risk of cardiovascular disease. So earlier detection and treatment of risk factors may have a significant impact on progression of non-alcoholic fatty liver disease. PMID:24765691

  6. 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

  7. 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

  8. The energetics of lactation in cooperatively breeding meerkats Suricata suricatta.

    PubMed

    Scantlebury, M; Russell, A F; McIlrath, G M; Speakman, J R; Clutton-Brock, T H

    2002-10-22

    Species may become obligate cooperative breeders when parents are unable to raise their offspring unassisted. We measured the daily energy expenditure of mothers, helpers and offspring during peak lactation in cooperatively breeding meerkats Suricata suricatta using the doubly labelled water technique. Lactating mothers expended more energy per day than allo-lactating subordinate females, non-lactating females or suckling offspring. Metabolizable energy intakes of lactating mothers were calculated from isotope-based estimates of offspring milk energy intake, and were not significantly different from the previously suggested maximal limit for mammals. Allo-lactating females were the only category of animals that lost weight during the period of study, probably because they spent more time babysitting than non-lactating females. Daily energy expenditure (DEE) of lactating mothers increased with litter size but decreased with the number of helpers. Calculations show that for every 10 helpers, even in the absence of allo-lactators, mothers are able to reduce their DEE during peak lactation by an amount equivalent to the energy cost of one pup. These results indicate that helpers have beneficial energetic consequences for lactating mothers in an obligate cooperatively breeding mammal.

  9. The energetics of lactation in cooperatively breeding meerkats Suricata suricatta.

    PubMed Central

    Scantlebury, M; Russell, A F; McIlrath, G M; Speakman, J R; Clutton-Brock, T H

    2002-01-01

    Species may become obligate cooperative breeders when parents are unable to raise their offspring unassisted. We measured the daily energy expenditure of mothers, helpers and offspring during peak lactation in cooperatively breeding meerkats Suricata suricatta using the doubly labelled water technique. Lactating mothers expended more energy per day than allo-lactating subordinate females, non-lactating females or suckling offspring. Metabolizable energy intakes of lactating mothers were calculated from isotope-based estimates of offspring milk energy intake, and were not significantly different from the previously suggested maximal limit for mammals. Allo-lactating females were the only category of animals that lost weight during the period of study, probably because they spent more time babysitting than non-lactating females. Daily energy expenditure (DEE) of lactating mothers increased with litter size but decreased with the number of helpers. Calculations show that for every 10 helpers, even in the absence of allo-lactators, mothers are able to reduce their DEE during peak lactation by an amount equivalent to the energy cost of one pup. These results indicate that helpers have beneficial energetic consequences for lactating mothers in an obligate cooperatively breeding mammal. PMID:12396490

  10. The energetics of lactation in cooperatively breeding meerkats Suricata suricatta.

    PubMed

    Scantlebury, M; Russell, A F; McIlrath, G M; Speakman, J R; Clutton-Brock, T H

    2002-10-22

    Species may become obligate cooperative breeders when parents are unable to raise their offspring unassisted. We measured the daily energy expenditure of mothers, helpers and offspring during peak lactation in cooperatively breeding meerkats Suricata suricatta using the doubly labelled water technique. Lactating mothers expended more energy per day than allo-lactating subordinate females, non-lactating females or suckling offspring. Metabolizable energy intakes of lactating mothers were calculated from isotope-based estimates of offspring milk energy intake, and were not significantly different from the previously suggested maximal limit for mammals. Allo-lactating females were the only category of animals that lost weight during the period of study, probably because they spent more time babysitting than non-lactating females. Daily energy expenditure (DEE) of lactating mothers increased with litter size but decreased with the number of helpers. Calculations show that for every 10 helpers, even in the absence of allo-lactators, mothers are able to reduce their DEE during peak lactation by an amount equivalent to the energy cost of one pup. These results indicate that helpers have beneficial energetic consequences for lactating mothers in an obligate cooperatively breeding mammal. PMID:12396490

  11. Tin-containing silicates: alkali salts improve methyl lactate yield from sugars.

    PubMed

    Tolborg, Søren; Sádaba, Irantzu; Osmundsen, Christian M; Fristrup, Peter; Holm, Martin S; Taarning, Esben

    2015-02-01

    This study focuses on increasing the selectivity to methyl lactate from sugars using stannosilicates as heterogeneous catalyst. All group I ions are found to have a promoting effect on the resulting methyl lactate yield. Besides, the alkali ions can be added both during the preparation of the catalyst or directly to the solvent mixture to achieve the highest reported yield of methyl lactate (ca. 75 %) from sucrose at 170 °C in methanol. The beneficial effect of adding alkali to the reaction media applies not only to highly defect-free Sn-Beta prepared through the fluoride route, but also to materials prepared by post-treatment of dealuminated commercial Beta zeolites, as well as ordered mesoporous stannosilicates, in this case Sn-MCM-41 and Sn-SBA-15. These findings open the door to the possibility of using other preparation methods or different Sn-containing silicates with equally high methyl lactate yields as Sn-Beta. PMID:25605624

  12. Targeting metabolic flexibility by simultaneously inhibiting respiratory complex I and lactate generation retards melanoma progression.

    PubMed

    Chaube, Balkrishna; Malvi, Parmanand; Singh, Shivendra Vikram; Mohammad, Naoshad; Meena, Avtar Singh; Bhat, Manoj Kumar

    2015-11-10

    Melanoma is a largely incurable skin malignancy owing to the underlying molecular and metabolic heterogeneity confounded by the development of resistance. Cancer cells have metabolic flexibility in choosing either oxidative phosphorylation (OXPHOS) or glycolysis for ATP generation depending upon the nutrient availability in tumor microenvironment. In this study, we investigated the involvement of respiratory complex I and lactate dehydrogenase (LDH) in melanoma progression. We show that inhibition of complex I by metformin promotes melanoma growth in mice via elevating lactate and VEGF levels. In contrast, it leads to the growth arrest in vitro because of enhanced extracellular acidification as a result of increased glycolysis. Inhibition of LDH or lactate generation causes decrease in glycolysis with concomitant growth arrest both in vitro and in vivo. Blocking lactate generation in metformin-treated melanoma cells results in diminished cell proliferation and tumor progression in mice. Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inhibiting both together causes depletion in cellular ATP pool resulting in metabolic catastrophe induced apoptosis. Overall, our study suggests that LDH and complex I play distinct roles in regulating glycolysis and cell proliferation. Inhibition of these two augments synthetic lethality in melanoma.

  13. Tin-containing silicates: alkali salts improve methyl lactate yield from sugars.

    PubMed

    Tolborg, Søren; Sádaba, Irantzu; Osmundsen, Christian M; Fristrup, Peter; Holm, Martin S; Taarning, Esben

    2015-02-01

    This study focuses on increasing the selectivity to methyl lactate from sugars using stannosilicates as heterogeneous catalyst. All group I ions are found to have a promoting effect on the resulting methyl lactate yield. Besides, the alkali ions can be added both during the preparation of the catalyst or directly to the solvent mixture to achieve the highest reported yield of methyl lactate (ca. 75 %) from sucrose at 170 °C in methanol. The beneficial effect of adding alkali to the reaction media applies not only to highly defect-free Sn-Beta prepared through the fluoride route, but also to materials prepared by post-treatment of dealuminated commercial Beta zeolites, as well as ordered mesoporous stannosilicates, in this case Sn-MCM-41 and Sn-SBA-15. These findings open the door to the possibility of using other preparation methods or different Sn-containing silicates with equally high methyl lactate yields as Sn-Beta.

  14. PNPLA3, the triacylglycerol synthesis/hydrolysis/storage dilemma, and nonalcoholic fatty liver disease.

    PubMed

    Sookoian, Silvia; Pirola, Carlos J

    2012-11-14

    Genome-wide and candidate gene association studies have identified several variants that predispose individuals to developing nonalcoholic fatty liver disease (NAFLD). However, the gene that has been consistently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain containing 3 (PNPLA3, also known as adiponutrin). A nonsynonymous single nucleotide polymorphism in PNPLA3 (rs738409 C/G, a coding variant that encodes an amino acid substitution  I148M) is significantly associated with fatty liver and histological disease severity, not only in adults but also in children. Nevertheless, how PNPLA3 influences the biology of fatty liver disease is still an open question. A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the  I148M variant promotes hepatic lipid synthesis due to a gain of function. We revise here the published data about the role of the  I148M variant in lipogenesis/lipolysis, and suggest putative areas of future research. For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation, and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3'UTR region (hsa-miR-769-3p and hsa-miR-516a-3p). In addition, interesting unanswered questions remain to be explored. For example, PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity, and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element, corroborated by the DNase I hypersensitivity site peak. Finally, an interaction between PNPLA3 and glycerol-3-phosphate acyltransferase 2 is suggested by data miming.

  15. Paeoniflorin Protects against Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice.

    PubMed

    Zhang, Lijing; Yang, Bin; Yu, Baoping

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Paeoniflorin, a natural product and active ingredient of Paeonia lactiflora, has been demonstrated to have many pharmacological effects including antiinflammatory and antihyperglycemic activity. We investigated the effects of paeoniflorin on NAFLD in mice and its underlying mechanisms. We examined this hypothesis using a well-established animal model of NAFLD. The effects of paeoniflorin on inflammation and glucolipid metabolism disorder were evaluated. The corresponding signaling pathways were measured using real-time polymerase chain reaction (PCR). We demonstrated that the mice developed obesity, dyslipidemia, and fatty liver, which formed the NAFLD model. Paeoniflorin attenuated NAFLD and exhibited potential cardiovascular protective effects in vivo by lowering body weight, hyperlipidemia, and insulin resistance; blocking inflammation; and inhibiting lipid ectopic deposition. Further investigation revealed that the antagonistic effect on hyperlipidemia and lipid ectopic deposition was related to lowering the lipid synthesis pathway (de novo pathway, 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoAR)), promoting fatty acid oxidation [peroxisome proliferator-activated receptor-alpha (PPARα), carnitine palmitoyltransferase-1, etc.] and increasing cholesterol output (PPARγ-liver X receptor-α-ATP-binding cassette transporter-1); the inhibitory effects on inflammation and hyperglycemia were mediated by blocking inflammatory genes activation and reducing gluconeogenic genes expression (phosphoenolpyruvate carboxykinase and G6Pase). These results suggest that paeoniflorin prevents the development of NAFLD and reduces the risks of atherosclerosis through multiple intracellular signaling pathways. It may therefore be a potential therapeutic compound for NAFLD. PMID:25972092

  16. Effects of endotoxin on the lactating mouse

    SciTech Connect

    Carr, J.K.

    1985-01-01

    The regulation of endogenous mouse mammary tumor virus (MMTV) sequences in trans by a host gene, the Lps locus on mouse chromosome 4, was suspected from a genetic linkage analysis. The Lps locus mediates the mouse's response to the injection of lipopolysaccharide (LPS) in the responder mouse while mice with the deficient allele are incapable of responding. Others have found that endotoxin exposure reduces milk production in lactating animals. This observation was confirmed in mice and extended by examining /sup 125/I-prolactin binding to liver membranes of lactating mice. Endotoxin treatment of responder mice increases liver prolactin binding within 15 minutes, followed by a decline over 6 hours. Scatchard analysis shows that the immediate increase comes from both increased affinity and abundance of the prolactin receptor. No such change in prolactin binding is seen in the non-responder following endotoxin treatment nor in /sup 125/I-insulin binding in responders.

  17. Structure-Function Relationships in Lactate Dehydrogenase

    PubMed Central

    Adams, Margaret J.; Buehner, Manfred; Chandrasekhar, K.; Ford, Geoffrey C.; Hackert, Marvin L.; Liljas, Anders; Rossmann, Michael G.; Smiley, Ira E.; Allison, William S.; Everse, Johannes; Kaplan, Nathan O.; Taylor, Susan S.

    1973-01-01

    The binding of coenzyme and substrate are considered in relation to the known primary and tertiary structure of lactate dehydrogenase (EC 1.1.1.27). The adenine binds in a hydrophobic crevice, and the two coenzyme phosphates are oriented by interactions with the protein. The positively charged guanidinium group of arginine 101 then folds over the negatively charged phosphates, collapsing the loop region over the active center and positioning the unreactive B side of the nicotinamide in a hydrophobic protein environment. Collapse of the loop also introduces various charged groups into the vicinity of the substrate binding site. The substrate is situated between histidine 195 and the C4 position on the nicotinamide ring, and is partially oriented by interactions between its carboxyl group and arginine 171. The spatial arrangements of these groups may provide the specificity for the L-isomer of lactate. PMID:4146647

  18. [Vitamin D deficiency during pregnancy and lactation].

    PubMed

    Walicka, Magdalena; Marcinowska-Suchowierska, Ewa

    2008-11-01

    Vitamin D deficiency is a common occurrence and concerns people all around the world, not withstanding pregnant women. Vitamin D is essential for normal mineralization of the fetal skeleton. Latest reports have confirmed that an optimal vitamin D supply is of great importance for health course of pregnancy and it influences the general state of the child's health after birth, as well as their whole life. It seems that the Recommended Dietary Allowance (the RDA) of vitamin D in pregnancy and lactation of 200-400 IU/d is too small and it needs to be changed. In this article we present: a new definition of vitamin D deficiency; its epidemiology and changes of calcium homeostasis during pregnancy and lactation; a review of literature related to the influence of vitamin D deficiency on the health of the mother and child, as well as controversies related to supplementary doses of vitamin D. PMID:19140502

  19. Lactate metabolism: a new paradigm for the third millennium

    PubMed Central

    Gladden, L B

    2004-01-01

    For much of the 20th century, lactate was largely considered a dead-end waste product of glycolysis due to hypoxia, the primary cause of the O2 debt following exercise, a major cause of muscle fatigue, and a key factor in acidosis-induced tissue damage. Since the 1970s, a ‘lactate revolution’ has occurred. At present, we are in the midst of a lactate shuttle era; the lactate paradigm has shifted. It now appears that increased lactate production and concentration as a result of anoxia or dysoxia are often the exception rather than the rule. Lactic acidosis is being re-evaluated as a factor in muscle fatigue. Lactate is an important intermediate in the process of wound repair and regeneration. The origin of elevated [lactate] in injury and sepsis is being re-investigated. There is essentially unanimous experimental support for a cell-to-cell lactate shuttle, along with mounting evidence for astrocyte–neuron, lactate–alanine, peroxisomal and spermatogenic lactate shuttles. The bulk of the evidence suggests that lactate is an important intermediary in numerous metabolic processes, a particularly mobile fuel for aerobic metabolism, and perhaps a mediator of redox state among various compartments both within and between cells. Lactate can no longer be considered the usual suspect for metabolic ‘crimes’, but is instead a central player in cellular, regional and whole body metabolism. Overall, the cell-to-cell lactate shuttle has expanded far beyond its initial conception as an explanation for lactate metabolism during muscle contractions and exercise to now subsume all of the other shuttles as a grand description of the role(s) of lactate in numerous metabolic processes and pathways. PMID:15131240

  20. The primary pathway for lactate oxidation in Desulfovibrio vulgaris

    PubMed Central

    Vita, Nicolas; Valette, Odile; Brasseur, Gaël; Lignon, Sabrina; Denis, Yann; Ansaldi, Mireille; Dolla, Alain; Pieulle, Laetitia

    2015-01-01

    The ability to respire sulfate linked to lactate oxidation is a key metabolic signature of the Desulfovibrio genus. Lactate oxidation by these incomplete oxidizers generates reductants through lactate dehydrogenase (LDH) and pyruvate-ferredoxin oxidoreductase (PFOR), with the latter catalyzing pyruvate conversion into acetyl-CoA. Acetyl-CoA is the source of substrate-level phosphorylation through the production of ATP. Here, we show that these crucial steps are performed by enzymes encoded by a nonacistronic transcriptional unit named now as operon luo (for lactate utilization operon). Using a combination of genetic and biochemical techniques, we assigned a physiological role to the operon genes DVU3027-28 and DVU3032-33. The growth of mutant Δ26-28 was highly disrupted on D-lactate, whereas the growth of mutant Δ32-33 was slower on L-lactate, which could be related to a decrease in the activity of D-lactate or L-lactate oxidase in the corresponding mutants. The DVU3027-28 and DVU3032-33 genes thus encode functional D-LDH and L-LDH enzymes, respectively. Scanning of the genome for lactate utilization revealed several lactate permease and dehydrogenase homologs. However, transcriptional compensation was not observed in any of the mutants except for lactate permease. Although there is a high degree of redundancy for lactate oxidase, it is not functionally efficient in LDH mutants. This result could be related to the identification of several operon enzymes, including LDHs, in the PFOR activity bands, suggesting the occurrence of a lactate-oxidizing supermolecular structure that can optimize the performance of lactate utilization in Desulfovibrio species. PMID:26167158

  1. The primary pathway for lactate oxidation in Desulfovibrio vulgaris.

    PubMed

    Vita, Nicolas; Valette, Odile; Brasseur, Gaël; Lignon, Sabrina; Denis, Yann; Ansaldi, Mireille; Dolla, Alain; Pieulle, Laetitia

    2015-01-01

    The ability to respire sulfate linked to lactate oxidation is a key metabolic signature of the Desulfovibrio genus. Lactate oxidation by these incomplete oxidizers generates reductants through lactate dehydrogenase (LDH) and pyruvate-ferredoxin oxidoreductase (PFOR), with the latter catalyzing pyruvate conversion into acetyl-CoA. Acetyl-CoA is the source of substrate-level phosphorylation through the production of ATP. Here, we show that these crucial steps are performed by enzymes encoded by a nonacistronic transcriptional unit named now as operon luo (for lactate utilization operon). Using a combination of genetic and biochemical techniques, we assigned a physiological role to the operon genes DVU3027-28 and DVU3032-33. The growth of mutant Δ26-28 was highly disrupted on D-lactate, whereas the growth of mutant Δ32-33 was slower on L-lactate, which could be related to a decrease in the activity of D-lactate or L-lactate oxidase in the corresponding mutants. The DVU3027-28 and DVU3032-33 genes thus encode functional D-LDH and L-LDH enzymes, respectively. Scanning of the genome for lactate utilization revealed several lactate permease and dehydrogenase homologs. However, transcriptional compensation was not observed in any of the mutants except for lactate permease. Although there is a high degree of redundancy for lactate oxidase, it is not functionally efficient in LDH mutants. This result could be related to the identification of several operon enzymes, including LDHs, in the PFOR activity bands, suggesting the occurrence of a lactate-oxidizing supermolecular structure that can optimize the performance of lactate utilization in Desulfovibrio species. PMID:26167158

  2. Visceral tissue growth and proliferation during the bovine lactation cycle.

    PubMed

    Baldwin, R L; McLeod, K R; Capuco, A V

    2004-09-01

    Twenty one multiparous, nonpregnant, lactating dairy cows were used to assess the impact of stage of lactation on visceral tissue mass and small intestinal cell proliferation. Cows were slaughtered at each of 4 stages of lactation: 14, 90, 120, and 240 d of lactation. With stage of lactation, DMI increased through d 90 and thereafter remained similar through d 240 (quadratic). Carcass weight and empty body weight (EBW) declined with stage of lactation through d 120 and increased thereafter (quadratic). As a percentage of EBW, rumen, small intestine, and liver weights increased with increasing stage of lactation (quadratic), increasing from 14 to 120 d and declining through 240 d. Stage of lactation did not have a measurable affect on reticulum, omasum, abomasum, or large intestine weights as a percentage of EBW. Visceral adipose mass as a percentage of EBW declined with stage of lactation to a minimum at 120 d and increased by 240 d (quadratic). Concentrations of RNA and DNA of digestive tract organs were largely unaffected by stage of lactation with the exception of the liver DNA concentration through d 120 (quadratic). The proliferative growth fraction (Ki67) was unaffected by stage of lactation. However, bromo-deoxyuridine labeling of jejunal crypts exhibited a cubic response with stage of lactation and tritiated thymidine incorporation by duodenal epithelium increased with stage of lactation through d 120, declining thereafter (quadratic). Mass of visceral tissues increase to meet the energetic demands of lactation and that increased absorption capacity of the intestines is achieved by hyperplastic growth of the intestinal epithelium.

  3. Peafowl lactate dehydrogenase: problem of isoenzyme identification.

    PubMed

    Rose, R G; Wilson, A C

    1966-09-16

    Peafowl, like other vertebrates, contain multiple forms of lactate dehydrogenase. The electrophoretic properties of the peafowl isoenzymes are unusual in that the isoenzyme from heart tissue can be either more or less anodic than that of muscle, depending on the pH. This finding focuses attention on the problem of isoenzyme identification. It is suggested that isoenzymes be identified on the basis of properties that are chemically and biologically more significant than electrophoretic mobility.

  4. Peafowl lactate dehydrogenase: problem of isoenzyme identification.

    PubMed

    Rose, R G; Wilson, A C

    1966-09-16

    Peafowl, like other vertebrates, contain multiple forms of lactate dehydrogenase. The electrophoretic properties of the peafowl isoenzymes are unusual in that the isoenzyme from heart tissue can be either more or less anodic than that of muscle, depending on the pH. This finding focuses attention on the problem of isoenzyme identification. It is suggested that isoenzymes be identified on the basis of properties that are chemically and biologically more significant than electrophoretic mobility. PMID:5917779

  5. Lactation studies of anticonvulsants: a quality review

    PubMed Central

    van der Meer, Douwe H; Wieringa, Andre; Wegner, Ilse; Wilffert, Bob; ter Horst, Peter G J

    2015-01-01

    AIM The aim of this review was to investigate the quality of the current literature on the transfer of anticonvulsants to breast milk to provide an overview of which anticonvulsants are in need of further research. METHODS We reviewed the quality of the available lactation studies for 19 anticonvulsants against the guidelines of the Food and Drug Administration (FDA) and the International Lactation Consultant Association (ILCA). RESULTS Except for one study on lamotrigine and one case report on gabapentin, no study on anticonvulsants had both the absolute infant dose (AID) and milk to plasma ratio (M : P) correctly assessed. Only one study on carbamazepine, phenytoin and vigabatrin was found that correctly assessed the AID. The main cause for this low number is the lack of essential details in published studies, since 25 of 62 studies were case reports, letters or abstracts. Other major shortcomings were the lack of information on sampling methods, the number of samples in a particular dose interval as well as the low number of study participants. CONCLUSION The quality of the current literature on the transfer of anticonvulsants to breast milk is low, except for lamotrigine, which makes it hard to draw conclusions about the safety of the use of anticonvulsants during the lactation period. Therefore, further research is needed. PMID:25291358

  6. Use of a Diabetes Self-Assessment Score to Predict Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis.

    PubMed

    Kim, Gyuri; Lee, Yong-Ho; Park, Young Min; Kim, Jungghi; Kim, Heesuk; Lee, Byung-Wan; Kang, Eun Seok; Cha, Bong-Soo; Lee, Hyun Chul; Kim, Dae Jung

    2015-07-01

    Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are strongly associated with obesity, insulin resistance, and type 2 diabetes. We recently developed and validated a self-assessment score in the Korean population to identify people at high risk for diabetes. The objective of this study was to evaluate whether the self-assessment risk score for diabetes can also be used to screen for the presence of NAFLD or NASH.The study population included 15,676 subjects (8313 men and 7363 women) over 20 years old who visited the National Health Insurance Service Ilsan Hospital in Korea between 2008 and 2010. Anthropometric, clinical, and laboratory data were analyzed during regular health checkups. Fatty liver disease was diagnosed using ultrasound, discrimination capability was assessed based on the area under the receiver operating characteristic curve (AUC), and evaluation measures, including sensitivity and specificity, were calculated. Multiple logistic analyses were also performed.We calculated a self-assessed risk score for diabetes (range: 0-11), and a cutoff of ≥5 identified 60% (50%) of men (women) at high risk for NAFLD, reflecting a sensitivity of 79% (85%), a specificity of 60% (66%), a positive predictive value (PPV) of 68% (51%), and a negative predictive value (NPV) of 73% (91%), with an AUC of 0.75 (0.82) for men (women). A cutoff point of ≥6 identified 43% (31%) of men (women) at high risk for NASH, reflecting a sensitivity of 80% (86%), a specificity of 64% (75%), a PPV of 30% (28%), and a NPV of 94% (98%), with an AUC of 0.77 (0.86) for men (women). The odds ratios that a 1-point increase in the diabetes risk scores would be associated with an increased risk for NAFLD and NASH were 1.20 [95% confidence interval (CI): 1.16-1.25] and 1.57 (95% CI: 1.49-1.65), respectively, in men, and 1.28 (95% CI: 1.21-1.34) and 1.89 (95% CI: 1.73-2.07), respectively, in women.The present study indicates that our self-assessment risk score

  7. Metabolic aspects of adult patients with nonalcoholic fatty liver disease.

    PubMed

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-08-21

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD. PMID:27610012

  8. The Gut Microbiota and Nonalcoholic Fatty Liver Disease.

    PubMed

    Quigley, Eamonn M; Monsour, Howard P

    2015-08-01

    With the recognition of the various metabolic functions of the gut microbiome and of its putative role in obesity, an investigation of the contribution of the bacterial populations of the gastrointestinal tract to the metabolic syndrome and its hepatic manifestation-nonalcoholic liver disease (NAFLD)-became inevitable. Furthermore, the central role of an altered microbiome in the precipitation of infectious and noninfectious complications of liver disease was described decades ago. The contribution of the microbiome to the pathogenesis of NAFLD has been extensively studied in animal models. Convincing evidence for a central role for an altered microbiome (through multiple mechanisms), coupled with such phenomena as impaired gut barrier function and an aberrant host immune response, has been amply demonstrated. The accumulation of a similar level of evidence from human studies has proven more challenging; however, incriminating data accumulate. Although animal studies have demonstrated the benefits of interventions that modulate the microbiome and of probiotics, in particular, in reducing steatosis and preventing progression to steatohepatitis, data in man are scanty and high-quality clinical trials of probiotics and other strategies are needed. PMID:26378643

  9. Genetic background in nonalcoholic fatty liver disease: A comprehensive review

    PubMed Central

    Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

    2015-01-01

    In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID:26494964

  10. Metabolic aspects of adult patients with nonalcoholic fatty liver disease

    PubMed Central

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD. PMID:27610012

  11. Dyslipidemia in patients with nonalcoholic fatty liver disease.

    PubMed

    Chatrath, Hemant; Vuppalanchi, Raj; Chalasani, Naga

    2012-02-01

    Patients with nonalcoholic fatty liver disease (NAFLD) often have dyslipidemia along with other features of metabolic syndrome such as obesity, diabetes mellitus, and hypertension. The dyslipidemia in NAFLD is characterized by increased serum triglycerides, increased small, dense low-density lipoprotein (LDL nontype A) particles, and low high-density lipoprotein (HDL) cholesterol. The pathogenesis of dyslipidemia in NAFLD is not well understood, but it is likely related to hepatic overproduction of the very low-density lipoprotein particles and dysregulated clearance of lipoproteins from the circulation. There is unequivocal evidence that cardiovascular disease is the most common cause of mortality in patients with NAFLD. Aggressive treatment of dyslipidemia plays a critical role in the overall management of patients with NAFLD. Statins are the first-line agents to treat high cholesterol and their dosage should be adjusted based on achieving therapeutic targets and tolerability. Although all statins appear to be effective in improving cholesterol levels in patients with NAFLD, there is more experience with atorvastatin in patients with NAFLD; furthermore, it is the only statin to date to show a reduced cardiovascular morbidity in patients with NAFLD. The risk for serious liver injury from statins is quite rare and patients with NAFLD are not at increased risk for statin hepatotoxicity. Omega-3 fatty acids are perhaps the first choice to treat hypertriglyceridemia because of their safety, tolerability, and efficacy in improving serum triglycerides, as well as their potential to improve liver disease. PMID:22418885

  12. MicroRNAs in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Baffy, György

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disorder. Strongly linked to obesity and diabetes, NAFLD has the characteristics of complex diseases with substantial heterogeneity. Accordingly, our ability to predict the risk of advanced NAFLD and provide efficient treatment may improve by a better understanding of the relationship between genotype and phenotype. MicroRNAs (miRNAs) play a major role in the fine-tuning of gene expression and they have recently emerged as novel biomarkers and therapeutic tools in the management of NAFLD. These short non-coding RNA sequences act by partial repression or degradation of targeted mRNAs. Deregulation of miRNAs has been associated with different stages of NAFLD, while their biological role in the pathogenesis remains to be fully understood. Systems biology analyses based on predicted target genes have associated hepatic miRNAs with molecular pathways involved in NAFLD progression such as cholesterol and lipid metabolism, insulin signaling, oxidative stress, inflammation, and pathways of cell survival and proliferation. Moreover, circulating miRNAs have been identified as promising noninvasive biomarkers of NAFLD and linked to disease severity. This rapidly growing field is likely to result in major advances in the pathomechanism, prognostication, and treatment of NAFLD. PMID:26690233

  13. Berberine Reduces Neurotoxicity Related to Nonalcoholic Steatohepatitis in Rats

    PubMed Central

    Ghareeb, Doaa A.; Khalil, Sofia; Hafez, Hani S.; Bajorath, Jürgen; Ahmed, Hany E. A.; Sarhan, Eman; Elwakeel, Eiman; El-Demellawy, Maha A.

    2015-01-01

    Berberine is a plant alkaloid that has several pharmacological effects such as antioxidant, antilipidemic, and anti-inflammatory effects. Nonalcoholic steatohepatitis (NASH) triggers different aspects of disorders such as impaired endogenous lipid metabolism, hypercholesterolemia, oxidative stress, and neurotoxicity. In this study, we examined the mechanism by which NASH induces neurotoxicity and the protective effect of berberine against both NASH and its associated neurotoxicity. NASH induced rats showed significant impairments in lipid metabolism with increased serum triglycerides, cholesterol, and low-density lipoprotein (LDL). The NASH induced group also demonstrated a significant oxidative stress which is characterized by increased TBARs level and decreased antioxidant capacity such as GSH and SOD levels. Moreover, the NASH induction was associated with inflammation which was demonstrated by increased TNFα and nitric oxide levels. Hyperglycemia and hyperinsulinemia were observed in the NASH induced group. Also, our results showed a significant increase in the expression of the acetylcholine esterase (AChE) and amyloid beta precursor protein (AβPP). These changes were significantly correlated with decreased insulin degrading enzyme (IDE) and beta-amyloid40 (Aβ40) and increased beta-amyloid42 (Aβ42) in the hippocampal region. Daily administration of berberine (50 mg/kg) for three weeks ameliorated oxidative stress, inflammation, hyperlipidemia, hyperglycemia, hyperinsulinemia, and the observed neurotoxicity. PMID:26576191

  14. Berberine Reduces Neurotoxicity Related to Nonalcoholic Steatohepatitis in Rats.

    PubMed

    Ghareeb, Doaa A; Khalil, Sofia; Hafez, Hani S; Bajorath, Jürgen; Ahmed, Hany E A; Sarhan, Eman; Elwakeel, Eiman; El-Demellawy, Maha A

    2015-01-01

    Berberine is a plant alkaloid that has several pharmacological effects such as antioxidant, antilipidemic, and anti-inflammatory effects. Nonalcoholic steatohepatitis (NASH) triggers different aspects of disorders such as impaired endogenous lipid metabolism, hypercholesterolemia, oxidative stress, and neurotoxicity. In this study, we examined the mechanism by which NASH induces neurotoxicity and the protective effect of berberine against both NASH and its associated neurotoxicity. NASH induced rats showed significant impairments in lipid metabolism with increased serum triglycerides, cholesterol, and low-density lipoprotein (LDL). The NASH induced group also demonstrated a significant oxidative stress which is characterized by increased TBARs level and decreased antioxidant capacity such as GSH and SOD levels. Moreover, the NASH induction was associated with inflammation which was demonstrated by increased TNFα and nitric oxide levels. Hyperglycemia and hyperinsulinemia were observed in the NASH induced group. Also, our results showed a significant increase in the expression of the acetylcholine esterase (AChE) and amyloid beta precursor protein (AβPP). These changes were significantly correlated with decreased insulin degrading enzyme (IDE) and beta-amyloid40 (Aβ 40) and increased beta-amyloid42 (Aβ 42) in the hippocampal region. Daily administration of berberine (50 mg/kg) for three weeks ameliorated oxidative stress, inflammation, hyperlipidemia, hyperglycemia, hyperinsulinemia, and the observed neurotoxicity.

  15. Extract of a polyherbal formulation ameliorates experimental nonalcoholic steatohepatitis

    PubMed Central

    Azeemuddin, Mohammed; Rafiq, Mohamed; Anturlikar, Suryakanth Dattatraya; Sharath Kumar, Lakkavalli Mohan; Patki, Pralhad Sadashiv; Babu, Uddagiri Venkanna; Shyam, Ramakrishnan

    2015-01-01

    The objective of the present study is to evaluate the effect of the extract of a well-known hepatospecific polyherbal formulation, Liv.52, in an experimental model of high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) in rats. Feeding a HFD for 15 weeks resulted in significant impairment of the lipid profile, elevation of hepatic enzyme markers, and insulin resistance in rats. The histological examination of the liver furthermore indicated fibrotic changes and fat deposition in hepatic tissues. The treatment with Liv.52 extract [125 mg/kg body weight per os (b.wt. p.o.)], which was administered from week 9 onward, reversed the HFD-induced changes to a statistically significant extent, compared to the untreated positive control animals. The effect observed with Liv.52 extract was comparable to that of pioglitazone (4 mg/kg b.wt.), a standard drug that is useful in the management of NASH. The treatment with Liv.52 extract significantly reduced steatosis, collagen deposition, and necrosis in hepatic tissues, which indicates its antifibrotic and antinecrotic properties. The results obtained in the present set of experiments indicate that Liv.52 extract effectively reverses metabolic and histological changes associated with HFD-induced NASH. PMID:27114939

  16. Silica nanoparticles grown and stabilized in organic nonalcoholic media.

    PubMed

    El Hawi, Nancy; Nayral, Céline; Delpech, Fabien; Coppel, Yannick; Cornejo, Alfonso; Castel, Annie; Chaudret, Bruno

    2009-07-01

    This work features an alternative approach to the well-documented preparation of silica nanoparticles in protic media. We present here the one-pot synthesis of silica nanoparticles of adjustable size (between 18 and 174 nm), prepared and stabilized in organic nonalcoholic solvents. This novel route is based on hydrolysis and condensation of tetraethoxysilane, using water as reactant and different primary amines (butylamine, octylamine, dodecylamine, hexadecylamine) as catalysts in tetrahydrofuran or dimethoxyethane. The growth rate can be finely adjusted, and the first stages of the formation are observed by transmission electronic microscopy, revealing a silicated network in which the silica particles are formed and then released in solution. The amine plays not only a catalyst role but is also implied, as well as the solvent, in the stabilization process and the size control of the particles. A detailed NMR study demonstrates a core-shell structure in which the silica core is surrounded by a layer of alkylammonium ions together with solvent. PMID:19496545

  17. Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis.

    PubMed

    Medina, Jesús; Fernández-Salazar, Luis I; García-Buey, Luisa; Moreno-Otero, Ricardo

    2004-08-01

    Nonalcoholic steatohepatitis (NASH) represents an advanced stage of fatty liver disease developed in the absence of alcohol abuse. Its increasing prevalence in western countries, the diagnostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and even cirrhosis make NASH a challenge for hepatologists. NASH is frequently associated with type 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved in its pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to self-enhancement of insulin resistance and hepatic accumulation of fat have been recently identified. Excess intracellular fatty acids, oxidant stress, tumor necrosis factor-alpha, and mitochondrial dysfunction are causes of hepatocellular injury, thereby leading to disease progression and to the establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing production of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, normalizing lipoprotein metabolism, and downregulating inflammatory mediators with probiotics have promising potential.

  18. Treatment of non-alcoholic fatty liver disease

    PubMed Central

    Tolman, Keith G; Dalpiaz, Anthony S

    2007-01-01

    Non-alcoholic fatty liver disease, defined as the presence of macrovascular steatosis in the presence of less than 20 gm of alcohol ingestion per day, is the most common liver disease in the USA. It is most commonly associated with insulin resistance/type 2 diabetes mellitus and obesity. It is manifested by steatosis, steatohepatitis, cirrhosis, and, rarely, hepatocellular carcinoma. Hepatic steatosis results from an imbalance between the uptake of fat and its oxidation and export. Insulin resistance, predisposing to lipolysis of peripheral fat with mobilization to and uptake of fatty acids by the liver, is the most consistent underlying pathogenic factor. It is not known why some patients progress to cirrhosis; however, the induction of CYP 2E1 with generation of reactive oxygen species appears to be important. Treatment is directed at weight loss plus pharmacologic therapy targeted toward insulin resistance or dyslipidemia. Bariatric surgery has proved effective. While no pharmacologic therapy has been approved, emerging data on thiazolidinediones have demonstrated improvement in both liver enzymes and histology. There are fewer, but promising data, with statins which have been shown to be hepatoprotective in other liver diseases. The initial enthusiasm for ursodeoxycholic acid has not been supported by histologic studies. PMID:18516264

  19. Autophagy: a new target for nonalcoholic fatty liver disease therapy.

    PubMed

    Mao, Yuqing; Yu, Fujun; Wang, Jianbo; Guo, Chuanyong; Fan, Xiaoming

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) has gained importance in recent decades due to drastic changes in diet, especially in Western countries. NAFLD occurs as a spectrum from simple hepatic steatosis, steatohepatitis to cirrhosis, and even hepatocellular carcinoma. Although the molecular mechanisms underlying the development of NAFLD have been intensively investigated, many issues remain to be resolved. Autophagy is a cell survival mechanism for disposing of excess or defective organelles, and has become a hot spot for research. Recent studies have revealed that autophagy is linked to the development of NAFLD and regulation of autophagy has therapeutic potential. Autophagy reduces intracellular lipid droplets by enclosing them and fusing with lysosomes for degradation. Furthermore, autophagy is involved in attenuating inflammation and liver injury. However, autophagy is regarded as a double-edged sword, as it may also affect adipogenesis and adipocyte differentiation. Moreover, it is unclear as to whether autophagy protects the body from injury or causes diseases and even death, and the association between autophagy and NAFLD remains controversial. This review is intended to discuss, comment, and outline the progress made in this field and establish the possible molecular mechanism involved. PMID:27099536

  20. Genetic background in nonalcoholic fatty liver disease: A comprehensive review.

    PubMed

    Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

    2015-10-21

    In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.

  1. The Effect of Bariatric Surgeries on Nonalcoholic Fatty Liver Disease

    PubMed Central

    Hassanian, Mazen; Al-Mulhim, Amnah; Al-Sabhan, Atheer; Al-Amro, Shaden; Bamehriz, Fahad; Abdo, Ayman; Al Khalidi, Hisham

    2014-01-01

    Objective: A review of published data addressing hepatic histopathological, metabolical, and functional changes following gastric banding, sleeve gastrectomy, gastric bypass surgery, and biliopancreatic with duodenal switch surgeries on nonalcoholic fatty liver disease (NAFLD). NAFLD is currently the most common chronic liver disease. Owing to the strong relationship between obesity and NAFLD, the idea of weight reduction as a method to treat NAFLD has rapidly emerged. Bariatric surgery has proved to be the most efficient method for weight reduction; hence, their beneficial effects on NAFLD have been evaluated by several studies. A literature review of published data was performed during the years 2012-2014 using PubMed with the following key words: Bariatric, NAFLD, steatosis, sleeve gastrectomy, gastric bypass, gastric banding, biliopancreatic diversion with duodenal switch, obesity, and insulin resistance (IR). Exclusion criteria were non-English articles and inherited NAFLD, pregnancy-induced NAFLD, and children. The majority of published data are in favor of indicating that bariatric surgeries improve the histologic and metabolic changes associated with NAFLD. The suggested mechanisms are: The reversal of IR, reduction of inflammatory markers, and improved histological features of NAFLD. Accordingly, bariatric surgeries are potentially one of the future methods in treating patients with morbid obesity and NAFLD. However, some questions remain unanswered, such as whether timing of surgery, type of surgery most effective, and whether bariatric surgeries are capable of curing the disease. Long-term and well-designed prospective studies are needed to address these issues. PMID:25253361

  2. Acetaminophen Pharmacokinetics in Children with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Barshop, Nicole J.; Capparelli, Edmund V.; Sirlin, Claude B.; Schwimmer, Jeffrey B.; Lavine, Joel E

    2010-01-01

    Objectives To evaluate UDP-glucuronyltransferase (UGT) activity and the pharmacokinetics of a single oral dose of acetaminophen (APAP) in children with non-alcoholic fatty liver disease (NAFLD). Methods Twelve boys 10–17 years old with biopsy-proven NAFLD and 12 age and gender-matched controls without NAFLD were recruited. Following administration of a single oral dose of APAP (5mg/kg, maximum 325mg), APAP and its glucuronide metabolite (APAP-G) were measured in plasma, urine, and sputum at various intervals up to 24 hours. The activity of UGT was estimated by the plasma ratio of APAP-G to APAP at 4 hours. Results Following administration of APAP, children with NAFLD had significantly higher concentrations of APAP-G in serum (p=.0071) and urine (p=.0210) compared to controls. No significant differences in APAP pharmacokinetics parameters were observed between the two groups. Conclusions APAP glucuronidation is altered in children with fatty liver disease. Despite the altered disposition of this metabolite, the pharmacokinetics of a single 5 mg/kg dose of APAP is the same in children with NAFLD as in children with normal liver function. PMID:21240014

  3. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

    PubMed Central

    Aigner, Elmar; Weiss, Günter; Datz, Christian

    2015-01-01

    Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the “dysmetabolic iron overload syndrome”. Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxyl-radicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications. PMID:25729473

  4. Soft drinks consumption and nonalcoholic fatty liver disease

    PubMed Central

    Nseir, William; Nassar, Fares; Assy, Nimer

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a common clinical condition which is associated with metabolic syndrome in 70% of cases. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress combine to increase free fatty acid delivery to the liver, and increased hepatic triglyceride accumulation contributes to fatty liver. Regular soft drinks have high fructose corn syrup which contains basic sugar building blocks, fructose 55% and glucose 45%. Soft drinks are the leading source of added sugar worldwide, and have been linked to obesity, diabetes, and metabolic syndrome. The consumption of soft drinks can increase the prevalence of NAFLD independently of metabolic syndrome. During regular soft drinks consumption, fat accumulates in the liver by the primary effect of fructose which increases lipogenesis, and in the case of diet soft drinks, by the additional contribution of aspartame sweetener and caramel colorant which are rich in advanced glycation end products that potentially increase insulin resistance and inflammation. This review emphasizes some hard facts about soft drinks, reviews fructose metabolism, and explains how fructose contributes to the development of obesity, diabetes, metabolic syndrome, and NAFLD. PMID:20518077

  5. Nonalcoholic Fatty Liver Disease Management: Dietary and Lifestyle Modifications.

    PubMed

    Nguyen, Vi; George, Jacob

    2015-08-01

    Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of abnormalities that can range from bland liver fat (steatosis), to hepatic inflammation and liver injury (steatohepatitis). It is estimated that NAFLD will become the principal cause of liver disease in Western nations and the leading indication for liver transplantation. Advancements in disease recognition and management are therefore paramount. Although the development of new, reliable drug therapies is vital, lifestyle interventions remain the most effective treatment modality. In addition to weight loss as a primary measure of treatment success, there is growing recognition that other endpoints, including the prevention or delay of diabetes onset, reduced cardiovascular events, prevention of cancer, and improved overall mortality, are equally important outcomes that can be independently modified by lifestyle change. Moreover, NAFLD is inextricably part of a complex, systemic disease process that is linked with deeply entrenched maladaptive lifestyle behaviors. Thus, a holistic, multidisciplinary, and individualized approach to disease management will be the key to achieving any realistic population-level change.

  6. Autophagy: a new target for nonalcoholic fatty liver disease therapy

    PubMed Central

    Mao, Yuqing; Yu, Fujun; Wang, Jianbo; Guo, Chuanyong; Fan, Xiaoming

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) has gained importance in recent decades due to drastic changes in diet, especially in Western countries. NAFLD occurs as a spectrum from simple hepatic steatosis, steatohepatitis to cirrhosis, and even hepatocellular carcinoma. Although the molecular mechanisms underlying the development of NAFLD have been intensively investigated, many issues remain to be resolved. Autophagy is a cell survival mechanism for disposing of excess or defective organelles, and has become a hot spot for research. Recent studies have revealed that autophagy is linked to the development of NAFLD and regulation of autophagy has therapeutic potential. Autophagy reduces intracellular lipid droplets by enclosing them and fusing with lysosomes for degradation. Furthermore, autophagy is involved in attenuating inflammation and liver injury. However, autophagy is regarded as a double-edged sword, as it may also affect adipogenesis and adipocyte differentiation. Moreover, it is unclear as to whether autophagy protects the body from injury or causes diseases and even death, and the association between autophagy and NAFLD remains controversial. This review is intended to discuss, comment, and outline the progress made in this field and establish the possible molecular mechanism involved. PMID:27099536

  7. Soft drinks consumption and nonalcoholic fatty liver disease.

    PubMed

    Nseir, William; Nassar, Fares; Assy, Nimer

    2010-06-01

    Nonalcoholic fatty liver disease (NAFLD) is a common clinical condition which is associated with metabolic syndrome in 70% of cases. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress combine to increase free fatty acid delivery to the liver, and increased hepatic triglyceride accumulation contributes to fatty liver. Regular soft drinks have high fructose corn syrup which contains basic sugar building blocks, fructose 55% and glucose 45%. Soft drinks are the leading source of added sugar worldwide, and have been linked to obesity, diabetes, and metabolic syndrome. The consumption of soft drinks can increase the prevalence of NAFLD independently of metabolic syndrome. During regular soft drinks consumption, fat accumulates in the liver by the primary effect of fructose which increases lipogenesis, and in the case of diet soft drinks, by the additional contribution of aspartame sweetener and caramel colorant which are rich in advanced glycation end products that potentially increase insulin resistance and inflammation. This review emphasizes some hard facts about soft drinks, reviews fructose metabolism, and explains how fructose contributes to the development of obesity, diabetes, metabolic syndrome, and NAFLD.

  8. Metabolic aspects of adult patients with nonalcoholic fatty liver disease

    PubMed Central

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD.

  9. Hepatocellular Carcinoma Management in Nonalcoholic Fatty Liver Disease Patients

    PubMed Central

    Oliveira, Claudia P.; Alvares-da-Silva, Mario R.; Tani, Claudia M.; Diniz, Marcio A.; Stefano, Jose T.; Chagas, Aline L.; Alencar, Regiane S.S.M.; Vezozzo, Denise C.P.; Santos, Gilmar R.; Campos, Priscila B.; Alves, Venancio AF.; Ratziu, Vlad; Carrilho, Flair J.

    2016-01-01

    Background/Aims: Nonalcoholic fatty liver disease (NAFLD) has emerged as an important cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The Barcelona Clinic Liver Cancer (BCLC) system is the preferred staging system to evaluate patients with HCC and links prognosis assessment with treatment recommendation. The aim of this retrospective study was to evaluate whether the BCLC staging system and its treatment algorithm are suitable for patients with HCC arising from NAFLD. Methods: Forty-two patients with HCC related to either to NAFLD or cryptogenic cirrhosis were retrieved retrospectively from 2 centers in Brazil. Patients were classified according to BCLC staging system. If the proposed HCC therapy could not be applied, the case was considered to represent deviations from the recommended BCLC guideline. Causes of treatment deviations were investigated. Results: There were 4 patients without evidence of cirrhosis according to liver biopsy and/or clinical evaluation. One (2%), 21 (50%), 10 (24%), 5 (12%), and 5 patients (12%) were classified initially to the very early (0), early (A), intermediate (B), advanced (C), and terminal (D) BCLC stages, respectively. Thirty-five patients (83%) were treated according to BCLC recommendations. There were 3 cases (of 5) of protocol deviation in BCLC C patients. The 1- and 2-year overall survival rates were 81% and 66%, respectively. Conclusions: The BCLC system is applied in most cases of NAFLD-related HCC cases. Deviation of BCLC is found more frequently in BCLC C stage patients. PMID:25268068

  10. ALCOHOLIC VERSUS NONALCOHOLIC CIRRHOSIS IN A RANDOMIZED CONTROLLED TRIAL OF EMERGENCY THERAPY OF BLEEDING VARICES

    PubMed Central

    Orloff, Marshall J.; Isenberg, Jon I.; Wheeler, Henry O.; Haynes, Kevin S.; Jinich-Brook, Horacio; Rapier, Roderick; Vaida, Florin; Hye, Robert J.; Orloff, Susan L.

    2010-01-01

    Background It has been proposed that portal-systemic shunts be avoided in alcoholic cirrhotics because survival rate is allegedly lower in alcoholics than in nonalcoholics. We examined this issue in a randomized controlled trial. Methods 211 unselected, consecutive patients with cirrhosis and bleeding esophageal varices were randomized to endoscopic sclerotherapy (EST) (n=106) or emergency portacaval shunt (EPCS) (105). Treatment was initiated within 8 hours. EST failure was treated by rescue PCS. 10-yr follow-up was 96%. Results Results strongly favored EPCS over EST (p<0.001). Among EPCS patients, 83% were alcoholic and 17% nonalcoholic. Outcomes were (1) permanent control of bleeding 100% vs. 100%; (2) 5-yr survival 71% vs.78%; (3) encephalopathy 14% vs. 19%; (4) yearly charges $38,300 vs. $43,000. Conclusions EPCS results were similar in alcoholic and nonalcoholic cirrhotics. EPCS is an effective first line emergency treatment in all forms of cirrhosis, including alcoholic. PMID:21195430

  11. Increased Brain Lactate Concentrations Without Increased Lactate Oxidation During Hypoglycemia in Type 1 Diabetic Individuals

    PubMed Central

    De Feyter, Henk M.; Mason, Graeme F.; Shulman, Gerald I.; Rothman, Douglas L.; Petersen, Kitt Falk

    2013-01-01

    Previous studies have reported that brain metabolism of acetate is increased more than twofold during hypoglycemia in type 1 diabetic (T1D) subjects with hypoglycemia unawareness. These data support the hypothesis that upregulation of blood-brain barrier monocarboxylic acid (MCA) transport may contribute to the maintenance of brain energetics during hypoglycemia in subjects with hypoglycemia unawareness. Plasma lactate concentrations are ∼10-fold higher than acetate concentrations, making lactate the most likely alternative MCA as brain fuel. We therefore examined transport of [3-13C]lactate across the blood-brain barrier and its metabolism in the brains of T1D patients and nondiabetic control subjects during a hypoglycemic clamp using 13C magnetic resonance spectroscopy. Brain lactate concentrations were more than fivefold higher (P < 0.05) during hypoglycemia in the T1D subjects compared with the control subjects. Surprisingly, we observed no increase in the oxidation of blood-borne lactate in the T1D subjects, as reflected by similar 13C fractional enrichments in brain glutamate and glutamine. Taken together, these data suggest that in addition to increased MCA transport at the blood-brain barrier, there may be additional metabolic adaptations that contribute to hypoglycemia unawareness in patients with T1D. PMID:23715622

  12. On line continuous monitoring of blood lactate in men by a wearable device based upon an enzymatic amperometric lactate sensor.

    PubMed

    Meyerhoff, C; Bischof, F; Mennel, F J; Sternberg, F; Bican, J; Pfeiffer, E F

    1993-01-01

    A wearable device for the continuous measurement of lactate in the blood was constructed by the combination of continuous blood sampling employing a double lumen catheter with an amperometric lactate sensor. In vitro, the lactate sensor turned out to have a linear concentration range between 0 and 15 mmol/l. The response time of the sensor itself amounted to 100 sec, whereas the lag time for blood sampling amounted to 2.2 min. In vivo, the lactate sensor was successfully used for the detection of changes of the blood lactate concentration following strenuous exercise in 7 healthy volunteers, in two cases up to 22 h. In conclusion, the technique of continuous blood sampling by the use of a double lumen catheter in combination with the amperometric lactate sensor is feasible and simplifies frequent blood lactate estimations.

  13. Interleukin-15-mediated inflammation promotes non-alcoholic fatty liver disease.

    PubMed

    Cepero-Donates, Yuneivy; Lacraz, Grégory; Ghobadi, Farnaz; Rakotoarivelo, Volatiana; Orkhis, Sakina; Mayhue, Marian; Chen, Yi-Guang; Rola-Pleszczynski, Marek; Menendez, Alfredo; Ilangumaran, Subburaj; Ramanathan, Sheela

    2016-06-01

    Interleukin-15 (IL-15) is essential for the homeostasis of lymphoid cells particularly memory CD8(+) T cells and NK cells. These cells are abundant in the liver, and are implicated in obesity-associated pathogenic processes. Here we characterized obesity-associated metabolic and cellular changes in the liver of mice lacking IL-15 or IL-15Rα. High fat diet-induced accumulation of lipids was diminished in the livers of mice deficient for IL-15 or IL-15Rα. Expression of enzymes involved in the transport of lipids in the liver showed modest differences. More strikingly, the liver tissues of IL15-KO and IL15Rα-KO mice showed decreased expression of chemokines CCl2, CCL5 and CXCL10 and reduced infiltration of mononuclear cells. In vitro, IL-15 stimulation induced chemokine gene expression in wildtype hepatocytes, but not in IL15Rα-deficient hepatocytes. Our results show that IL-15 is implicated in the high fat diet-induced lipid accumulation and inflammation in the liver, leading to fatty liver disease.

  14. Interleukin-15-mediated inflammation promotes non-alcoholic fatty liver disease.

    PubMed

    Cepero-Donates, Yuneivy; Lacraz, Grégory; Ghobadi, Farnaz; Rakotoarivelo, Volatiana; Orkhis, Sakina; Mayhue, Marian; Chen, Yi-Guang; Rola-Pleszczynski, Marek; Menendez, Alfredo; Ilangumaran, Subburaj; Ramanathan, Sheela

    2016-06-01

    Interleukin-15 (IL-15) is essential for the homeostasis of lymphoid cells particularly memory CD8(+) T cells and NK cells. These cells are abundant in the liver, and are implicated in obesity-associated pathogenic processes. Here we characterized obesity-associated metabolic and cellular changes in the liver of mice lacking IL-15 or IL-15Rα. High fat diet-induced accumulation of lipids was diminished in the livers of mice deficient for IL-15 or IL-15Rα. Expression of enzymes involved in the transport of lipids in the liver showed modest differences. More strikingly, the liver tissues of IL15-KO and IL15Rα-KO mice showed decreased expression of chemokines CCl2, CCL5 and CXCL10 and reduced infiltration of mononuclear cells. In vitro, IL-15 stimulation induced chemokine gene expression in wildtype hepatocytes, but not in IL15Rα-deficient hepatocytes. Our results show that IL-15 is implicated in the high fat diet-induced lipid accumulation and inflammation in the liver, leading to fatty liver disease. PMID:26868085

  15. Polymorphisms in the interleukin-10 gene promoter and the risk of alcoholism and alcoholic liver disease in Caucasian Spaniard men.

    PubMed

    Auguet, Teresa; Vidal, Francesc; Broch, Montserrat; Olona, Montserrat; Aguilar, Carmen; Morancho, Beatriz; López-Dupla, Miguel; Quer, Joan-Carles; Sirvent, Joan-Josep; Richart, Cristóbal

    2010-05-01

    Controversy surrounds the possible influence of the single nucleotide polymorphisms (SNPs) of the interleukin-10 (IL-10) gene promoter on the risk for alcoholic liver disease. Our aim was to determine whether the SNP of the IL-10 gene promoter are associated with an increased risk for alcoholism and for alcoholic liver disease in male Spaniards. The -627 C>A SNP of the IL-10 gene promoter was assessed in a cohort of 344 Caucasian Spanish men, 168 alcoholics, and 176 nonalcoholics. The alcoholic group comprised 79 individuals without liver histopathologic abnormalities and 89 patients with chronic alcoholic liver disease. The nonalcoholic group was made of 62 healthy controls and 114 patients with chronic nonalcoholic liver disease. Genotyping was performed using PCR and automatic sequencing analysis methods on white cell DNA. Genotype and allele frequencies were compared by using the chi(2) test. Overall, no differences in either genotype and allele distribution was observed when comparing the four patient categories defined (P=0.62 and P=0.33, respectively). Subset analyses showed no differences in the genotype and allele distributions between all alcoholic and all nonalcoholic subjects (P=0.55 and P=0.29, respectively). This study failed to detect significant associations of the IL-10 -627C>A SNP and alcoholism or alcoholic liver disease in a cohort of Caucasian male Spaniards.

  16. Nonalcoholic fatty liver disease and hepatic cirrhosis: Comparison with viral hepatitis-associated steatosis

    PubMed Central

    Haga, Yuki; Kanda, Tatsuo; Sasaki, Reina; Nakamura, Masato; Nakamoto, Shingo; Yokosuka, Osamu

    2015-01-01

    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. PMID:26675364

  17. 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. PMID:26675364

  18. [NUCLEAR STRUCTURE IN THE SECRETORY CELLS OF MAMMARY GLANDS IN LACTATING AND NON-LACTATING RATS].

    PubMed

    Tyutina, K V; Skopichev, V G; Bogolyubov, D S; Bogolyubova, I O

    2016-01-01

    The features of structural and functional organization of the main nuclear compartments and distribution of their key molecular components (chromatin-remodeling protein ATRX, RNA polymerase I and II, and the splicing factor SC35) has been studied in the nuclei of mammary gland cells at different functional states. No significant differences between the nuclei of the cells in the lactating and non-lactating mammary glands have been revealed at the ultrastructural level. At the same time, photometric analysis has revealed higher intensity of nucleoplasmic immunofluorescent staining of mammary glands in the lactating animals when antibodies against the proteins ATRX and SC35 were used. Apparently, this observation reflects the changes of the structural and functional status of chromatin as well as the redistribution of splicing factors between the sites of their deposition and transcription. PMID:27228661

  19. Brain lactate metabolism: the discoveries and the controversies

    PubMed Central

    Dienel, Gerald A

    2012-01-01

    Potential roles for lactate in the energetics of brain activation have changed radically during the past three decades, shifting from waste product to supplemental fuel and signaling molecule. Current models for lactate transport and metabolism involving cellular responses to excitatory neurotransmission are highly debated, owing, in part, to discordant results obtained in different experimental systems and conditions. Major conclusions drawn from tabular data summarizing results obtained in many laboratories are as follows: Glutamate-stimulated glycolysis is not an inherent property of all astrocyte cultures. Synaptosomes from the adult brain and many preparations of cultured neurons have high capacities to increase glucose transport, glycolysis, and glucose-supported respiration, and pathway rates are stimulated by glutamate and compounds that enhance metabolic demand. Lactate accumulation in activated tissue is a minor fraction of glucose metabolized and does not reflect pathway fluxes. Brain activation in subjects with low plasma lactate causes outward, brain-to-blood lactate gradients, and lactate is quickly released in substantial amounts. Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an ‘opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain. PMID:22186669

  20. An Animal Model for the Juvenile Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

    PubMed Central

    Marin, Veronica; Rosso, Natalia; Dal Ben, Matteo; Raseni, Alan; Boschelle, Manuela; Degrassi, Cristina; Nemeckova, Ivana; Nachtigal, Petr; Avellini, Claudio; Tiribelli, Claudio; Gazzin, Silvia

    2016-01-01

    Non Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) are the hepatic manifestations of the metabolic syndrome; worrisome is the booming increase in pediatric age. To recreate the full spectrum of juvenile liver pathology and investigate the gender impact, male and female C57Bl/6 mice were fed with high fat diet plus fructose in the drinking water (HFHC) immediately after weaning (equal to 3-years old human), and disease progression followed for 16 weeks, until adults (equal to 30-years old human). 100% of subjects of both genders on HFHC diet developed steatosis in 4weeks, and some degree of fibrosis in 8weeks, with the 86% of males and 15% of females presenting a stage 2 fibrosis at 16weeks. Despite a similar final liver damage both groups, a sex difference in the pathology progression was observed. Alterations in glucose homeostasis, dyslipidemia, hepatomegaly and obese phenotype were evident from the very beginning in males with an increased hepatic inflammatory activity. Conversely, such alterations were present in females only at the end of the HFHC diet (with the exception of insulin resistance and the hepatic inflammatory state). Interestingly, only females showed an altered hepatic redox state. This juvenile model appears a good platform to unravel the underlying gender dependent mechanisms in the progression from NAFLD to NASH, and to characterize novel therapeutic approaches. PMID:27391242

  1. Mancozeb, a fungicide routinely used in agriculture, worsens nonalcoholic fatty liver disease in the human HepG2 cell model.

    PubMed

    Pirozzi, Anna Virginia Adriana; Stellavato, Antonietta; La Gatta, Annalisa; Lamberti, Monica; Schiraldi, Chiara

    2016-05-13

    Mancozeb, a manganese/zinc ethylene-bis-dithiocarbamate, is a fungicide routinely used in pest control programs. However, it has been found to have deleterious effects on human health and on the environment. Indeed, its massive use has raised the issue of possible health risks for agrarian communities; the molecule can also reach human cells via the food chain and alter metabolism, endocrine activity and cell survival. In particular, mancozeb induces many toxic effects on hepatic cell metabolism. For this reason, we investigated its effect in an in vitro model of hepatic damage, namely fatty acid-induced nonalcoholic fatty liver disease in the HepG2 cell line. We found that the hepatic toxicity of the fungicide exacerbated fatty acid-induced steatosis, as manifested by an increase in intracellular lipid droplet accumulation. Furthermore, mancozeb altered cell metabolism and induced cell death through upregulation of lactate dehydrogenase and cytochrome c, respectively, in dose-dependent manners. Therefore, mancozeb may play an important role in the pathogenesis and progression of chronic disease in humans and represents a danger for human health in high doses. PMID:27016407

  2. Parity, Lactation, and Breast Cancer Subtypes in African American Women: Results from the AMBER Consortium

    PubMed Central

    Viscidi, Emma; Troester, Melissa A.; Hong, Chi-Chen; Schedin, Pepper; Bethea, Traci N.; Bandera, Elisa V.; Borges, Virginia; McKinnon, Craig; Haiman, Christopher A.; Lunetta, Kathryn; Kolonel, Laurence N.; Rosenberg, Lynn; Olshan, Andrew F.; Ambrosone, Christine B.

    2014-01-01

    Background African American (AA) women have a disproportionately high incidence of estrogen receptor–negative (ER-) breast cancer, a subtype with a largely unexplained etiology. Because childbearing patterns also differ by race/ethnicity, with higher parity and a lower prevalence of lactation in AA women, we investigated the relation of parity and lactation to risk of specific breast cancer subtypes. Methods Questionnaire data from two cohort and two case-control studies of breast cancer in AA women were combined and harmonized. Case patients were classified as ER+ (n = 2446), ER- (n = 1252), or triple negative (ER-, PR-, HER2-; n = 567) based on pathology data; there were 14180 control patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in polytomous logistic regression analysis with adjustment for study, age, reproductive and other risk factors. Results ORs for parity relative to nulliparity was 0.92 (95% CI = 0.81 to 1.03) for ER+, 1.33 (95% CI = 1.11 to 1.59) for ER-, and 1.37 (95% CI = 1.06 to 1.70) for triple-negative breast cancer. Lactation was associated with a reduced risk of ER- (OR = 0.81, 95% CI = 0.69 to 0.95) but not ER+ cancer. ER- cancer risk increased with each additional birth in women who had not breastfed, with an OR of 1.68 (95% CI = 1.15 to 2.44) for 4 or more births relative to one birth with lactation. Conclusions The findings suggest that parous women who have not breastfed are at increased risk of ER- and triple-negative breast cancer. Promotion of lactation may be an effective tool for reducing occurrence of the subtypes that contribute disproportionately to breast cancer mortality. PMID:25224496

  3. Effect of acid-base alterations on hepatic lactate utilization

    PubMed Central

    Goldstein, Philip J.; Simmons, Daniel H.; Tashkin, Donald P.

    1972-01-01

    1. The effect of acid-base changes on hepatic lactate utilization was investigated in anaesthetized, mechanically ventilated dogs. 2. Portal vein flow and hepatic artery flow were measured with electromagnetic flowmeters, lactate concentration of portal vein, arterial and mixed hepatic venous blood was determined by an enzymatic technique, and hepatic lactate uptake was calculated using the Fick principle. 3. Respiratory alkalosis (Δ pH 0·25 ± 0·02) in four dogs resulted in a significant fall in total hepatic blood flow (-22 ± 4%) and a significant rise in both arterial lactate concentration (2·18 ± 0·32 m-mole/l.) and hepatic lactate utilization (3·9 ± 1·2 μmole/min.kg). 4. 0·6 M-Tris buffer infusion (Δ pH 0·21 ± 0·02) in four dogs produced no significant changes in liver blood flow, arterial lactate concentration or hepatic lactate uptake. 5. Respiratory acidosis (Δ pH -0·20 ± 0·03) in six dogs and metabolic acidosis (Δ pH -0·20 ± 0·02) in four dogs produced no significant changes in liver blood flow, decreases in arterial lactate concentration of 0·38 ± 0·09 m-mole/l. (P < 0·05) and 0·13 ± 0·13 m-mole/l., respectively, and no significant changes in hepatic lactate uptake. 6. A significant correlation (r = 0·63; P < 0·01) was found between hepatic lactate utilization and arterial lactate concentration during the hyperlactataemia associated with respiratory alkalosis. 7. Hyperlactataemia induced in four dogs by infusion of buffered sodium lactate (Δ pH 0·05 ± 0·01;% Δ liver blood flow 29 ± 7%) was also significantly correlated with hepatic lactate utilization (r = 0·70; P < 0·01) and the slope of the regression was similar to that during respiratory alkalosis. 8. These data suggest that the hyperlactataemia of alkalosis is not due to impaired hepatic utilization of lactate and that the principal determinant of hepatic lactate uptake during alkalosis or lactate infusion is blood lactate concentration, rather than liver

  4. The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: Expression and action in brain.

    PubMed

    Morland, Cecilie; Lauritzen, Knut Husø; Puchades, Maja; Holm-Hansen, Signe; Andersson, Krister; Gjedde, Albert; Attramadal, Håvard; Storm-Mathisen, Jon; Bergersen, Linda Hildegard

    2015-07-01

    We have proposed that lactate is a "volume transmitter" in the brain and underpinned this by showing that the lactate receptor, G-protein-coupled receptor 81 (GPR81, also known as HCA1 or HCAR1), which promotes lipid storage in adipocytes, is also active in the mammalian brain. This includes the cerebral neocortex and the hippocampus, where it can be stimulated by physiological concentrations of lactate and by the HCAR1 agonist 3,5-dihydroxybenzoate to reduce cAMP levels. Cerebral HCAR1 is concentrated on the postsynaptic membranes of excitatory synapses and also is enriched at the blood-brain barrier. In synaptic spines and in adipocytes, HCAR1 immunoreactivity is also located on subplasmalemmal vesicular organelles, suggesting trafficking to and from the plasma membrane. Through activation of HCAR1, lactate can act as a volume transmitter that links neuronal activity, cerebral blood flow, energy metabolism, and energy substrate availability, including a glucose- and glycogen-saving response. HCAR1 may contribute to optimizing the cAMP concentration. For instance, in the prefrontal cortex, excessively high cAMP levels are implicated in impaired cognition in old age, fatigue, stress, and schizophrenia and in the deposition of phosphorylated tau protein in Alzheimer's disease. HCAR1 could serve to ameliorate these conditions and might also act through downstream mechanisms other than cAMP. Lactate exits cells through monocarboxylate transporters in an equilibrating manner and through astrocyte anion channels activated by depolarization. In addition to locally produced lactate, lactate produced by exercising muscle as well as exogenous HCAR1 agonists, e.g., from fruits and berries, might activate the receptor on cerebral blood vessels and brain cells. PMID:25881750

  5. The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: Expression and action in brain.

    PubMed

    Morland, Cecilie; Lauritzen, Knut Husø; Puchades, Maja; Holm-Hansen, Signe; Andersson, Krister; Gjedde, Albert; Attramadal, Håvard; Storm-Mathisen, Jon; Bergersen, Linda Hildegard

    2015-07-01

    We have proposed that lactate is a "volume transmitter" in the brain and underpinned this by showing that the lactate receptor, G-protein-coupled receptor 81 (GPR81, also known as HCA1 or HCAR1), which promotes lipid storage in adipocytes, is also active in the mammalian brain. This includes the cerebral neocortex and the hippocampus, where it can be stimulated by physiological concentrations of lactate and by the HCAR1 agonist 3,5-dihydroxybenzoate to reduce cAMP levels. Cerebral HCAR1 is concentrated on the postsynaptic membranes of excitatory synapses and also is enriched at the blood-brain barrier. In synaptic spines and in adipocytes, HCAR1 immunoreactivity is also located on subplasmalemmal vesicular organelles, suggesting trafficking to and from the plasma membrane. Through activation of HCAR1, lactate can act as a volume transmitter that links neuronal activity, cerebral blood flow, energy metabolism, and energy substrate availability, including a glucose- and glycogen-saving response. HCAR1 may contribute to optimizing the cAMP concentration. For instance, in the prefrontal cortex, excessively high cAMP levels are implicated in impaired cognition in old age, fatigue, stress, and schizophrenia and in the deposition of phosphorylated tau protein in Alzheimer's disease. HCAR1 could serve to ameliorate these conditions and might also act through downstream mechanisms other than cAMP. Lactate exits cells through monocarboxylate transporters in an equilibrating manner and through astrocyte anion channels activated by depolarization. In addition to locally produced lactate, lactate produced by exercising muscle as well as exogenous HCAR1 agonists, e.g., from fruits and berries, might activate the receptor on cerebral blood vessels and brain cells.

  6. A comparison of potato and vertebrate lactate dehydrogenases.

    PubMed Central

    Poerio, E; Davies, D D

    1980-01-01

    A 2000-fold purification of L(+)-lactate dehydrogenase from potatoes is reported. Five isoenzymes of lactate dehydrogenase can be detected in crude extracts of potato, and three of these are present in the purified preparation. The enzyme (mol.wt. 150 000), which is composed of four subunits (mol.wt. 37 500), is active with the same oxo acids and hydroxy acids that have been reported as substrates with the same oxo acids and hydroxy acids that have been reported as substrates for vertebrate lactate dehydrogenases. These similarities between potato and vertebrate lactate dehydrogenases contrast sharply with some other reports on potato lactate dehydrogenase. These discrepancies are discussed in relation to the proposition that vertebrate and potato lactate dehydrogenases share a common evolutionary origin. PMID:7236200

  7. NEUROENDOCRINE ACTIONS AND REGULATION OF HYPOTHALAMIC NEUROPEPTIDE Y DURING LACTATION

    PubMed Central

    Crowley, W,R.; Ramoz, G.; Torto, R.; Keefe, K.A.; Wang, J. J.; Kalra, S. P.

    2007-01-01

    The expression of neuropeptide Y (NPY) and its co-messenger, agouti-related peptide (AgRP), in arcuate neurons of the hypothalamus is increased during lactation in rats. Our research has been addressing the questions of the physiological actions of these peptides during lactation and the physiological signals associated with lactation that result in increased expression of their genes. Our studies indicate that NPY and AgRP exert pleiotropic actions during lactation that help integrate neuroendocrine regulation of energy balance with controls over anterior and posterior pituitary hormone secretion. Further, reciprocal signaling to the NPY/AgRP system by leptin and ghrelin is responsible for the changes in expression of these hypothalamic peptides in lactating animals, and thus, may contribute to regulation of food intake and the various neuroendocrine adaptations of lactation. PMID:17241697

  8. Essential role for a novel population of binucleated mammary epithelial cells in lactation.

    PubMed

    Rios, Anne C; Fu, Nai Yang; Jamieson, Paul R; Pal, Bhupinder; Whitehead, Lachlan; Nicholas, Kevin R; Lindeman, Geoffrey J; Visvader, Jane E

    2016-01-01

    The mammary gland represents a unique tissue to study organogenesis as it predominantly develops in the post-natal animal and undergoes dramatic morphogenetic changes during puberty and the reproductive cycle. The physiological function of the mammary gland is to produce milk to sustain the newborn. Here we view the lactating gland through three-dimensional confocal imaging of intact tissue. We observed that the majority of secretory alveolar cells are binucleated. These cells first arise in very late pregnancy due to failure of cytokinesis and are larger than mononucleated cells. Augmented expression of Aurora kinase-A and Polo-like kinase-1 at the lactogenic switch likely mediates the formation of binucleated cells. Our findings demonstrate an important physiological role for polyploid mammary epithelial cells in lactation, and based on their presence in five different species, suggest that binucleated cells evolved to maximize milk production and promote the survival of offspring across all mammalian species. PMID:27102712

  9. Essential role for a novel population of binucleated mammary epithelial cells in lactation.

    PubMed

    Rios, Anne C; Fu, Nai Yang; Jamieson, Paul R; Pal, Bhupinder; Whitehead, Lachlan; Nicholas, Kevin R; Lindeman, Geoffrey J; Visvader, Jane E

    2016-04-22

    The mammary gland represents a unique tissue to study organogenesis as it predominantly develops in the post-natal animal and undergoes dramatic morphogenetic changes during puberty and the reproductive cycle. The physiological function of the mammary gland is to produce milk to sustain the newborn. Here we view the lactating gland through three-dimensional confocal imaging of intact tissue. We observed that the majority of secretory alveolar cells are binucleated. These cells first arise in very late pregnancy due to failure of cytokinesis and are larger than mononucleated cells. Augmented expression of Aurora kinase-A and Polo-like kinase-1 at the lactogenic switch likely mediates the formation of binucleated cells. Our findings demonstrate an important physiological role for polyploid mammary epithelial cells in lactation, and based on their presence in five different species, suggest that binucleated cells evolved to maximize milk production and promote the survival of offspring across all mammalian species.

  10. Essential role for a novel population of binucleated mammary epithelial cells in lactation

    PubMed Central

    Rios, Anne C.; Fu, Nai Yang; Jamieson, Paul R.; Pal, Bhupinder; Whitehead, Lachlan; Nicholas, Kevin R.; Lindeman, Geoffrey J.; Visvader, Jane E.

    2016-01-01

    The mammary gland represents a unique tissue to study organogenesis as it predominantly develops in the post-natal animal and undergoes dramatic morphogenetic changes during puberty and the reproductive cycle. The physiological function of the mammary gland is to produce milk to sustain the newborn. Here we view the lactating gland through three-dimensional confocal imaging of intact tissue. We observed that the majority of secretory alveolar cells are binucleated. These cells first arise in very late pregnancy due to failure of cytokinesis and are larger than mononucleated cells. Augmented expression of Aurora kinase-A and Polo-like kinase-1 at the lactogenic switch likely mediates the formation of binucleated cells. Our findings demonstrate an important physiological role for polyploid mammary epithelial cells in lactation, and based on their presence in five different species, suggest that binucleated cells evolved to maximize milk production and promote the survival of offspring across all mammalian species. PMID:27102712

  11. FGF21 ameliorates nonalcoholic fatty liver disease by inducing autophagy.

    PubMed

    Zhu, Shenglong; Wu, Yunzhou; Ye, Xianlong; Ma, Lei; Qi, Jianying; Yu, Dan; Wei, Yuquan; Lin, Guangxiao; Ren, Guiping; Li, Deshan

    2016-09-01

    The aim of this study is to evaluate the role of fibroblast growth factor 21 (FGF21) in nonalcoholic fatty liver disease (NAFLD) and seek to determine if its therapeutic effect is through induction of autophagy. In this research, Monosodium L-glutamate (MSG)-induced obese mice or normal lean mice were treated with vehicle, Fenofibrate, and recombinant murine FGF21, respectively. After 5 weeks of treatment, metabolic parameters including body weight, blood glucose and lipid levels, hepatic and fat gene expression levels were monitored and analyzed. Also, fat-loaded HepG2 cells were treated with vehicle or recombinant murine FGF21. The expression levels of proteins associated with autophagy were detected by western blot, real-time PCR, and transmission electron microscopy (TEM). Autophagic flux was monitored by laser confocal microscopy and western blot. Results showed that FGF21 significantly reduced body weight (P < 0.01) and serum triglyceride, improved insulin sensitivity, and reversed hepatic steatosis in the MSG model mice. In addition, FGF21 significantly increased the expression of several proteins related to autophagy both in MSG mice and fat-loaded HepG2 cells, such as microtubule associated protein 1 light chain 3, Bcl-2-interacting myosin-like coiled-coil protein-1 (Beclin-1), and autophagy-related gene 5. Furthermore, the evidence of TEM revealed an increased number of autophagosomes and lysosomes in the model cells treated with FGF21. In vitro experimental results also showed that FGF21 remarkably increased autophagic flux. Taken together, FGF21 corrects multiple metabolic parameters on NAFLD in vitro and in vivo by inducing autophagy. PMID:27435856

  12. Comparative efficacy of interventions on nonalcoholic fatty liver disease (NAFLD)

    PubMed Central

    Sawangjit, Ratree; Chongmelaxme, Bunchai; Phisalprapa, Pochamana; Saokaew, Surasak; Thakkinstian, Ammarin; Kowdley, Kris V.; Chaiyakunapruk, Nathorn

    2016-01-01

    Abstract Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) has significantly increased over the last decades. Despite existence of several interventions, there remains unclear which interventions work the best. Methods: A systematic review and network meta-analysis of randomized trials comparing efficacy of all treatment options in NAFLD were performed to determine comparative efficacy and safety of interventions in the management of NAFLD. Several electronic databases were searched up to Nov 15, 2015. Outcomes include liver histological outcomes (i.e., fibrosis), all-cause mortality, cirrhosis, and safety. A network meta-analysis was applied to estimate pooled risk ratios (RR). Quality of evidence was assessed using GRADE criteria. Results: A total of 44 studies (n = 3802) were eligible. When compared with placebo, obeticholic acid (OCA) was the only intervention that significantly improved fibrosis with RR (95% CI) of 1.91 (1.15, 3.16), while pentoxyfylline (PTX) demonstrated improved fibrosis without statistical significance with RR (95% CI) of 2.27 (0.81, 6.36). Only thiazolidinedione (TZD) and vitamin E use resulted in significant increase in resolution of NASH, while OCA, TZD, and vitamin E significantly improved other outcomes including NAS, steatosis, ballooning, and inflammation outcomes. Quality of evidence varied from very low (i.e., metformin, PTX on mean change of ballooning grade) to high (OCA, TZD, vitamin E on improving histological outcomes). Limitations of this study were lack of relevant long-term outcomes (e.g., cirrhosis, death, safety), possible small study effect, and few head-to-head studies. Conclusions: Our study suggests potential efficacy of OCA, TZD, and vitamin E in improving histologic endpoints in NAFLD. These findings are however based on a small number of studies. Additional studies are awaited to strengthen this network meta-analysis. PMID:27512874

  13. Non-Alcoholic Fatty Liver Disease (NAFLD) in Obesity

    PubMed Central

    Patell, Rushad; Dosi, Rupal; Joshi, Harshal; Sheth, Smit; Shah, Purav; Jasdanwala, Sarfaraz

    2014-01-01

    Background and Objectives: Limited studies have been undertaken to characterize Non-Alcoholic Fatty Liver Disease (NAFLD) in the Indian population. The main objective of our study was to document the prevalence of NAFLD amongst a cohort of obese Indian patients and demonstrate its relationship with other components of the metabolic syndrome. Methods: A total of 60 adult obese patients were subjected to a detailed history, clinical exam, anthropometric study and laboratory workup. Focus was on liver function and components of the metabolic syndrome like blood pressure, glycemic status and lipid profile. Subjects enrolled were divided into two groups Group A (n=48), with NAFLD and Group B (n=12) without NAFLD. The two groups were then compared amongst themselves as well as with data from previous similar studies. Results: A comparison of the anthropometric measurements revealed a statistically significant difference between the Body mass index (BMI) and Waist Hip Ratio of the two groups and in the mean triglyceride values between the two groups. Although the mean bilirubin levels measured in the serum were not statistically different the mean levels of SGOT and SGPT in the two groups was found to be statistically significant. On the contrary no significant difference in the values of alkaline phosphatase and synthetic liver functions could be discerned. A statistically highly significant difference in the mean liver span is seen. Interpretation and Conclusions: NAFLD is common in Indian obese populations and is associated with significant differences in anthropometric, clinical, laboratory and ultrasonographic aspects as compared with obese individuals not affected with liver disease. PMID:24596725

  14. 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

  15. Mechanism of Altered Metformin Distribution in Nonalcoholic Steatohepatitis

    PubMed Central

    Clarke, John D.; Dzierlenga, Anika L.; Nelson, Nicholas R.; Li, Hui; Werts, Samantha; Goedken, Michael J.

    2015-01-01

    Metformin is an antihyperglycemic drug that is widely prescribed for type 2 diabetes mellitus and is currently being investigated for the treatment of nonalcoholic steatohepatitis (NASH). NASH is known to alter hepatic membrane transporter expression and drug disposition similarly in humans and rodent models of NASH. Metformin is almost exclusively eliminated through the kidney primarily through active secretion mediated by Oct1, Oct2, and Mate1. The purpose of this study was to determine how NASH affects kidney transporter expression and metformin pharmacokinetics. A single oral dose of [14C]metformin was administered to C57BL/6J (wild type [WT]) and diabetic ob/ob mice fed either a control diet or a methionine- and choline-deficient (MCD) diet. Metformin plasma concentrations were slightly increased in the WT/MCD and ob/control groups, whereas plasma concentrations were 4.8-fold higher in ob/MCD mice compared with WT/control. The MCD diet significantly increased plasma half-life and mean residence time and correspondingly decreased oral clearance in both genotypes. These changes in disposition were caused by ob/ob- and MCD diet–specific decreases in the kidney mRNA expression of Oct2 and Mate1, whereas Oct1 mRNA expression was only decreased in ob/MCD mice. These results indicate that the diabetic ob/ob genotype and the MCD disease model alter kidney transporter expression and alter the pharmacokinetics of metformin, potentially increasing the risk of drug toxicity. PMID:26016715

  16. The Association between Nonalcoholic Fatty Pancreas Disease and Diabetes

    PubMed Central

    Yang, Yi-Ching; Chen, Ming-Fong; Chang, Chih-Jen

    2013-01-01

    Background Fatty infiltration of the pancreas has been shown to interfere with insulin secretion. Both insulin sensitivity and secretion are important in the pathogenesis of diabetes and prediabetes. However, the relationship between diabetes, prediabetes, and fatty pancreas remains unknown. We aim to investigate the relationships that fatty pancreas and nonalcoholic fatty liver disease (NAFLD) have with prediabetes and diabetes in a Chinese population. Patients and Methods This was a cross-sectional study. A total of 7,464 subjects were recruited. NAFLD and fatty pancreas were assessed by sonography. Clinico-metabolic parameters were compared among subjects with normoglycemia, prediabetes, and diabetes. Multinomial logistic regression was used to evaluate the relationship between fatty pancreas and NAFLD and diabetes or prediabetes with adjustment for cardiometabolic risk factors. Results With an increase in glycemia, a significantly greater proportion of subjects had NAFLD and fatty pancreas (test for trend p<0.05). Similar trends were also found for hypertension, general and central obesity, low-HDL cholesterol, and hypertriglyceridemia. In the logistic regression analysis, age, hypertension, male gender, hypertriglyceridemia, and central obesity were significantly associated with prediabetes and diabetes. Furthermore, the ORs of prediabetes and diabetes for NAFLD were 1.798 (95% CI 1.544–2.094) and 2.578 (95% CI 2.024–3.284), respectively. In addition, fatty pancreas was independently related to diabetes (OR, 1.379; 95% CI, 1.047–1.816) and prediabetes (OR, 1.222; 95% CI, 1.002–1.491) in male subjects. Conclusions Both NAFLD and fatty pancreas were associated with diabetes independent of age, gender, adiposity, and other cardiometabolic risk factors. Fatty pancreas was also related to prediabetes in males. PMID:23671610

  17. Prolactin and the dietary protein/carbohydrate ratio regulate the expression of SNAT2 amino acid transporter in the mammary gland during lactation.

    PubMed

    Velázquez-Villegas, Laura A; López-Barradas, Adriana M; Torres, Nimbe; Hernández-Pando, Rogelio; León-Contreras, Juan Carlos; Granados, Omar; Ortíz, Victor; Tovar, Armando R

    2015-05-01

    The sodium coupled neutral amino acid transporter 2 (SNAT2/SAT2/ATA2) is expressed in the mammary gland (MG) and plays an important role in the uptake of alanine and glutamine which are the most abundant amino acids transported into this tissue during lactation. Thus, the aim of this study was to assess the amount and localization of SNAT2 before delivery and during lactation in rat MG, and to evaluate whether prolactin and the dietary protein/carbohydrate ratio might influence SNAT2 expression in the MG, liver and adipose tissue during lactation. Our results showed that SNAT2 protein abundance in the MG increased during lactation and this increase was maintained along this period, while 24 h after weaning it tended to decrease. To study the effect of prolactin on SNAT2 expression, we incubated MG explants or T47D cells transfected with the SNAT2 promoter with prolactin, and we observed in both studies an increase in the SNAT2 expression or promoter activity. Consumption of a high-protein/low carbohydrate diet increased prolactin concentration, with a concomitant increase in SNAT2 expression not only in the MG during lactation, but also in the liver and adipose tissue. There was a correlation between SNAT2 expression and serum prolactin levels depending on the amount of dietary protein/carbohydrate ratio consumed. These findings suggest that prolactin actively supports lactation providing amino acids to the gland through SNAT2 for the synthesis of milk proteins.

  18. Enhanced responsiveness to selective serotonin reuptake inhibitors during lactation.

    PubMed

    Jury, Nicholas J; McCormick, Betsy A; Horseman, Nelson D; Benoit, Stephen C; Gregerson, Karen A

    2015-01-01

    The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence

  19. Glucose and lactate kinetics in American eel Anguilla rostrata.

    PubMed

    Cornish, I; Moon, T W

    1985-07-01

    Simultaneous infusion of [6-3H]glucose and [U-14C]lactate was used to calculate the turnover rate of glucose, the irreversible replacement rate of lactate, and the rates of the exchange of carbon atoms between glucose and lactate in free-swimming American eels (Anguilla rostrata) fed or food deprived for 6, 15, and 36 (maturing) mo. The mean turnover rate of glucose in fed animals averaged 1.0 mg X min-1 X 100 g-1, while the lactate irreversible replacement rate was approximately 4.0 micrograms X min-1 X 100 g-1. The conversion of 35% of lactate carbon to glucose implied a substantial Cori cycle activity, but this amounted to less than 1% of total glucose production. Food deprivation for 6 mo altered few kinetic patterns, except for an increased lactate irreversible replacement rate and a minor increase in gluconeogenesis from lactate. After a 15-mo fast, glucose turnover decreased to 0.09 +/- 0.02 mg X min-1 X 100 g-1. Plasma lactate concentrations and production rates continuously increased during the experiment. Maturing eels that had been food deprived for 36 mo maintained glucose and lactate concentrations and kinetics similar to values in animals food deprived for only 6 mo. This study stresses the importance of carbohydrate in the metabolism of this species under fed and food-deprived conditions and further supports the tolerance of Anguillid species to food deprivation.

  20. Lactate Storm Marks Cerebral Metabolism following Brain Trauma*

    PubMed Central

    Lama, Sanju; Auer, Roland N.; Tyson, Randy; Gallagher, Clare N.; Tomanek, Boguslaw; Sutherland, Garnette R.

    2014-01-01

    Brain metabolism is thought to be maintained by neuronal-glial metabolic coupling. Glia take up glutamate from the synaptic cleft for conversion into glutamine, triggering glial glycolysis and lactate production. This lactate is shuttled into neurons and further metabolized. The origin and role of lactate in severe traumatic brain injury (TBI) remains controversial. Using a modified weight drop model of severe TBI and magnetic resonance (MR) spectroscopy with infusion of 13C-labeled glucose, lactate, and acetate, the present study investigated the possibility that neuronal-glial metabolism is uncoupled following severe TBI. Histopathology of the model showed severe brain injury with subarachnoid and hemorrhage together with glial cell activation and positive staining for Tau at 90 min post-trauma. High resolution MR spectroscopy of brain metabolites revealed significant labeling of lactate at C-3 and C-2 irrespective of the infused substrates. Increased 13C-labeled lactate in all study groups in the absence of ischemia implied activated astrocytic glycolysis and production of lactate with failure of neuronal uptake (i.e. a loss of glial sensing for glutamate). The early increase in extracellular lactate in severe TBI with the injured neurons rendered unable to pick it up probably contributes to a rapid progression toward irreversible injury and pan-necrosis. Hence, a method to detect and scavenge the excess extracellular lactate on site or early following severe TBI may be a potential primary therapeutic measure. PMID:24849602

  1. Is lactate the new panacea for endothelial dysfunction?

    PubMed

    Nalos, Marek; Tang, Benjamin M; Nanan, Ralph

    2014-01-01

    Fluid resuscitation in the critically ill is a hot topic. The current strategy of rapid and adequate resuscitation in shock followed by conservative fluid administration is often difficult to achieve with standard crystalloid solutions. Research into alternative intravenous fluids tailored to individual patient needs is required. In the previous issue of Critical Care, Somasetia and colleagues compare the effects of hypertonic sodium lactate with the World Health Organization-recommended strategy of Ringer's lactate resuscitation in children with severe Dengue, a viral infection for which causal treatment and vaccination are not available. The results not only suggest unimpaired lactate metabolism during shock in children but document improvement in endothelial barrier function, limited coagulopathy, and avoidance of fluid overload with hypertonic sodium lactate. Their study invites several important questions to be answered. Is hypertonicity or lactate per se important for the beneficial effects? Are the metabolic or anti-inflammatory effects responsible? Is the raised lactate in shock an adaptive response? Should reduction in lactate levels be the goal of resuscitation? These questions may trigger further research into the role of lactate and lactate-based intravenous fluids in resuscitation of the critically ill. PMID:25672811

  2. 21 CFR 862.1445 - Lactate dehydrogenase isoenzymes test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... dehydrogenase isoenzymes test system is a device intended to measure the activity of lactate dehydrogenase isoenzymes (a group of enzymes with similar biological activity) in serum. Measurements of...

  3. 21 CFR 862.1445 - Lactate dehydrogenase isoenzymes test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... dehydrogenase isoenzymes test system is a device intended to measure the activity of lactate dehydrogenase isoenzymes (a group of enzymes with similar biological activity) in serum. Measurements of...

  4. 21 CFR 862.1445 - Lactate dehydrogenase isoenzymes test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... dehydrogenase isoenzymes test system is a device intended to measure the activity of lactate dehydrogenase isoenzymes (a group of enzymes with similar biological activity) in serum. Measurements of...

  5. 21 CFR 862.1445 - Lactate dehydrogenase isoenzymes test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... dehydrogenase isoenzymes test system is a device intended to measure the activity of lactate dehydrogenase isoenzymes (a group of enzymes with similar biological activity) in serum. Measurements of...

  6. 21 CFR 862.1445 - Lactate dehydrogenase isoenzymes test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... dehydrogenase isoenzymes test system is a device intended to measure the activity of lactate dehydrogenase isoenzymes (a group of enzymes with similar biological activity) in serum. Measurements of...

  7. Amperometric detection of L-lactate using nitrogen-doped carbon nanotubes modified with lactate oxidase.

    PubMed

    Goran, Jacob M; Lyon, Jennifer L; Stevenson, Keith J

    2011-11-01

    Nitrogen-doped carbon nanotubes (N-CNTs) provide a simple, robust, and unique platform for biosensing. Their catalytic activity toward the oxygen reduction reaction (ORR) and subsequent hydrogen peroxide (H(2)O(2)) disproportionation creates a sensitive electrochemical response to enzymatically generated H(2)O(2) on the N-CNT surface, eliminating the need for additional peroxidases or electron-transfer mediators. Glassy carbon electrodes were modified with 7.4 atom % N-CNTs, lactate oxidase (LOx), and a tetrabutylammonium bromide (TBABr)-modified Nafion binder. The resulting amperometric l-lactate biosensors displayed a sensitivity of 0.040 ± 0.002 A M(-1) cm(-2), a low operating potential of -0.23 V (vs Hg/Hg(2)SO(4)), a repeatability of 1.6% relative standard deviation (RSD) for 200 μM samples of lactate, a fabrication reproducibility of 5.0% (RSD), a limit of detection of 4.1 ± 1.6 μM, and a linear range of 14-325 μM. Additionally, over a 90 day period, the repeatability for 200 μM samples of lactate remained below 3.4% (RSD). Direct electron transfer was observed between the LOx redox-active center and the N-CNTs with the electroactive surface coverage determined to be 0.27 nmol cm(-2).

  8. Correlations between lactate and ventilatory thresholds and the maximal lactate steady state in elite cyclists.

    PubMed

    Van Schuylenbergh, R; Vanden Eynde, B; Hespel, P

    2004-08-01

    We investigated the validity of different lactate and ventilatory threshold methods, to estimate heart rate and power output corresponding with the maximal lactate steady-state (MLSS) in elite cyclists. Elite cyclists (n = 21; 21 +/- 0.4 y; VO2peak, 5.4 +/- 0.2 l x min (-1)) performed either one (n = 10) or two (n = 11) maximal graded exercise tests, as well as two to three 30-min constant-load tests to determine MLSS, on their personal race bicycle which was mounted on an ergometer. Initial workload for the graded tests was 100 Watt and was increased by either 5 % of body mass (in Watt) with every 30 s (T30 s), or 60 % of body mass (in Watt) with every 6 min (T6min). MLSS was defined as the highest constant workload during which lactate increased no more than 1 mmol x l (-1) from min 10 to 30. In T30 s and T6 min the 4 mmol (TH-La4), the Conconi (TH-Con) and dmax (TH-Dm) lactate threshold were determined. The dmax lactate threshold was defined as the point that yields the maximal distance from the lactate curve to the line formed by the lowest and highest lactate values of the curve. In T30 s also ventilatory (TH-Ve) and Vslope (TH-Vs) thresholds were calculated. Time to exhaustion was 36 +/- 1 min for T30 s versus 39 +/- 1 min for T6 min. None of the threshold measures in T30 s, except TH-Vs (r2 = 0.77 for heart rate) correlated with either MLSS heart rate or power output. During T6 min, power output at TH-Dm was closely correlated with MLSS power (r2=0.72). Low correlations were found between MLSS heart rate and heart rate measured at TH-Dm (r2=0.46) and TH-La4 (r2=0.25), respectively, during T6 min. It is concluded that it is not possible to precisely predict heart rate or power output corresponding with MLSS in elite cyclists, from a single graded exercise test causing exhaustion within 35-40 min. The validity of MLSS predicted from an incremental test must be verified by a 30-min constant-load test.

  9. Comparison of Alcoholic and Non-Alcoholic Students in a Community College Addictions Program.

    ERIC Educational Resources Information Center

    Hohman, Melinda M.

    1998-01-01

    One hundred eighty community college students enrolled in an alcohol and drug counseling certification program were surveyed to determine differences between recovering alcoholic/addicts and nonalcoholics. Alcoholic students had less education and income, were more likely to be enrolled for personal growth, or to obtain a job in the addictions…

  10. Attributional Style, Depressive Features, and Self-Esteem: Adult Children of Alcoholic and Nonalcoholic Parents.

    ERIC Educational Resources Information Center

    Bush, Stephanie I.; And Others

    1995-01-01

    Undergraduate adult children of alcoholics (ACOAs) (n=57) were compared with children of nonalcoholic parents (n=100) on depression, self-esteem, and attributional style. ACOAs were found to have higher depression scores and lower self-esteem and were more likely to have a depressive attributional style. (SLD)

  11. Blood lactate levels of decathletes during competition.

    PubMed Central

    Beaulieu, P; Ottoz, H; Grange, C; Thomas, J; Bensch, C

    1995-01-01

    There are many detailed physiological profiles of athletes who participate in a wide variety of sporting activities but few data have been obtained on decathletes. This study defines some physiological characteristics of these athletes and measures capillary lactate concentrations [La(b)] during a laboratory test of progressive maximal exhaustion and the different events during competition. The treadmill test is similar to the 100 m, 400 m and 1500 m in terms of [La(b)] accumulation but only similar to the 1500 m in terms of velocity. The 400 m is the most demanding event with the greatest blood lactate accumulation (mean(s.d.) 16.38(2.36) mmol l-1). The [La(b)] at the end of the 110 m hurdles is significantly lower than in any other racing events (mean(s.d.) 6.96(1.32) mmol l-1) compared with mean(s.d.) 12.14(2.87) and mean(s.d.) 11.44(2.16) for the 100 m and 1500 m respectively. The [La(b)] after the long jump, the high jump and the pole vault are not significantly different (mean(s.d.) 5.30(2.23), 4.64(1.39) and 5.36(1.34) mmol l-1) respectively). PMID:7551765

  12. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease.

    PubMed

    Tallino, Savannah; Duffy, Megan; Ralle, Martina; Cortés, María Paz; Latorre, Mauricio; Burkhead, Jason L

    2015-10-01

    Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low-Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change > 2, P < 0.02). Low dietary Cu decreased hepatic and serum Cu (P ≤ 0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis.

  13. Cellular cholesterol accumulation modulates high fat high sucrose (HFHS) diet-induced ER stress and hepatic inflammasome activation in the development of non-alcoholic steatohepatitis.

    PubMed

    Bashiri, Amir; Nesan, Dinushan; Tavallaee, Ghazaleh; Sue-Chue-Lam, Ian; Chien, Kevin; Maguire, Graham F; Naples, Mark; Zhang, Jing; Magomedova, Lilia; Adeli, Khosrow; Cummins, Carolyn L; Ng, Dominic S

    2016-07-01

    Non-alcoholic steatohepatitis (NASH), is the form of non-alcoholic fatty liver disease posing risk to progress into serious long term complications. Human and pre-clinical models implicate cellular cholesterol dysregulation playing important role in its development. Mouse model studies suggest synergism between dietary cholesterol and fat in contributing to NASH but the mechanisms remain poorly understood. Our laboratory previously reported the primary importance of hepatic endoplasmic reticulum cholesterol (ER-Chol) in regulating hepatic ER stress by comparing the responses of wild type, Ldlr-/-xLcat+/+ and Ldlr-/-xLcat-/- mice, to a 2% high cholesterol diet (HCD). Here we further investigated the roles of ER-Chol and ER stress in HFHS diet-induced NASH using the same strains. With HFHS diet feeding, both WT and Ldlr-/-xLcat+/+ accumulate ER-Chol in association with ER stress and inflammasome activation but the Ldlr-/-xLcat-/- mice are protected. By contrast, all three strains accumulate cholesterol crystal, in correlation with ER-Chol, albeit less so in Ldlr-/-xLcat-/- mice. By comparison, HCD feeding per se (i) is sufficient to promote steatosis and activate inflammasomes, and (ii) results in dramatic accumulation of cholesterol crystal which is linked to inflammasome activation in Ldlr-/-xLcat-/- mice, independent of ER-Chol. Our data suggest that both dietary fat and cholesterol each independently promote steatosis, cholesterol crystal accumulation and inflammasome activation through distinct but complementary pathways. In vitro studies using palmitate-induced hepatic steatosis in HepG2 cells confirm the key roles by cellular cholesterol in the induction of steatosis and inflammasome activations. These novel findings provide opportunities for exploring a cellular cholesterol-focused strategy for treatment of NASH. PMID:27090939

  14. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease.

    PubMed

    Tallino, Savannah; Duffy, Megan; Ralle, Martina; Cortés, María Paz; Latorre, Mauricio; Burkhead, Jason L

    2015-10-01

    Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low-Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change > 2, P < 0.02). Low dietary Cu decreased hepatic and serum Cu (P ≤ 0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis. PMID:26033743

  15. Protective role of autophagy in methionine-choline deficient diet-induced advanced nonalcoholic steatohepatitis in mice.

    PubMed

    Chen, Rui; Wang, Quanxing; Song, Shaohua; Liu, Fang; He, Bin; Gao, Xiaogang

    2016-01-01

    The methionine choline-deficient (MCD) diet leads to severe liver injury similar to human nonalcoholic steatohepatitis (NASH). Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. The goal of this study was to elucidate the role of autophagy in MCD-induced steatosis, fibrosis, inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in mice. Mice were fed with MCD diet and treated with rapamycin (an autophagy enhancer) or chloroquine (an autophagy inhibitor) for 10 weeks. Liver injury was evaluated biochemically and histologically together with hepatic gene expression analysis. Autophagic flux was impaired in livers of mice fed with MCD diet, evidenced by reduced ratio of LC3-II/LC3-I and increased protein expression of p62. It was found that autophagy activation by rapamycin attenuated MCD-induced steatosis, fibrosis, inflammation, mitochondrial dysfunction, and ER stress. By contrast, MCD mice treated with chloroquine developed more liver injury. In conclusions, the autophagic pathway plays an important protective role in MCD-induced advanced NASH. Thus, pharmacological promotion of autophagy may provide a novel therapeutic strategy for treatment of NASH.

  16. Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease

    PubMed Central

    Shoji, Hirotaka; Yoshio, Sachiyo; Mano, Yohei; Kumagai, Erina; Sugiyama, Masaya; Korenaga, Masaaki; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Aikata, Hiroshi; Hyogo, Hideyuki; Chayama, Kazuaki; Ohashi, Tomohiko; Ito, Kiyoaki; Yoneda, Masashi; Nozaki, Yuichi; Kawaguchi, Takumi; Torimura, Takuji; Abe, Masanori; Hiasa, Yoichi; Fukai, Moto; Kamiyama, Toshiya; Taketomi, Akinobu; Mizokami, Masashi; Kanto, Tatsuya

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. Activation of macrophages and hepatic stellate cells is a critical step that promotes liver fibrosis. We aimed to explore the feasibility of interleukin-34 (IL-34), a key regulator of macrophages, as a fibrosis marker in patients with NAFLD. We enrolled 197 liver biopsy-proven NAFLD patients. We evaluated the serum levels of IL-34, macrophage-colony stimulating factor (M-CSF), soluble CD163 (sCD163), 40 cytokines/chemokines, hyaluronic acid, type IV collagen 7s, and clinically-approved fibrosis scores. IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis. Immunostaining experiments, using resected liver specimens from NAFLD patients, revealed that IL-34 was mainly expressed on liver fibroblasts. IL-34 based fibrosis score (0.0387*IL-34 (pg/ml) + 0.3623*type IV collagen 7s (ng/ml) + 0.0184*age (year)–1.1850) was a practical predictive model of liver fibrosis. Using receiver-operating characteristic analyses, the area under the curve, sensitivity, and specificity of IL-34 based fibrosis score were superior or comparable to the other fibrosis biomarkers and scores. In conclusion, the IL-34 based fibrosis score, including serum IL-34, type IV collagen 7s and age, is a feasible diagnostic marker of liver fibrosis in NAFLD patients. PMID:27363523

  17. Roles of Fas/Fasl, Bcl-2/Bax, and Caspase-8 in rat nonalcoholic fatty liver disease pathogenesis.

    PubMed

    Li, C P; Li, J H; He, S Y; Li, P; Zhong, X L

    2014-05-23

    The aim of this study was to investigate the roles of Fas/FasL, Bcl-2/Bax, and Caspase-8 mRNA expressions in nonalcoholic fatty liver disease (NAFLD). The apoptosis percentage was measured by flow cytometry, the immunohistochemical assay was performed for the determination of Fas, FasL, Bcl-2, and Bax expressions, and a real-time polymerase chain reaction (PCR) assay was performed to detect Caspase-8 mRNA expression. Flow cytometry showed that the apoptosis percentage of the rat liver in the experimental group increased, which increased more obviously with the extension of modeling time. Immunohistochemistry showed that with increasing hepatic steatosis, Fas and FasL protein staining intensified and the number of positive cells increased; the number of positive cells for Bcl-2 and Bax gradually increased on the 4th, 8th, and 12th weeks in the experimental group, whereas the Bcl-2/Bax ratio decreased. The real-time PCR assay showed that Caspase-8 mRNA expression increased with increasing hepatic steatosis and inflammation, exhibiting a progressively rising trend. Hepatocyte apoptosis could promote NAFLD progression; Fas, FasL, and Caspase-8 mRNA activation were important contributing factors to NAFLD. The upregulation of Bax and Bcl-2 expression might be one important mechanism of the apoptosis in NAFLD.

  18. Progression of alcoholic and non-alcoholic steatohepatitis: common metabolic aspects of innate immune system and oxidative stress.

    PubMed

    Sakaguchi, Shuhei; Takahashi, Shougo; Sasaki, Takamitsu; Kumagai, Takeshi; Nagata, Kiyoshi

    2011-01-01

    Growing evidence indicates that the innate immune system and oxidative stress caused by gut-derived endotoxins play a key role in alcoholic liver disease (ALD). Intracellular mechanisms associated with endotoxin-induced signaling play a crucial role in the initiation and progression of ALD. It is now widely accepted that activation of the innate immune system and increased release of pro-inflammatory cytokines and other mediators play an important role in the development of ALD. Accumulating evidence suggests that alcohol-mediated upregulation of CYP2E1 expression may initiate lipid peroxidation via reactive oxygen species. Non-alcoholic steatohepatitis (NASH) is a liver disease characterized by histopathological features similar to those observed in ALD, but in the absence of significant alcohol consumption. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divided disease mechanisms into "first and second hits." This model considered the development of steatosis to be the "first hit," increasing the sensitivity of the liver to the putative "second hit," leading to hepatocyte injury, inflammation, and oxidative stress. We have emphasized the important role of gut-derived bacterial toxins, the innate immune system, and oxidative stress in the common pathogenic mechanism in ALD and NASH progression.

  19. Common pathogenic mechanism in development progression of liver injury caused by non-alcoholic or alcoholic steatohepatitis.

    PubMed

    Nagata, Kiyoshi; Suzuki, Hiroyuki; Sakaguchi, Shuhei

    2007-12-01

    This review showed the common pathogenic mechanism in the development of non-alcoholic or alcoholic steatohepatitis. In particular, we describe the role of innate immune system and oxidative stress caused by gut-derived endotoxin. Gut-derived endotoxin plays an important role in alcoholic liver injury. It was reported that acute ethanol administration reduced activation of Kupffer cells. It is therefore possible that alcohol-induced hepatocellular damage occurs as a result of bacterial or endotoxin translocation under a reduction of the reticuloendothelial system (RES) function in alcoholic liver disease (ALD). On the other hand, recently, attention has been directed toward the effect of ethanol ingestion on Kupffer cell function, which is stimulated by gut-derived endotoxin via mechanisms dependent on increased gut permeability and the possible relationship between Kupffer cells and alcohol-induced liver injury. It is generally accepted that activation of the innate immune system and increased release of proinflammatory cytokines and other mediators plays an important role in the development of ALD. It was shown that Kupffer cells activation by endotoxin via Toll-like receptor (TLR-4) is involved in alcohol-induced liver injury and that ethanol-induced oxidative stress is important in the regulation of transcription factor NF-kappaB activation and that cytokine production by Kupffer cells. TNF-alpha and free radicals are produced in early alcohol-induced liver injury. In support of this finding, the pathology caused by alcohol was blocked nearly completely in TNF-alpha receptor 1. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of the CYP2E1 form of cytochrome P450 enzymes by ethanol. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divides disease mechanisms into "first and

  20. Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis.

    PubMed

    Heinrichs, Daniel; Berres, Marie-Luise; Coeuru, Melanie; Knauel, Meike; Nellen, Andreas; Fischer, Petra; Philippeit, Claudia; Bucala, Richard; Trautwein, Christian; Wasmuth, Hermann E; Bernhagen, Jürgen

    2014-12-01

    MIF is an inflammatory cytokine but is hepatoprotective in models of hepatotoxin-induced liver fibrosis. Hepatic fibrosis can also develop from metabolic liver disease, such as nonalcoholic fatty liver disease (NASH). We investigated the role of MIF in high-fat or methionine- and choline-deficient diet mouse models of NASH. Mif(-/-) mice showed elevated liver triglyceride levels (WT, 53±14 mg/g liver; Mif(-/-), 103±7 mg/g liver; P<0.05) and a 2-3-fold increased expression of lipogenic genes. Increased fatty degeneration in the livers of Mif(-/-) mice was associated with increased hepatic inflammatory cells (1.6-fold increase in F4/80(+) macrophages) and proinflammatory cytokines (e.g., 2.3-fold increase in Tnf-α and 2-fold increase in Il-6 expression). However, inflammatory cells and cytokines were decreased by 50-90% in white adipose tissue (WAT) of Mif(-/-) mice. Subset analysis showed that macrophage phenotypes in livers of Mif(-/-) mice were skewed toward M2 (e.g., 1.7-fold and 2.5-fold increase in Arg1 and Il-13, respectively, and 2.5-fold decrease in iNos), whereas macrophages were generally reduced in WAT of these mice (70% reduction in mRNA expression of F4/80(+) macrophages). The protective MIF effect was scrutinized in isolated hepatocytes. MIF reversed inflammation-induced triglyceride accumulation in Hepa1-6 cells and primary hepatocytes and also attenuated oleic acid-elicited triglyceride increase in 3T3-L1 adipocytes. Protection from fatty hepatocyte degeneration was paralleled by a 2- to 3-fold reduction by MIF of hepatocyte proinflammatory cytokine production. Blockade of MIF receptor cluster of differentiation 74 (CD74) but not of CXCR2 or CXCR4 fully reverted the protective effect of MIF, comparable to AMPK inhibition. In summary, we demonstrate that MIF mediates hepatoprotection through the CD74/AMPK pathway in hepatocytes in metabolic models of liver injury. PMID:25122558

  1. Exercise training reverses endothelial dysfunction in nonalcoholic fatty liver disease.

    PubMed

    Pugh, Christopher J A; Spring, Victoria S; Kemp, Graham J; Richardson, Paul; Shojaee-Moradie, Fariba; Umpleby, A Margot; Green, Daniel J; Cable, N Timothy; Jones, Helen; Cuthbertson, Daniel J

    2014-11-01

    Nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease (CVD). Endothelial dysfunction is an early manifestation of atherosclerosis and an important prognostic marker for future cardiovascular events. The aim of this study was twofold: to examine 1) the association between liver fat, visceral adipose tissue (VAT), and endothelial dysfunction in obese NAFLD patients and 2) the impact of supervised exercise training on this vascular defect. Brachial artery endothelial function was assessed by flow-mediated dilatation (FMD) in 34 obese NAFLD patients and 20 obese controls of similar age and cardiorespiratory fitness [peak oxygen uptake (V̇o2 peak)] (48 ± 2 vs. 47 ± 2 yr; 27 ± 1 vs. 26 ± 2 ml·kg−1·min−1−1). Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively. Twenty-one NAFLD patients completed either 16 wk of supervised moderate-intensity exercise training (n = 13) or conventional care (n = 8). Differences between NAFLD and controls were compared using independent t-tests and effects of interventions by analysis of covariance. NAFLD patients had higher liver fat [11.6% (95% CI = 7.4, 18.1), P < 0.0005] and VAT [1.6 liters (95% CI = 1.2, 2.0), P < 0.0001] than controls and exhibited impaired FMD compared with controls [−3.6% (95% CI = −4.9, −2.2), P < 0.0001]. FMD was inversely correlated with VAT (r = −0.54, P = 0.001) in NAFLD, although the impairment in FMD remained following covariate adjustment for VAT [3.1% (95% CI = 1.8, 4.5), P < 0.001]. Exercise training, but not conventional care, significantly improved V̇o2 peak [9.1 ml·kg−1·min−1 (95% CI = 4.1, 14.1); P = 0.001] and FMD [3.6% (95% CI = 1.6, 5.7), P = 0.002]. Endothelial dysfunction in NAFLD cannot be fully explained by excess VAT but can be reversed with exercise training; this has potential implications for the primary prevention of CVD in NAFLD.

  2. Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis.

    PubMed

    Heinrichs, Daniel; Berres, Marie-Luise; Coeuru, Melanie; Knauel, Meike; Nellen, Andreas; Fischer, Petra; Philippeit, Claudia; Bucala, Richard; Trautwein, Christian; Wasmuth, Hermann E; Bernhagen, Jürgen

    2014-12-01

    MIF is an inflammatory cytokine but is hepatoprotective in models of hepatotoxin-induced liver fibrosis. Hepatic fibrosis can also develop from metabolic liver disease, such as nonalcoholic fatty liver disease (NASH). We investigated the role of MIF in high-fat or methionine- and choline-deficient diet mouse models of NASH. Mif(-/-) mice showed elevated liver triglyceride levels (WT, 53±14 mg/g liver; Mif(-/-), 103±7 mg/g liver; P<0.05) and a 2-3-fold increased expression of lipogenic genes. Increased fatty degeneration in the livers of Mif(-/-) mice was associated with increased hepatic inflammatory cells (1.6-fold increase in F4/80(+) macrophages) and proinflammatory cytokines (e.g., 2.3-fold increase in Tnf-α and 2-fold increase in Il-6 expression). However, inflammatory cells and cytokines were decreased by 50-90% in white adipose tissue (WAT) of Mif(-/-) mice. Subset analysis showed that macrophage phenotypes in livers of Mif(-/-) mice were skewed toward M2 (e.g., 1.7-fold and 2.5-fold increase in Arg1 and Il-13, respectively, and 2.5-fold decrease in iNos), whereas macrophages were generally reduced in WAT of these mice (70% reduction in mRNA expression of F4/80(+) macrophages). The protective MIF effect was scrutinized in isolated hepatocytes. MIF reversed inflammation-induced triglyceride accumulation in Hepa1-6 cells and primary hepatocytes and also attenuated oleic acid-elicited triglyceride increase in 3T3-L1 adipocytes. Protection from fatty hepatocyte degeneration was paralleled by a 2- to 3-fold reduction by MIF of hepatocyte proinflammatory cytokine production. Blockade of MIF receptor cluster of differentiation 74 (CD74) but not of CXCR2 or CXCR4 fully reverted the protective effect of MIF, comparable to AMPK inhibition. In summary, we demonstrate that MIF mediates hepatoprotection through the CD74/AMPK pathway in hepatocytes in metabolic models of liver injury.

  3. Resveratrol inhibits nonalcoholic fatty liver disease in rats

    PubMed Central

    Bujanda, Luis; Hijona, Elizabeth; Larzabal, Mikel; Beraza, Marta; Aldazabal, Pablo; García-Urkia, Nerea; Sarasqueta, Cristina; Cosme, Angel; Irastorza, Belen; González, Alberto; Arenas, Juan I

    2008-01-01

    Background The prevalence of nonalcoholic fatty liver disease (NAFLD) is high. NAFLD is linked to obesity, diabetes mellitus, and hypertriglyceridemia. Approximately 20% of patients with NAFLD will eventually develop cirrhosis. Our purpose was to investigate whether resveratrol decreased hepatic steatosis in an animal model of steatosis, and whether this therapeutic approach resulted in a decrease in tumor necrosis factor α (TNF-α) production, lipid peroxidation and oxidative stress. Methods Male Wistar CRL: Wi (Han) (225 g) rats were randomized into three groups. A control group (n = 12) was given free access to regular dry rat chow for 4 weeks. The steatosis (n = 12) and resveratrol (n = 12) groups were given free access to feed (a high carbohydrate-fat free modified diet) and water 4 days per week, and fasted for the remaining 3 days for 4 weeks. Rats in the resveratrol group were given resveratrol 10 mg daily by the oral route. All rats were killed at 4 weeks and assessed for fatty infiltration and bacterial translocation. Levels of TNF-α in serum, hepatic malondialdehyde (MDA), oxidative stress (superoxide dismutase, glutathione peroxidase, catalase and nitric oxide synthase) and biochemical parameters were measured. Results Fat deposition was decreased in the resveratrol group as compared to the steatosis group (Grade 1 vs Grade 3, P < 0.05). TNF-α and MDA levels were significantly increased in the steatosis group (TNF-α; 33.4 ± 5.2 vs 26.24 ± 3.47 pg/ml and MDA; 9.08 ± 0.8 vs 3.17 ± 1.45 μM respectively, P < 0.05). This was accompanied by increased superoxide dismutase, glutathione peroxidase and catalase and decreased nitric oxide synthase in the liver of resveratrol group significantly (P < 0.05 vs steatosis group). Bacterial translocation was not found in any of the groups. Glucose levels were decreased in the group of rats given resveratrol (P < 0.05). Conclusion Resveratrol decreased NAFLD severity in rats. This effect was mediated, at least

  4. Regional differences in adipocyte lactate production from glucose

    SciTech Connect

    Newby, F.D.; Sykes, M.N.; DiGirolamo, M. )

    1988-11-01

    Having shown that lactate is an important product of glucose metabolism by rat epididymal adipocytes, the authors investigated possible regional differences in adipocyte lactate production and the role of the animals' nutritional state and stage of development. (U-{sup 14}C)glucose metabolism, lactate production, and response to insulin were measured in fat cells isolated from four adipose regions from young lean and older fatter rats, killed either in the fed state or after fasting for 48 h. In the absence of insulin, mesenteric fat cells from either age group metabolized significantly more glucose per cell and converted more glucose to lactate than cells from other depots, regardless of nutritional state. Adipocytes from fasted lean rats showed a significant increase in the relative glucose conversion to lactate in all depots when compared with cells from fed lean rats. Fasting of older fatter rats, however, had limited effects on the relative adipocyte glucose conversion to lactate since lactate production was already high. Mesenteric fat cells had the lowest relative response to insulin, possibly due to the high basal rate of glucose metabolism. These findings indicate that differences exist among adipose regions in the rates of glucose metabolism, lactate production and response to insulin. The anatomical location of the mesenteric adipose depot, coupled with a high metabolic rate and blood perfusion, suggests that mesenteric adipocytes may provide a unique and more direct contribution of metabolic substrates for hepatic metabolism than adipocytes from other depots.

  5. Serial Determinations of Blood Lactate in Respiratory Distress Syndrome

    PubMed Central

    Beca, J. P.; Scopes, J. W.

    1972-01-01

    Blood lactate was measured 4-hourly in 21 newborn babies with respiratory distress syndrome, of whom 13 survived and 8 died. In general, lactate levels were higher in babies who died than in survivors, but there were inconsistencies which were uninterpretable if only a single estimation were made in a baby. Analysis of serial determinations showed that all patients in whom the lactate level never exceeded 35 mg/100 ml survived, and babies with high but falling values also did well. Only those who had rising lactate values, even if initially normal, died. In most cases a high or normal Pao2 was associated with normal or decreasing lactate level; but babies with Pao2 below 60 mmHg had often also normal or decreasing lactate levels. Some babies had high and increasing lactate levels despite having normal Pao2. In order to use lactate levels for prognosis in respiratory distress syndrome (RDS) serial determinations are required. It is concluded that there may be a wide range of hypoxaemia without oxygen deficit in body tissues, so that it is not possible to define a `lower acceptable Pao2' which will define adequate tissue oxygenation. PMID:5046772

  6. Glycogen synthesis from lactate in a chronically active muscle

    SciTech Connect

    Talmadge, R.J.; Scheide, J.I.; Silverman, H.

    1989-05-01

    In response to neural overactivity (pseudomyotonia), gastrocnemius muscle fibers from C57Bl/6Jdy2J/dy2J mice have different metabolic profiles compared with normal mice. A population of fibers in the fast-twitch superficial region of the dy2J gastrocnemius stores unusually high amounts of glycogen, leading to an increased glycogen storage in the whole muscle. The dy2J muscle also contains twice as much lactate as normal muscle. A (/sup 14/C)lactate intraperitoneal injection leads to preferential /sup 14/C incorporation into glycogen in the dy2J muscle compared with normal muscle. To determine whether skeletal muscles were incorporating lactate into glycogen without body organ (liver, kidney) input, gastrocnemius muscles were bathed in 10 mM (/sup 14/C)lactate with intact neural and arterial supply but with impeded venous return. The contralateral gastrocnemius serves as a control for body organ input. By using this in situ procedure, we demonstrate that under conditions of high lactate both normal and dy2J muscle can directly synthesize glycogen from lactate. In this case, normal whole muscle incorporates (14C) lactate into glycogen at a higher rate than dy2J whole muscle. Autoradiography, however, suggests that the high-glycogen-containing muscle fibers in the dy2J muscle incorporate lactate into glycogen at nearly four times the rate of normal or surrounding muscle fibers.

  7. Lactate transport and receptor actions in cerebral malaria.

    PubMed

    Mariga, Shelton T; Kolko, Miriam; Gjedde, Albert; Bergersen, Linda H

    2014-01-01

    Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolized mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate's role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood-brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM.

  8. Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

    PubMed Central

    Simon, Yvette; Kessler, Sonja M; Gemperlein, Katja; Bohle, Rainer M; Müller, Rolf; Haybaeck, Johannes; Kiemer, Alexandra K

    2014-01-01

    AIM: To characterize how insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol. METHODS: Non-alcoholic steatohepatitis (NASH) was induced in wild-type mice and in mice overexpressing p62 specifically in the liver by feeding the mice a methionine and choline deficient (MCD) diet for either two or four weeks. As a control, animals were fed a methionine and choline supplemented diet. Serum triglycerides, cholesterol, glucose, aspartate aminotransferase and alanine transaminase were determined by standard analytical techniques. Hepatic gene expression was determined by real-time reverse transcription-polymerase chain reaction. Generation of reactive oxygen species in liver tissue was quantified as thiobarbituric acid reactive substances using a photometric assay and malondialdehyde as a standard. Tissue fatty acid profiles and cholesterol levels were analyzed by gas chromatography-mass spectrometry after hydrolysis. Hepatocellular iron accumulation was determined by Prussian blue staining in paraffin-embedded formalin-fixed tissue. Filipin staining on frozen liver tissue was used to quantify hepatic free cholesterol levels. Additionally, nuclear localization of the nuclear factor kappa B (NF-κB) subunit p65 was examined in frozen tissues. RESULTS: Liver-specific overexpression of the insulin-like growth factor 2 mRNA binding protein 2-2 (IGF2BP2-2/IMP2-2/p62) induces steatosis with regular chow and amplifies NASH-induced fibrosis in the MCD mouse model. Activation of NF-κB and expression of NF-κB target genes suggested an increased inflammatory response in p62 transgenic animals. Analysis of hepatic lipid composition revealed an elevation of monounsaturated fatty acids as well as increased hepatic cholesterol. Moreover, serum cholesterol was significantly elevated in p62 transgenic mice. Dietary cholesterol represents a critical factor for the development of NASH from hepatic steatosis

  9. Pharmacologic ER Stress Induces Non-alcoholic Steatohepatitis in an Animal Model

    PubMed Central

    Lee, Jin-Sook; Zheng, Ze; Mendez, Roberto; Ha, Seung-Wook; Xie, Youming; Zhang, Kezhong

    2012-01-01

    Endoplasmic reticulum (ER) stress refers to a condition of accumulation of unfolded or misfolded proteins in the ER lumen, which is known to activate an intracellular stress signaling termed Unfolded Protein Response (UPR). A number of pharmacologic reagents or pathophysiologic stimuli can induce ER stress and activation of the UPR signaling, leading to alteration of cell physiology that is associated with the initiation and progression of a variety of diseases. Non-alcoholic steatohepatitis (NASH), characterized by hepatic steatosis and inflammation, has been considered the precursor or the hepatic manifestation of metabolic disease. In this study, we delineated the toxic effect and molecular basis by which pharmacologic ER stress, induced by a bacterial nucleoside antibiotic tunicamycin (TM), promotes NASH in an animal model. Mice of C57BL/6J strain background were challenged with pharmacologic ER stress by intraperitoneal injection of TM. Upon TM injection, mice exhibited a quick NASH state characterized by hepatic steatosis and inflammation. An increase in hepatic triglycerides (TG) and a decrease in plasma lipids, including plasma TG, plasma cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL), were observed in the TM-treated mice. In response to TM challenge, cleavage of sterol responsive binding protein (SREBP)-1a and SREBP-1c, the key trans-activators for lipid and sterol biosynthesis, was dramatically increased in the liver. Consistent with the hepatic steatosis phenotype, expression of some key regulators and enzymes in de novo lipogenesis and lipid droplet formation was up-regulated, while expression of those involved in lipolysis and fatty acid oxidation was down-regulated in the liver of mice challenged with TM. Moreover, TM treatment significantly increased phosphorylation of NF-κB inhibitors (IκB), leading to the activation of NF-κB-mediated inflammatory pathway in the liver. Our study not only confirmed that

  10. Association of homocysteine level with biopsy-proven non-alcoholic fatty liver disease: a meta-analysis

    PubMed Central

    Dai, Yining; Zhu, Jinzhou; Meng, Di; Yu, Chaohui; Li, Youming

    2016-01-01

    Previous studies have reported inconsistent findings regarding the association between plasmatic higher of homocysteine level and non-alcoholic fatty liver disease. We aimed to investigate this association by conducting a meta-analysis. Literature was searched on PubMed from inception to January 2015. Eight studies evaluating plasma level of homocysteine in biopsy-proven non-alcoholic fatty liver disease subjects compared to healthy controls were included. Compared with the controls, non-alcoholic fatty liver disease patients witnessed a higher level of homocysteine [standard mean difference (SMD): 0.66 µmol/L, 95% CI: 0.41, 0.92 µmol/L], and were associated with a significant increased risk for hyperhomocysteinemia [odds ratio (OR) 5.09, 95% CI: 1.69, 15.32]. In addition, patients with non-alcoholic fatty liver presented 0.45 µmol/L higher levels of homocysteine compared to healthy controls (95% CI: 0.09, 0.82 µmol/L), whereas non-alcoholic steatohepatitis patients had 1.02 µmol/L higher levels of homocysteine (95% CI: 0.28, 1.76 µmol/L). There was neither difference of folate level nor vitamin B12 level between non-alcoholic fatty liver disease subjects and healthy controls. This study revealed that non-alcoholic fatty liver disease patients presented an increased serum concentration of homocysteine, and were associated with an increased risk of hyperhomocysteinemia. Further studies are needed to demonstrate a causal role of hyperhomocysteinemia in non-alcoholic fatty liver disease. PMID:26798201

  11. Maternal aggression by lactating group-living Japanese macaque females.

    PubMed

    Troisi, A; D'Amato, F R; Carnera, A; Trinca, L

    1988-12-01

    This study analyzed the influence of lactation on aggression by group-living Japanese macaque females. Data collected during 268 hr of observation showed that lactating females exhibited much more aggression than did females in any other reproductive condition under investigation. This postpartum aggression showed distinctive features in terms of time course during lactation and target selectivity but it was not characterized by a higher intensity and severity. Aggression increased progressively during the first 6 weeks of lactation, reached its highest levels between 7th and 9th weeks postpartum, and thereafter diminished. The relative percentages of threat, chase, and physical attack did not change with the reproductive condition. Lactating females were selective in their choice of targets, with young females being the recipients of nearly 90% of the total of their aggression.

  12. Managing the lactating sow for optimal weaning and rebreeding performance.

    PubMed

    Tokach, M D; Dial, G D

    1992-11-01

    Management of the lactating sow influences milk production and subsequent reproduction through changes in nutrient intake. The management goal during lactation is to maximize feed intake. Decreasing the effective environmental temperature, increasing the nutrient density of the lactation diet, maintaining fresh adequate supplies of feed and water, and preventing excess weight gain during the prior gestation period will increase nutrient intake during lactation. Effective environmental temperature of the lactating sow can be maintained in the thermoneutral zone by using drip cooling, increased ventilation rates and flooring materials with superior conductive properties. Sow parity, genetics, litter size, and disease level will also influence feed intake. Management practices must account for these factors and, thus, should be tailored to individual farm situations to ensure adequate nutrient intake and prevent aberrations in subsequent reproductive performance.

  13. Regulation and function of lactate oxidation in Streptococcus faecium.

    PubMed

    London, J

    1968-04-01

    Regulation of the synthesis and function of an l(+)-specific lactate-oxidizing enzyme system found in a homofermentative Streptococcus was investigated. With the exception of fructose, aerobic growth at the expense of a variety of substrates resulted in the formation of a lactate oxidation system; anaerobic growth resulted in a marked reduction or complete loss of lactate-oxidizing activity. Growth on fructose, under aerobic and anaerobic conditions, invariably produced a decrease in the activity of the lactate oxidation system. A negative control, activated by an early intermediate product of glycolysis, appeared to be responsible for repression of the lactate-oxidizing enzyme(s). The enzyme system confers upon the organism the ability to grow aerobically at the expense of l(+)-lactic acid.

  14. Thermoregulatory ability of female rats during pregnancy and lactation.

    PubMed

    Knecht, E A; Toraason, M A; Wright, G L

    1980-11-01

    Thermoregulatory ability of female rats was examined before pregnancy, during gestation, and during lactation. Thermoregulatory pattern, colonic temperature, evaporative water loss, and survival time were monitored during terminal heating (39.5 +/- 0.9 degrees C) designed to allow prolonged survival (3-4 h) with a sustained thermoregulatory effort. Results confirmed our previously reported observation of decreased thermoregulatory ability in lactating dams, with evidence suggesting thermoregulatory impairment during late gestation. Lactating dams displayed a type III thermoregulatory pattern, and established a rate of evaporative water loss effective for thermostasis at an elevated colonic temperature. However, survival time was significantly decreased compared to nonreproducing females. In contrast, prior heat acclimation tended to increase the survival time of lactating dams. It was concluded that the reduction in thermoregulatory ability observed in lactating dams was related to their inability to maintain a rate of evaporative water loss effective for thermostasis at an elevated colonic temperature. PMID:7192056

  15. l-Lactate mediates neuroprotection against ischaemia by increasing TREK1 channel expression in rat hippocampal astrocytes in vitro.

    PubMed

    Banerjee, Aditi; Ghatak, Swagata; Sikdar, Sujit Kumar

    2016-07-01

    Brain ischaemia is a highly debilitating condition where shortage of oxygen and glucose leads to profuse cell death. Lactate is a neuroprotective metabolite whose concentrations increase up to 15-30 mmol/L during ischaemia and TREK1 is a neuroprotective potassium channel which is upregulated during ischaemia. The aim of this study was to investigate the effect of l-lactate on TREK1 expression and to evaluate the role of l-lactate-TREK1 interaction in conferring neuroprotection in ischaemia-prone hippocampus. We show that 15-30 mmol/L l-lactate increases functional TREK1 protein expression by 1.5-3-fold in hippocampal astrocytes using immunostaining and electrophysiology. Studies with transcription blocker actinomycin-D and quantitative PCR indicate that the increase in TREK1 expression is due to enhanced TREK1 mRNA transcription. We further report that l-lactate-mediated increase in TREK1 expression is via protein kinase A (PKA)-dependent pathway. This is the first report of an ischaemic metabolite affecting functional expression of an ion channel. Our studies in an in vitro model of ischaemia using oxygen glucose deprivation show that 30 mmol/L l-lactate fails to reduce cell death in rat hippocampal slices treated with TREK1 blockers, PKA inhibitors and gliotoxin. The above effects were specific to l-lactate as pyruvate failed to increase TREK1 expression and reduce cell death. l-Lactate-induced TREK1 upregulation is a novel finding of physiological significance as TREK1 channels contribute to neuroprotection by enhancing potassium buffering and glutamate clearance capacity of astrocytes. We propose that l-lactate promotes neuronal survival in hippocampus by increasing TREK1 channel expression via PKA pathway in astrocytes during ischaemia. Insufficient blood supply to the brain leads to cerebral ischaemia and increase in extracellular lactate concentrations. We incubated hippocampal astrocytes in lactate and observed increase in TREK1 channel expression via

  16. l-Lactate mediates neuroprotection against ischaemia by increasing TREK1 channel expression in rat hippocampal astrocytes in vitro.

    PubMed

    Banerjee, Aditi; Ghatak, Swagata; Sikdar, Sujit Kumar

    2016-07-01

    Brain ischaemia is a highly debilitating condition where shortage of oxygen and glucose leads to profuse cell death. Lactate is a neuroprotective metabolite whose concentrations increase up to 15-30 mmol/L during ischaemia and TREK1 is a neuroprotective potassium channel which is upregulated during ischaemia. The aim of this study was to investigate the effect of l-lactate on TREK1 expression and to evaluate the role of l-lactate-TREK1 interaction in conferring neuroprotection in ischaemia-prone hippocampus. We show that 15-30 mmol/L l-lactate increases functional TREK1 protein expression by 1.5-3-fold in hippocampal astrocytes using immunostaining and electrophysiology. Studies with transcription blocker actinomycin-D and quantitative PCR indicate that the increase in TREK1 expression is due to enhanced TREK1 mRNA transcription. We further report that l-lactate-mediated increase in TREK1 expression is via protein kinase A (PKA)-dependent pathway. This is the first report of an ischaemic metabolite affecting functional expression of an ion channel. Our studies in an in vitro model of ischaemia using oxygen glucose deprivation show that 30 mmol/L l-lactate fails to reduce cell death in rat hippocampal slices treated with TREK1 blockers, PKA inhibitors and gliotoxin. The above effects were specific to l-lactate as pyruvate failed to increase TREK1 expression and reduce cell death. l-Lactate-induced TREK1 upregulation is a novel finding of physiological significance as TREK1 channels contribute to neuroprotection by enhancing potassium buffering and glutamate clearance capacity of astrocytes. We propose that l-lactate promotes neuronal survival in hippocampus by increasing TREK1 channel expression via PKA pathway in astrocytes during ischaemia. Insufficient blood supply to the brain leads to cerebral ischaemia and increase in extracellular lactate concentrations. We incubated hippocampal astrocytes in lactate and observed increase in TREK1 channel expression via

  17. Managing Migraine During Pregnancy and Lactation.

    PubMed

    Wells, Rebecca Erwin; Turner, Dana P; Lee, Michelle; Bishop, Laura; Strauss, Lauren

    2016-04-01

    While over half of women with migraine report improvement during pregnancy, having a history of migraine may increase the chance of negative health outcomes. The state of pregnancy increases the risk of several dangerous secondary headache disorders, especially those associated with hypertensive disorders of pregnancy, and providers need to know the red flags to diagnose and treat emergently. Non-pharmacological migraine treatments can be instituted in advance of pregnancy as many are considered the safest options during pregnancy, but understanding the safety of medications and dietary supplements ensures appropriate care for the refractory migraine patient. New controversy exists over the safety of several historically routine and safe migraine treatment options in pregnancy, such as magnesium, acetaminophen, ondansetron, and butalbital. While it is not clear if breastfeeding decreases the postpartum recurrence of migraine, understanding safe treatment options during lactation can allow women to continue breastfeeding while achieving migraine relief.

  18. Lactation-induced cadmium-binding proteins

    SciTech Connect

    Bhattacharyya, M.H.; Solaiman, D.; Garvey, J.S.; Miyazaki, W.Y.

    1987-01-01

    Previously we have demonstrated an increase during midlactation in /sup 109/Cd adsorption and increased retention by the duodenum, kidney, and mammary tissue of mouse dams receiving environmental levels of cadmium//sup 109/Cd via drinking water, with little change in /sup 109/Cd retention in liver and jejunum compared to nonpregnant controls. Results are reported here of a study of cadmium deposition during midlactation as associated with induction of metallothionein (MT). A cadmium/hemoglobin (Cd/Hb) assay and radioimmunoassay for MT which measures heat-stable cadmium binding capacity in tissues was used to determine MT concentrations in fractions of kidney, liver, duodenum, and jejunum from female mice. Both assays demonstrated clear lactation-induced increases in MT concentrations in liver, kidney, and duodenum, with MT concentrations falling rapidly to control levels after weaning. 4 refs., 1 tab.

  19. L-lactate transport in Ehrlich ascites-tumour cells.

    PubMed

    Spencer, T L; Lehninger, A L

    1976-02-15

    Ehrlich ascites-tumour cells were investigated with regard to their stability to transport L-lactate by measuring either the distribution of [14C]lactate or concomitant H+ ion movements. The movement of lactate was dependent on the pH difference across the cell membrane and was electroneutral, as evidenced by an observed 1:1 antiport for OH- ions or 1:1 symport with H+ ions. 2. Kinetic experiments showed that lactate transport was saturable, with an apparent Km of approx. 4.68 mM and a Vmax. as high as 680 nmol/min per mg of protein at pH 6.2 and 37 degrees C. 3. Lactate transport exhibited a high temperature dependence (activation energy = 139 kJ/mol). 4. Lactate transport was inhibited competitively by (a) a variety of other substituted monocarboxylic acids (e.g. pyruvate, Ki = 6.3 mM), which were themselves transported, (b) the non-transportable analogues alpha-cyano-4-hydroxycinnamate (Ki = 0.5 mM), alpha-cyano-3-hydroxycinnamate (Ki = 2mM) and DL-p-hydroxyphenyl-lactate (Ki = 3.6 mM) and (c) the thiol-group reagent mersalyl (Ki = 125 muM). 5. Transport of simple monocarboxylic acids, including acetate and propionate, was insensitive to these inhibitors; they presumably cross the membrane by means of a different mechanism. 6. Experiments using saturating amounts of mersalyl as an "inhibitor stop" allowed measurements of the initial rates of net influx and of net efflux of [14C]lactate. Influx and efflux of lactate were judged to be symmetrical reactions in that they exhibited similar concentration dependence. 7. It is concluded that lactate transport in Ehrlich ascites-tumour cells is mediated by a carrier capable of transporting a number of other substituted monocarboxylic acids, but not unsubstituted short-chain aliphatic acids.

  20. Factors Affecting on Serum Lactate After Cardiac Surgery

    PubMed Central

    Joudi, Marjan; Fathi, Mehdi; Soltani, Ghasem; Izanloo, Azra

    2014-01-01

    Background: The relation between elevated blood lactate level and mortality and morbidity rates after coronary bypass surgery is a proven subject. One of the factors that seems to affect directly the blood lactate level is the storage duration of packed red blood cells. Objectives: This study aimed to evaluate the effect of storage duration of transfused blood on serum lactate during cardiac surgery and up to 24 hours after that in the ICU. Patients and Methods: In a cross-sectional study, 228 patients referred to three hospitals of Mashhad University of Medical Sciences for open cardiac surgery, was enrolled using systematic random sampling method. Immediately after accessing arterial line, the first sample of arterial blood gas (ABG) was obtained. For evaluation of lactate levels, the next samples were obtained at the end of surgery and after 24 hours of staying ICU. Results: Among 5 factors which affected lactate level during surgery, diabetes and higher ejection fraction (EF) reduced changes of the lactate level. On the other hand, the number of infused blood units, duration of on-pump time, and the mean storage duration of blood units were associated with elevated serum lactate during surgery. A significant relationship was found between blood storage duration and serum lactate levels 24 hours after surgery. Conclusions: Comparing the serum lactate level before operation and 24 hours after the operation showed that the number of received blood units had a significant effect on serum lactate. We found no significant effect for blood storage duration; however, the number of given blood units was more significant. PMID:25632379

  1. L-lactate transport in Ehrlich ascites-tumour cells.

    PubMed Central

    Spencer, T L; Lehninger, A L

    1976-01-01

    Ehrlich ascites-tumour cells were investigated with regard to their stability to transport L-lactate by measuring either the distribution of [14C]lactate or concomitant H+ ion movements. The movement of lactate was dependent on the pH difference across the cell membrane and was electroneutral, as evidenced by an observed 1:1 antiport for OH- ions or 1:1 symport with H+ ions. 2. Kinetic experiments showed that lactate transport was saturable, with an apparent Km of approx. 4.68 mM and a Vmax. as high as 680 nmol/min per mg of protein at pH 6.2 and 37 degrees C. 3. Lactate transport exhibited a high temperature dependence (activation energy = 139 kJ/mol). 4. Lactate transport was inhibited competitively by (a) a variety of other substituted monocarboxylic acids (e.g. pyruvate, Ki = 6.3 mM), which were themselves transported, (b) the non-transportable analogues alpha-cyano-4-hydroxycinnamate (Ki = 0.5 mM), alpha-cyano-3-hydroxycinnamate (Ki = 2mM) and DL-p-hydroxyphenyl-lactate (Ki = 3.6 mM) and (c) the thiol-group reagent mersalyl (Ki = 125 muM). 5. Transport of simple monocarboxylic acids, including acetate and propionate, was insensitive to these inhibitors; they presumably cross the membrane by means of a different mechanism. 6. Experiments using saturating amounts of mersalyl as an "inhibitor stop" allowed measurements of the initial rates of net influx and of net efflux of [14C]lactate. Influx and efflux of lactate were judged to be symmetrical reactions in that they exhibited similar concentration dependence. 7. It is concluded that lactate transport in Ehrlich ascites-tumour cells is mediated by a carrier capable of transporting a number of other substituted monocarboxylic acids, but not unsubstituted short-chain aliphatic acids. PMID:7237

  2. Comprehensive review on lactate metabolism in human health.

    PubMed

    Adeva-Andany, M; López-Ojén, M; Funcasta-Calderón, R; Ameneiros-Rodríguez, E; Donapetry-García, C; Vila-Altesor, M; Rodríguez-Seijas, J

    2014-07-01

    Metabolic pathways involved in lactate metabolism are important to understand the physiological response to exercise and the pathogenesis of prevalent diseases such as diabetes and cancer. Monocarboxylate transporters are being investigated as potential targets for diagnosis and therapy of these and other disorders. Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. Pyruvate may be either oxidized to carbon dioxide producing energy or transformed into glucose. Pyruvate oxidation requires oxygen supply and the cooperation of pyruvate dehydrogenase, the tricarboxylic acid cycle, and the mitochondrial respiratory chain. Enzymes of the gluconeogenesis pathway sequentially convert pyruvate into glucose. Congenital or acquired deficiency on gluconeogenesis or pyruvate oxidation, including tissue hypoxia, may induce lactate accumulation. Both obese individuals and patients with diabetes show elevated plasma lactate concentration compared to healthy subjects, but there is no conclusive evidence of hyperlactatemia causing insulin resistance. Available evidence suggests an association between defective mitochondrial oxidative capacity in the pancreatic β-cells and diminished insulin secretion that may trigger the development of diabetes in patients already affected with insulin resistance. Several mutations in the mitochondrial DNA are associated with diabetes mellitus, although the pathogenesis remains unsettled. Mitochondrial DNA mutations have been detected in a number of human cancers. d-lactate is a lactate enantiomer normally formed during glycolysis. Excess d-lactate is generated in diabetes, particularly during diabetic ketoacidosis. d-lactic acidosis is typically associated with small bowel resection. PMID:24929216

  3. Comprehensive review on lactate metabolism in human health.

    PubMed

    Adeva-Andany, M; López-Ojén, M; Funcasta-Calderón, R; Ameneiros-Rodríguez, E; Donapetry-García, C; Vila-Altesor, M; Rodríguez-Seijas, J

    2014-07-01

    Metabolic pathways involved in lactate metabolism are important to understand the physiological response to exercise and the pathogenesis of prevalent diseases such as diabetes and cancer. Monocarboxylate transporters are being investigated as potential targets for diagnosis and therapy of these and other disorders. Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. Pyruvate may be either oxidized to carbon dioxide producing energy or transformed into glucose. Pyruvate oxidation requires oxygen supply and the cooperation of pyruvate dehydrogenase, the tricarboxylic acid cycle, and the mitochondrial respiratory chain. Enzymes of the gluconeogenesis pathway sequentially convert pyruvate into glucose. Congenital or acquired deficiency on gluconeogenesis or pyruvate oxidation, including tissue hypoxia, may induce lactate accumulation. Both obese individuals and patients with diabetes show elevated plasma lactate concentration compared to healthy subjects, but there is no conclusive evidence of hyperlactatemia causing insulin resistance. Available evidence suggests an association between defective mitochondrial oxidative capacity in the pancreatic β-cells and diminished insulin secretion that may trigger the development of diabetes in patients already affected with insulin resistance. Several mutations in the mitochondrial DNA are associated with diabetes mellitus, although the pathogenesis remains unsettled. Mitochondrial DNA mutations have been detected in a number of human cancers. d-lactate is a lactate enantiomer normally formed during glycolysis. Excess d-lactate is generated in diabetes, particularly during diabetic ketoacidosis. d-lactic acidosis is typically associated with small bowel resection.

  4. [The comparison of concentration of endogenous ethanol blood serum in alcoholics and in non-alcoholics at different stages of abstinence].

    PubMed

    Lukaszewicz, A; Markowski, T; Pawlak, D

    1997-01-01

    In this report the concentration of endogenous ethanol in blood serum in alcoholics at different stages of abstinence and in non-alcoholics was studied. 36 people--26 alcoholics and 10 non-alcoholics were examined and gas chromatography was used. It was revealed that the longer the period of abstinence in alcoholics, the lower the concentration of endogenous ethanol in blood serum. Moreover, the alcoholics showed a higher concentration of endogenous ethanol in blood serum as compared to non-alcoholics.

  5. Effect of oxygen on glucose metabolism: utilization of lactate in Staphylococcus aureus as revealed by in vivo NMR studies.

    PubMed

    Ferreira, Maria Teresa; Manso, Ana S; Gaspar, Paula; Pinho, Mariana G; Neves, Ana Rute

    2013-01-01

    The ability to successfully adapt to changing host conditions is crucial for full virulence of bacterial pathogens. Staphylococcus aureus has to cope with fluctuating oxygen concentrations during the course of infection. Hence, we studied the effect of oxygen on glucose metabolism in non-growing S. aureus COL-S cells by in vivo(13)C-NMR. Glucose catabolism was probed at different oxygen concentrations in suspensions of cells grown aerobically (direct effects on metabolism) or anaerobically (transcriptional adjustment to oxygen deprivation). In aerobically-grown cells, the rate of glucose consumption diminished progressively with decreasing oxygen concentrations. Additionally, oxygen deprivation resulted in biphasic glucose consumption, with the second phase presenting a higher rate. The fructose-1,6-bisphosphate pool peaked while glucose was still abundant, but the transient maximum varied with the oxygen concentration. As oxygen became limiting mannitol/mannitol-1-phosphate were detected as products of glucose catabolism. Under anoxic conditions, accumulation of mannitol-1-phosphate ceased with the switch to higher glucose consumption rates, which implies the activation of a more efficient means by which NAD(+) can be regenerated. The distribution of end-products deriving from glucose catabolism was dramatically affected by oxygen: acetate increased and lactate decreased with the oxygen concentration; ethanol was formed only anaerobically. Moreover, oxygen promoted the energetically favourable conversion of lactate into acetate, which was particularly noticeable under fully oxygenated conditions. Interestingly, under aerobiosis growing S. aureus cells also converted lactate to acetate, used simultaneously glucose and lactate as substrates for growth, and grew considerably well on lactate-medium. We propose that the efficient lactate catabolism may endow S. aureus with a metabolic advantage in its ecological niche.

  6. Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Pirola, Carlos J.; Scian, Romina; Gianotti, Tomas Fernández; Dopazo, Hernán; Rohr, Cristian; Martino, Julio San; Castaño, Gustavo O.; Sookoian, Silvia

    2015-01-01

    Abstract The 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification whose role in the pathogenesis of metabolic-related complex diseases remains unexplored; 5-hmC appears to be prevalent in the mitochondrial genome. The Ten-Eleven-Translocation (TET) family of proteins is responsible for catalyzing the conversion of 5-methylcytosine to 5-hmC. We hypothesized that epigenetic editing by 5-hmC might be a novel mechanism through which nonalcoholic fatty liver disease (NAFLD)-associated molecular traits could be explained. Hence, we performed an observational study to explore global levels of 5-hmC in fresh liver samples of patients with NAFLD and controls (n = 90) using an enzyme-linked-immunosorbent serologic assay and immunohistochemistry. We also screened for genetic variation in TET 1–3 loci by next generation sequencing to explore its contribution to the disease biology. The study was conducted in 2 stages (discovery and replication) and included 476 participants. We observed that the amount of 5-hmC in the liver of both NAFLD patients and controls was relatively low (up to 0.1%); a significant association was found with liver mitochondrial DNA copy number (R = 0.50, P = 0.000382) and PPARGC1A-mRNA levels (R = −0.57, P = 0.04). We did not observe any significant difference in the 5-hmC nuclear immunostaining score between NAFLD patients and controls; nevertheless, we found that patients with NAFLD (0.4 ± 0.5) had significantly lower nonnuclear-5-hmC staining compared with controls (1.8 ± 0.8), means ± standard deviation, P = 0.028. The missense p.Ile1123Met variant (TET1-rs3998860) was significantly associated with serum levels of caspase-generated CK-18 fragment-cell death biomarker in the discovery and replication stage, and the disease severity (odds ratio: 1.47, 95% confidence interval: 1.10–1.97; P = 0.005). The p.Ile1762Val substitution (TET2-rs2454206) was associated with liver PPARGC1A-methylation and

  7. Systemic symptoms in non-alcoholic fatty liver disease.

    PubMed

    Newton, Julia L

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in the Western world and the incidence of the disease is constantly increasing. Most patients with NAFLD do not present with symptoms directly attributable to their underlying liver disease. It is increasingly recognized, however, that those with NAFLD describe a range of non-specific symptoms, which include fatigue and daytime sleepiness, may be the presenting problem and can impact dramatically upon quality of life in this patient group. The recognition of systemic symptoms in NAFLD has important implications for patients as many are potentially modifiable with targeted interventions. Fatigue appears to be a significant problem in NAFLD and the severity of fatigue is not associated with severity of NAFLD or any parameters of liver damage. Instead, fatigue in these patients shows a strong relationship with the symptom of daytime sleepiness and autonomic dysfunction. Daytime sleepiness can frequently be associated with obstructive sleep apnoea in those with NAFLD and is therefore treatable with evidence-based interventions. Recent studies have confirmed the presence of autonomic nervous system dysfunction in those with early stages of NAFLD. The presence of autonomic nervous system dysfunction leads to symptoms such as postural dizziness and syncope and is also associated with a number of clinical consequences in hepatic and non-hepatic diseases such as cognitive dysfunction, falls and fall-related injuries. On direct questioning, problems with memory and concentration are frequently described by those with NAFLD, with our studies confirming that 50% of NAFLD patients experience mild cognitive symptoms and up to 46% moderate or severe cognitive impairment. There were no positive correlations between cognitive symptoms and biochemical or histological markers of liver damage severity, confirming that cognitive impairment in early-stage NAFLD is not related to hepatic encephalopathy. Falls are

  8. Biochemical and structural characterization of Cryptosporidium parvum Lactate dehydrogenase.

    PubMed

    Cook, William J; Senkovich, Olga; Hernandez, Agustin; Speed, Haley; Chattopadhyay, Debasish

    2015-03-01

    The protozoan parasite Cryptosporidium parvum causes waterborne diseases worldwide. There is no effective therapy for C. parvum infection. The parasite depends mainly on glycolysis for energy production. Lactate dehydrogenase is a major regulator of glycolysis. This paper describes the biochemical characterization of C. parvum lactate dehydrogenase and high resolution crystal structures of the apo-enzyme and four ternary complexes. The ternary complexes capture the enzyme bound to NAD/NADH or its 3-acetylpyridine analog in the cofactor binding pocket, while the substrate binding site is occupied by one of the following ligands: lactate, pyruvate or oxamate. The results reveal distinctive features of the parasitic enzyme. For example, C. parvum lactate dehydrogenase prefers the acetylpyridine analog of NADH as a cofactor. Moreover, it is slightly less sensitive to gossypol inhibition compared with mammalian lactate dehydrogenases and not inhibited by excess pyruvate. The active site loop and the antigenic loop in C. parvum lactate dehydrogenase are considerably different from those in the human counterpart. Structural features and enzymatic properties of C. parvum lactate dehydrogenase are similar to enzymes from related parasites. Structural comparison with malate dehydrogenase supports a common ancestry for the two genes.

  9. Fiber optic biosensors for hydrogen peroxide and L-lactate

    NASA Astrophysics Data System (ADS)

    Schubert, Florian; Rinneberg, Herbert H.; Wang, Fang

    1995-02-01

    An optical fiber biosensor for the selective determination of hydrogen peroxide has been developed as the base sensor for the construction of multienzyme optodes involving lactate converting enzymes for the analysis of lactic acid. The optode uses the H2O2 dependent oxidation of homovanillic acid by horseradish peroxidase (HRP) as the sensing reaction. The fluorescence of the dimeric product formed is used as the measuring signal related to the concentration of H2O2. HRP was immobilized on a membrane and combined with a bifurcated fiber optic probe. Under optimized conditions the sensor responds linearly to hydrogen peroxide between 1 micrometers ol/l and 0.12 mmol/l and exhibits a half life of 90 days. Using a lactate oxidase-HRP membrane, the sensor is suitable for lactate measurement with a linear range of 3 micrometers ol/l-0.2 mmol/l. To increase the sensitivity for lactate, lactate dehydrogenase was coimmobilized on the sensor membrane. In the presence of NADH the signal for lactate is amplified fourfold through the internal analyte recycling accomplished by the lactate-converting enzymes.

  10. Gastrointestinal absorption of cadmium in mice during gestation and lactation

    SciTech Connect

    Bhattacharyya, M.H.; Whelton, B.D.; Peterson, D.P.

    1982-01-01

    The effect on cadmium retention of continuous exposure to drinking water containing low levels of cadmium during pregnancy and lactation was studied in mice. Female mice were provided drinking water ad libitum containing /sup 109/CdCl/sub 2/ (0.03 ..mu..Ci /sup 109/Cd/ml, 0.11 ppb total cadmium) throughout either gestation, lactation, or a combined period of pregnancy and lactation. Nonpregnant control mice were exposed to the same cadmium solution for similar time periods. Dams in all three experimental groups retained two to three times cadmium (expressed as percentage of ingested dose) than did nonpregnant controls. The /sup 109/Cd contents of liver, kidney, mammary tissue, and duodenum increased strikingly in all three groups. Increases in kidney and mammary tissue were particularly apparent during lactation, with increases of fivefold for kidney and at least ninefold for mammary tissue, compared to levels in nonpregnant controls. Increases in /sup 109/Cd retention by the duodenum were fivefold during gestation and three- to fourfold during lactation. The kidneys of dams exposed during lactation retained 53% of the whole body /sup 109/Cd, while kidneys of nonpregnant controls retained only 27%. Results indicate that pregnant and lactating mice absorb and subsequently retain substantially more cadmium from their diets than do nonpregnant mice.

  11. [Synthesis and localization of L-lactate oxidase in yeasts].

    PubMed

    Arinbasarova, A Iu; Biriukova, E N; Suzina, N E; Medentsev, A G

    2014-01-01

    Conditions for L-lactate oxidase synthesis by the yeast Yarrowia lpolytica were investigated. The enzyme was found to be synthesized during growth on L-lactate in the exponential growth phase. L-lactate oxidase synthesis was observed, also on glucose after adaptation to stress conditions (oxidative or thermal stress) r during the stationary growth phase after glucose consumption. The cells grown on L-lactate exhibited high levels of antioxidant enzymes (catalase, superoxide dismutase, glucose-6-phosphate dehydrogenase, and glutathione reductase), which exceeded those of glucose-grown cells. The ultrastructure of L-lactate-grown cellsand of those grown on glucose and adapted to various stress.conditions was also found to besimilar, with increased mitochondria, elevated number and size ofperoxisomes, and formation of lipid and polyphosphate inclusions. In order to determine the intracellular localization of L-lactate oxidase, the cells were disintegrated by the lytic enzyme complex from Helix pomatia. Centrifugation of the homogenate in Percoll gradient resulted in the isolation of purified fractions of the native mitochondria and peroxisomes. L-Lactate oxidase was shown to be localized in peroxisomes. PMID:25844463

  12. Lactate transport and receptor actions in cerebral malaria

    PubMed Central

    Mariga, Shelton T.; Kolko, Miriam; Gjedde, Albert; Bergersen, Linda H.

    2014-01-01

    Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolized mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate’s role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood–brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM. PMID:24904266

  13. Gastrointestinal transport of calcium and glucose in lactating ewes.

    PubMed

    Klinger, Stefanie; Schröder, Bernd; Gemmer, Anja; Reimers, Julia; Breves, Gerhard; Herrmann, Jens; Wilkens, Mirja R

    2016-06-01

    During lactation, mineral and nutrient requirements increase dramatically, particularly those for Ca and glucose. In contrast to monogastric species, in ruminants, it is rather unclear to which extend this physiological change due to increased demand for milk production is accompanied by functional adaptations of the gastrointestinal tract (GIT). Therefore, we investigated potential modulations of Ca and glucose transport mechanisms in the GIT of lactating and dried-off sheep. Ussing-chamber technique was applied to determine the ruminal and jejunal Ca flux rates. In the jejunum, electrophysiological properties in response to glucose were recorded. Jejunal brush-border membrane vesicles (BBMV) served to characterize glucose uptake via sodium-linked glucose transporter 1 (SGLT1), and RNA and protein expression levels of Ca and glucose transporting systems were determined. Ruminal Ca flux rate data showed a trend for higher absorption in lactating sheep. In the jejunum, small Ca absorption could only be observed in lactating ewes. From the results, it may be assumed that lactating ewes compensate for the Ca loss by increasing bone mobilization rather than by increasing supply through absorption from the GIT Presence of SGLT1 in the jejunum of both groups was shown by RNA and protein identification, but glucose uptake into BBMV could only be detected in lactating sheep. This, however, could not be attributed to electrogenic glucose absorption in lactating sheep under Ussing-chamber conditions, providing evidence that changes in jejunal glucose uptake may include additional factors, that is, posttranslational modifications such as phosphorylation.

  14. Biochemical and structural characterization of Cryptosporidium parvum Lactate dehydrogenase.

    PubMed

    Cook, William J; Senkovich, Olga; Hernandez, Agustin; Speed, Haley; Chattopadhyay, Debasish

    2015-03-01

    The protozoan parasite Cryptosporidium parvum causes waterborne diseases worldwide. There is no effective therapy for C. parvum infection. The parasite depends mainly on glycolysis for energy production. Lactate dehydrogenase is a major regulator of glycolysis. This paper describes the biochemical characterization of C. parvum lactate dehydrogenase and high resolution crystal structures of the apo-enzyme and four ternary complexes. The ternary complexes capture the enzyme bound to NAD/NADH or its 3-acetylpyridine analog in the cofactor binding pocket, while the substrate binding site is occupied by one of the following ligands: lactate, pyruvate or oxamate. The results reveal distinctive features of the parasitic enzyme. For example, C. parvum lactate dehydrogenase prefers the acetylpyridine analog of NADH as a cofactor. Moreover, it is slightly less sensitive to gossypol inhibition compared with mammalian lactate dehydrogenases and not inhibited by excess pyruvate. The active site loop and the antigenic loop in C. parvum lactate dehydrogenase are considerably different from those in the human counterpart. Structural features and enzymatic properties of C. parvum lactate dehydrogenase are similar to enzymes from related parasites. Structural comparison with malate dehydrogenase supports a common ancestry for the two genes. PMID:25542170

  15. ZnT4 (SLC30A4)-null ("lethal milk") mice have defects in mammary gland secretion and hallmarks of precocious involution during lactation.

    PubMed

    McCormick, Nicholas H; Lee, Sooyeon; Hennigar, Stephen R; Kelleher, Shannon L

    2016-01-01

    During lactation, highly specialized secretory mammary epithelial cells (MECs) produce and secrete huge quantities of nutrients and nonnutritive factors into breast milk. The zinc (Zn) transporter ZnT4 (SLC30A4) transports Zn into the trans-Golgi apparatus for lactose synthesis, and across the apical cell membrane for efflux from MECs into milk. This is consistent with observations in "lethal milk" (lm/lm) mice, which have a truncation mutation in SLC30A4, and present with not only low milk Zn concentration, but also smaller mammary glands, decreased milk volume, and lactation failure by lactation day 2. However, the molecular underpinnings of these defects are not understood. Here, we used lactating C57BL/6J(lm/lm) (ZnT4-null) mice to explore the consequences of a ZnT4-null phenotype on mammary gland function during early lactation. Lactating C57BL/6J(lm/lm) mice had significantly fewer, smaller, and collapsed alveoli comprising swollen, lipid-filled MECs during early lactation. These defects were associated with decreased Akt expression and STAT5 activation, indicative of defects in MEC secretion. In addition, increased expression of ZnT2, TNF-α, and cleaved e-cadherin concomitant with increased activation of STAT3 implicated the loss of ZnT4 in precocious activation of involution. Collectively, our study indicates that the loss of ZnT4 has profound consequences on MEC secretion and may promote tissue remodeling in the mammary gland during early lactation. PMID:26538236

  16. Cerebral lactate dynamics across sleep/wake cycles

    PubMed Central

    Rempe, Michael J.; Wisor, Jonathan P.

    2015-01-01

    Cerebral metabolism varies dramatically as a function of sleep state. Brain concentration of lactate, the end product of glucose utilization via glycolysis, varies as a function of sleep state, and like slow wave activity (SWA) in the electroencephalogram (EEG), increases as a function of time spent awake or in rapid eye movement sleep and declines as a function of time spent in slow wave sleep (SWS). We sought to determine whether lactate concentration exhibits homeostatic dynamics akin to those of SWA in SWS. Lactate concentration in the cerebral cortex was measured by indwelling enzymatic biosensors. A set of equations based conceptually on Process S (previously used to quantify the homeostatic dynamics of SWA) was used to predict the sleep/wake state-dependent dynamics of lactate concentration in the cerebral cortex. Additionally, we applied an iterative parameter space-restricting algorithm (the Nelder-Mead method) to reduce computational time to find the optimal values of the free parameters. Compared to an exhaustive search, this algorithm reduced the computation time required by orders of magnitude. We show that state-dependent lactate concentration dynamics can be described by a homeostatic model, but that the optimal time constants for describing lactate dynamics are much smaller than those of SWA. This disconnect between lactate dynamics and SWA dynamics does not support the concept that lactate concentration is a biochemical mediator of sleep homeostasis. However, lactate synthesis in the cerebral cortex may nonetheless be informative with regard to sleep function, since the impact of glycolysis on sleep slow wave regulation is only just now being investigated. PMID:25642184

  17. Pregnancy and lactation differentially modify the transcriptional regulation of steroidogenic enzymes through DNA methylation mechanisms in the hippocampus of aged rats.

    PubMed

    Rossetti, María F; Varayoud, Jorgelina; Lazzarino, Gisela P; Luque, Enrique H; Ramos, Jorge G

    2016-07-01

    In the present study, we examined the mRNA expression and DNA methylation state of steroidogenic enzymes in the hippocampus of young adult (90-days-old) and middle-aged (450-days-old) nulliparous rats, and middle-aged multiparous rats subjected to three pregnancies with and without lactation. Aging decreased the mRNA levels of steroidogenic-related genes, while pregnancy and lactation significantly reduced the effect of aging, maintaining high expression levels of cytochrome P450 side-chain cleavage (P450scc), steroid 5α-reductase-1 (5αR-1), cytochrome P450arom (P450arom) and aldosterone synthase (P450(11β)-2). In addition, pregnancy and lactation diminished the methylation state of the 5αR-1 promoter and increased the transcription of brain-derived neurotrophic factor, synaptophysin and spinophilin. Pregnancy without lactation increased P450scc and 5αR-1 gene expression and decreased the methylation of their promoters. We concluded that the age-related decrease in the mRNA expression of steroidogenic enzymes is differentially attenuated by pregnancy and lactation in the rat hippocampus and that differential methylation mechanisms could be involved.

  18. Male 11β-HSD1 Knockout Mice Fed Trans-Fats and Fructose Are Not Protected From Metabolic Syndrome or Nonalcoholic Fatty Liver Disease

    PubMed Central

    Larner, Dean P.; Morgan, Stuart A.; Gathercole, Laura L.; Doig, Craig L.; Guest, Phil; Weston, Christopher; Hazeldine, Jon; Tomlinson, Jeremy W.; Stewart, Paul M.

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) defines a spectrum of conditions from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis and is regarded as the hepatic manifestation of the metabolic syndrome. Glucocorticoids can promote steatosis by stimulating lipolysis within adipose tissue, free fatty acid delivery to liver and hepatic de novo lipogenesis. Glucocorticoids can be reactivated in liver through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme activity. Inhibition of 11β-HSD1 has been suggested as a potential treatment for NAFLD. To test this, male mice with global (11β-HSD1 knockout [KO]) and liver-specific (LKO) 11β-HSD1 loss of function were fed the American Lifestyle Induced Obesity Syndrome (ALIOS) diet, known to recapitulate the spectrum of NAFLD, and metabolic and liver phenotypes assessed. Body weight, muscle and adipose tissue masses, and parameters of glucose homeostasis showed that 11β-HSD1KO and LKO mice were not protected from systemic metabolic disease. Evaluation of hepatic histology, triglyceride content, and blinded NAFLD activity score assessment indicated that levels of steatosis were similar between 11β-HSD1KO, LKO, and control mice. Unexpectedly, histological analysis revealed significantly increased levels of immune foci present in livers of 11β-HSD1KO but not LKO or control mice, suggestive of a transition to NASH. This was endorsed by elevated hepatic expression of key immune cell and inflammatory markers. These data indicate that 11β-HSD1-deficient mice are not protected from metabolic disease or hepatosteatosis in the face of a NAFLD-inducing diet. However, global deficiency of 11β-HSD1 did increase markers of hepatic inflammation and suggests a critical role for 11β-HSD1 in restraining the transition to NASH. PMID:27384305

  19. Male 11β-HSD1 Knockout Mice Fed Trans-Fats and Fructose Are Not Protected From Metabolic Syndrome or Nonalcoholic Fatty Liver Disease.

    PubMed

    Larner, Dean P; Morgan, Stuart A; Gathercole, Laura L; Doig, Craig L; Guest, Phil; Weston, Christopher; Hazeldine, Jon; Tomlinson, Jeremy W; Stewart, Paul M; Lavery, Gareth G

    2016-09-01

    Nonalcoholic fatty liver disease (NAFLD) defines a spectrum of conditions from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis and is regarded as the hepatic manifestation of the metabolic syndrome. Glucocorticoids can promote steatosis by stimulating lipolysis within adipose tissue, free fatty acid delivery to liver and hepatic de novo lipogenesis. Glucocorticoids can be reactivated in liver through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme activity. Inhibition of 11β-HSD1 has been suggested as a potential treatment for NAFLD. To test this, male mice with global (11β-HSD1 knockout [KO]) and liver-specific (LKO) 11β-HSD1 loss of function were fed the American Lifestyle Induced Obesity Syndrome (ALIOS) diet, known to recapitulate the spectrum of NAFLD, and metabolic and liver phenotypes assessed. Body weight, muscle and adipose tissue masses, and parameters of glucose homeostasis showed that 11β-HSD1KO and LKO mice were not protected from systemic metabolic disease. Evaluation of hepatic histology, triglyceride content, and blinded NAFLD activity score assessment indicated that levels of steatosis were similar between 11β-HSD1KO, LKO, and control mice. Unexpectedly, histological analysis revealed significantly increased levels of immune foci present in livers of 11β-HSD1KO but not LKO or control mice, suggestive of a transition to NASH. This was endorsed by elevated hepatic expression of key immune cell and inflammatory markers. These data indicate that 11β-HSD1-deficient mice are not protected from metabolic disease or hepatosteatosis in the face of a NAFLD-inducing diet. However, global deficiency of 11β-HSD1 did increase markers of hepatic inflammation and suggests a critical role for 11β-HSD1 in restraining the transition to NASH.

  20. LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease

    PubMed Central

    Mina, Marco; Gnani, Daniela; De Stefanis, Cristiano; Crudele, Annalisa; Rychlicki, Chiara; Petrini, Stefania; Bruscalupi, Giovannella; Agostinelli, Laura; Stronati, Laura; Cucchiara, Salvatore; Musso, Giovanni; Furlanello, Cesare; Svegliati-Baroni, Gianluca; Nobili, Valerio; Alisi, Anna

    2015-01-01

    Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH). We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-ĸB, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH. In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH. PMID:26573228

  1. Male 11β-HSD1 Knockout Mice Fed Trans-Fats and Fructose Are Not Protected From Metabolic Syndrome or Nonalcoholic Fatty Liver Disease.

    PubMed

    Larner, Dean P; Morgan, Stuart A; Gathercole, Laura L; Doig, Craig L; Guest, Phil; Weston, Christopher; Hazeldine, Jon; Tomlinson, Jeremy W; Stewart, Paul M; Lavery, Gareth G

    2016-09-01

    Nonalcoholic fatty liver disease (NAFLD) defines a spectrum of conditions from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis and is regarded as the hepatic manifestation of the metabolic syndrome. Glucocorticoids can promote steatosis by stimulating lipolysis within adipose tissue, free fatty acid delivery to liver and hepatic de novo lipogenesis. Glucocorticoids can be reactivated in liver through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme activity. Inhibition of 11β-HSD1 has been suggested as a potential treatment for NAFLD. To test this, male mice with global (11β-HSD1 knockout [KO]) and liver-specific (LKO) 11β-HSD1 loss of function were fed the American Lifestyle Induced Obesity Syndrome (ALIOS) diet, known to recapitulate the spectrum of NAFLD, and metabolic and liver phenotypes assessed. Body weight, muscle and adipose tissue masses, and parameters of glucose homeostasis showed that 11β-HSD1KO and LKO mice were not protected from systemic metabolic disease. Evaluation of hepatic histology, triglyceride content, and blinded NAFLD activity score assessment indicated that levels of steatosis were similar between 11β-HSD1KO, LKO, and control mice. Unexpectedly, histological analysis revealed significantly increased levels of immune foci present in livers of 11β-HSD1KO but not LKO or control mice, suggestive of a transition to NASH. This was endorsed by elevated hepatic expression of key immune cell and inflammatory markers. These data indicate that 11β-HSD1-deficient mice are not protected from metabolic disease or hepatosteatosis in the face of a NAFLD-inducing diet. However, global deficiency of 11β-HSD1 did increase markers of hepatic inflammation and suggests a critical role for 11β-HSD1 in restraining the transition to NASH. PMID:27384305

  2. Targeting Cell Death and Sterile Inflammation Loop for the Treatment of Nonalcoholic Steatohepatitis

    PubMed Central

    Wree, Alexander; Mehal, Wajahat Z.; Feldstein, Ariel E.

    2016-01-01

    Nonalcoholic fatty liver disease represents a wide spectrum of conditions and is currently the most common form of chronic liver disease affecting both adults and children in the United States and many other parts of the world. Great effort has been focused on the development of novel therapies for those patients with the more advanced forms of the disease, in particular those with nonalcoholic steatohepatitis (NASH) and liver fibrosis that can be associated with significant morbidity and mortality. In this review, the authors focus on the role of cell death and sterile inflammatory pathways as well as the self-perpetuating deleterious cycle they may trigger as novel therapeutic targets for the treatment of fibrotic NASH. PMID:26870930

  3. Obesity and non-alcoholic fatty liver disease: Disparate associations among Asian populations

    PubMed Central

    Wong, Robert J; Ahmed, Aijaz

    2014-01-01

    Obesity is a global epidemic contributing to an increasing prevalence of obesity-related systemic disorders, including nonalcoholic fatty liver disease. The rising prevalence of nonalcoholic steatohepatitis (NASH) will in the near future lead to end-stage liver disease in a large cohort of patients with NASH-related cirrhosis and NASH is predicted to be a leading indication for liver transplantation in the coming decade. However, the prevalence of obesity and the progression of hepatic histological damage associated with NASH exhibit significant ethnic disparities. Despite a significantly lower body mass index and lower rates of obesity compared to other ethnic groups, Asians continue to demonstrate a significant prevalence of hypertension, diabetes, metabolic syndrome and NASH. Ethnic disparities in central adiposity and visceral fat distribution have been hypothesized to contribute to these ethnic disparities. The current review focuses on the epidemiology of obesity and NASH among Asian populations. PMID:24868320

  4. SIRT3 as a Regulator of Non-alcoholic Fatty Liver Disease.

    PubMed

    Cho, Eun-Hee

    2014-09-01

    Non-alcoholic fatty liver disease (NAFLD) is a hepatic presentation of obesity and metabolic syndrome. NAFLD includes a large spectrum of hepatic pathologies that range from simple steatosis and non-alcoholic steatohepatitis (NASH), to liver cirrhosis without an all-encompassing approved therapeutic strategy. Mitochondrial dysfunction is a key component of many metabolic diseases, such as obesity, type 2 diabetes, cancer, NAFLD, and aging. Sirtuin 3 (SIRT3) is a NAD(+)-dependent deacetylase that regulates many of the mitochondrial proteins that are involved with metabolic homeostasis, oxidative stress, and cell survival. This review discusses the association between mitochondrial dysfunction and insulin resistance and later explore the possibility that SIRT3 plays a protective role against NAFLD by improving mitochondrial dysfunction. PMID:26064858

  5. 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

  6. Host factors are dominant in the development of post-liver transplant non-alcoholic steatohepatitis

    PubMed Central

    Boga, Salih; Munoz-Abraham, Armando Salim; Rodriguez-Davalos, Manuel I; Emre, Sukru H; Jain, Dhanpat; Schilsky, Michael L

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a recognized problem in patients after orthotopic liver transplantation and may lead to recurrent graft injury. As the increased demand for liver allografts fail to match the available supply of donor organs, split liver transplantation (SLT) has emerged as an important technique to increase the supply of liver grafts. SLT allows two transplants to occur from one donor organ, and provides a unique model for observing the pathogenesis of NAFLD with respect to the role of recipient environmental and genetic factors. Here we report on two recipients of a SLT from the same deceased donor where only one developed non-alcoholic steatohepatitis (NASH), suggesting that host factors are critical for the development of NASH. PMID:27239259

  7. 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

  8. 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

    2015-10-01

    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

  9. Fulminant hepatitis in a patient with hepatocellular carcinoma related to nonalcoholic steatohepatitis treated with sorafenib.

    PubMed

    Brandi, Giovanni; De Lorenzo, Stefania; Di Girolamo, Stefania; Bellentani, Stefano; Saccoccio, Gioconda; Biasco, Guido

    2015-01-01

    We describe a case of acute liver failure in a patient with advanced hepatocellular carcinoma related to nonalcoholic steatohepatitis during sorafenib treatment. A 74-year-old man with diabetes mellitus and hypertension was diagnosed with hepatocellular carcinoma associated with fatty liver. Three weeks after sorafenib therapy, at Eastern Cooperative Oncology Group performance status 3, he developed jaundice, general weakness, flapping tremor, nausea, and anorexia. Sorafenib was stopped: laboratory tests showed a relevant elevation of transaminases suggesting diagnosis of acute hepatitis. During hospital admission, the patient died of liver failure. Sorafenib is the first successful target therapy effective for advanced hepatocellular carcinoma. The most common adverse events are fatigue, hand-foot skin reaction, skin rash/desquamation, diarrhea, and hypertension, whereas liver dysfunction is uncommon. To our knowledge, this is the first patient reported in the literature with hepatocellular carcinoma related to nonalcoholic steatohepatitis who died of rapid worsening of liver function during sorafenib treatment. PMID:25702656

  10. Gut microbiota and non-alcoholic fatty liver disease: new insights.

    PubMed

    Aron-Wisnewsky, J; Gaborit, B; Dutour, A; Clement, K

    2013-04-01

    Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. A 'two-hit' mechanism has been proposed; however, the complete physiopathogenesis remains incompletely understood. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis.

  11. Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis

    PubMed Central

    Dongiovanni, Paola; Romeo, Stefano; Valenti, Luca

    2015-01-01

    Liver fat accumulation generally related to systemic insulin resistance characterizes nonalcoholic fatty liver disease (NAFLD), which in the presence of nonalcoholic steatohepatitis (NASH) can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease in Western countries. Epidemiological, familial, and twin studies provide evidence for a strong genetic component of NAFLD susceptibility. Recently, genome-wide association studies led to the identification of the major inherited determinants of hepatic fat accumulation: patatin-like phospholipase domain-containing 3 (PNPLA3) I148M gene and transmembrane 6 superfamily member 2 (TM6SF2) E167K gene variants, involved in lipid droplets remodelling and very low-density lipoproteins secretion, are the major determinants of interindividual differences in liver steatosis, and susceptibility to progressive NASH. In this review, we aimed to provide an overview of recent insights into the genetics of hepatic fat accumulation and steatohepatitis. PMID:26273621

  12. Nonalcoholic fatty liver disease and the metabolic syndrome: clinical implications and treatment.

    PubMed

    Rahimi, Robert S; Landaverde, Carmen

    2013-02-01

    The prevalence of nonalcoholic fatty liver disease (NAFLD) is expected to rise along with the global obesity epidemic. As NAFLD is the most common cause of chronic liver disease in the United States, it has become a major health concern. It affects all ethnicities, with the highest prevalence among the Hispanic population. Individuals with nonalcoholic steatohepatitis (NASH), the more serious form of NAFLD, are at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Since NAFLD is intricately associated with the metabolic syndrome and insulin resistance, increased risk of cardiovascular disease and mortality become a real concern. It has recently been shown that current nutrition trends, such as increased consumption of high-fructose corn syrup and certain types of fats, may have an important role in the increased NAFLD prevalence. As there are no ideal treatment options available for NAFLD, a multifaceted treatment approach should be tailored to each individual patient. PMID:23286927

  13. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease.

    PubMed

    Ferolla, Silvia M; Armiliato, Geyza N A; Couto, Cláudia A; Ferrari, Teresa C A

    2014-12-01

    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. 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

  15. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease.

    PubMed

    Ferolla, Silvia M; Armiliato, Geyza N A; Couto, Cláudia A; Ferrari, Teresa C A

    2014-12-03

    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.

  16. Host factors are dominant in the development of post-liver transplant non-alcoholic steatohepatitis.

    PubMed

    Boga, Salih; Munoz-Abraham, Armando Salim; Rodriguez-Davalos, Manuel I; Emre, Sukru H; Jain, Dhanpat; Schilsky, Michael L

    2016-05-28

    Non-alcoholic fatty liver disease (NAFLD) is a recognized problem in patients after orthotopic liver transplantation and may lead to recurrent graft injury. As the increased demand for liver allografts fail to match the available supply of donor organs, split liver transplantation (SLT) has emerged as an important technique to increase the supply of liver grafts. SLT allows two transplants to occur from one donor organ, and provides a unique model for observing the pathogenesis of NAFLD with respect to the role of recipient environmental and genetic factors. Here we report on two recipients of a SLT from the same deceased donor where only one developed non-alcoholic steatohepatitis (NASH), suggesting that host factors are critical for the development of NASH. PMID:27239259

  17. Fulminant hepatitis in a patient with hepatocellular carcinoma related to nonalcoholic steatohepatitis treated with sorafenib.

    PubMed

    Brandi, Giovanni; De Lorenzo, Stefania; Di Girolamo, Stefania; Bellentani, Stefano; Saccoccio, Gioconda; Biasco, Guido

    2015-04-28

    We describe a case of acute liver failure in a patient with advanced hepatocellular carcinoma related to nonalcoholic steatohepatitis during sorafenib treatment. A 74-year-old man with diabetes mellitus and hypertension was diagnosed with hepatocellular carcinoma associated with fatty liver. Three weeks after sorafenib therapy, at Eastern Cooperative Oncology Group performance status 3, he developed jaundice, general weakness, flapping tremor, nausea, and anorexia. Sorafenib was stopped: laboratory tests showed a relevant elevation of transaminases suggesting diagnosis of acute hepatitis. During hospital admission, the patient died of liver failure. Sorafenib is the first successful target therapy effective for advanced hepatocellular carcinoma. The most common adverse events are fatigue, hand-foot skin reaction, skin rash/desquamation, diarrhea, and hypertension, whereas liver dysfunction is uncommon. To our knowledge, this is the first patient reported in the literature with hepatocellular carcinoma related to nonalcoholic steatohepatitis who died of rapid worsening of liver function during sorafenib treatment.

  18. Debate on the use of hormonal contraceptives during lactation.

    PubMed

    Nilsson, S; Nygren, K G

    1980-04-01

    Contraceptive steroids taken during the lactation period will, in small measure, be transferred to the milk. The side effects from estrogens administered during lactation are enough to contraindicate their use at this time. Low-dose gestagens are sufficient to achieve contraceptive effect. A study of 6-7-year-old children whose mothers took OCs (oral contraceptives) during lactation is being conducted currently to ascertain longterm side effects or possible effects outside the hypothalamic-pituitary-gonadal axis. However, at this time the minipill of 30 mcg d-norgestrel daily is considered safe for a nursing mother and her baby.

  19. Gut Microbiota and Clinical Disease: Obesity and Nonalcoholic Fatty Liver Disease

    PubMed Central

    Seo, Ji Hyun; Youn, Hee-Shang

    2013-01-01

    The prevalence of obesity is increasing worldwide. Obesity can cause hyperlipidemia, hypertension, cardiovascular diseases, metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Many environmental or genetic factors have been suggested to contribute to the development of obesity, but there is no satisfactory explanation for its increased prevalence. This review discusses the latest updates on the role of the gut microbiota in obesity and NAFLD. PMID:24010102

  20. The endoplasmic reticulum as a potential therapeutic target in nonalcoholic fatty liver disease

    PubMed Central

    Gentile, Christopher L; Pagliassotti, Michael J

    2008-01-01

    The endoplasmic reticulum (ER) has emerged as a key to understanding the development and consequences of hepatic fat accumulation in nonalcoholic fatty liver disease (NAFLD). An essential function of this organelle is the proper assembly of proteins that are destined for intracellular organelles and the cell surface. Recent evidence suggests that chemical chaperones that enhance the functional capacity of the ER improve liver function in obesity and NAFLD. These chaperones may therefore provide a novel potential therapeutic strategy in NAFLD. PMID:18821470

  1. Non-alcoholic fatty liver disease (NAFLD): a tale of fat and sugar?

    PubMed

    Longato, Lisa

    2013-01-01

    The global diffusion of the so-called Western diet, which is enriched in fat and carbohydrates, such as fructose, has been proposed to be an underlying cause of the increased prevalence of metabolic conditions, including non-alcoholic fatty liver disease (NAFLD). This Smart Card summarizes the main metabolic and hepatic histological features of rodent models fed with diets combining high fat and fructose. PMID:23866299

  2. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease.

    PubMed

    Villanova, Nicola; Moscatiello, Simona; Ramilli, Stefano; Bugianesi, Elisabetta; Magalotti, Donatella; Vanni, Ester; Zoli, Marco; Marchesini, Giulio

    2005-08-01

    Nonalcoholic fatty liver disease (NAFLD) is consistently associated with features of the metabolic syndrome, a condition carrying a high risk of cardiovascular events. We measured the vasodilatory response of the brachial artery in response to ischemia (a test of endothelial function) (FMV) as well as cardiovascular risk profile in 52 NAFLD cases and 28 age- and sex-matched controls. The 10-year risk of coronary events was calculated according to the Framingham equation and the scores derived from the PROCAM study and NCEP-ATPIII proposals. FMV was 6.33% +/- 5.93% in NAFLD versus 12.22% +/- 5.05% in controls (P < .0001), and higher in pure fatty liver (9.93%) compared with nonalcoholic steatohepatitis (4.94%) (P = .010). No differences were observed in flow-independent vasodilation (response to sublingual nitroglycerin). Percent FMV was negatively associated with insulin resistance (homeostasis model assessment) in the whole population (r = -0.243; P = .030). In logistic regression analysis, NAFLD was associated with a percent FMV in the lower tertile (OR, 6.7; 95% CI, 1.26-36.1), after adjustment for age, sex, body mass index, and insulin resistance. Among NAFLD patients, low FMV was associated with nonalcoholic steatohepatitis (adjusted OR, 6.8; 95% CI, 1.2-40.2). The 10-year probability of cardiovascular events was moderately increased in NAFLD, and particularly in nonalcoholic steatohepatitis. In conclusion, our study provides evidence of endothelial dysfunction and increased risk of cardiovascular events in NAFLD. The risk of advanced liver disease is well recognized in NAFLD patients, but the large majority of cases might experience cardiovascular disease in the long term, indirectly limiting the burden of liver failure. PMID:15981216

  3. [The assessment of cardiovascular risk factors in patients with nonalcoholic fatty liver disease].

    PubMed

    Chubirko, K I; Ivachevs'ka, V V; Hechko, M M; Chopeĭ, I V; Stan, M P; Koshelia, I I

    2014-01-01

    Article presents the result of assessmaent of cardiovascular risk factors in patients with nonalcoholic fatty liver disease (NAFLD). The results show the presence of cardiovascular risk factors in patients with NAFLD, namely the increase of waist and hip circumferences compared with patients of the control group, hyperglycemia and dyslipidemia, decrease in apolipoprotein A1 (AroA1) compared to practically healthy people. PMID:25796862

  4. Comparative transcriptome analysis reveals different molecular mechanisms of Bacillus coagulans 2-6 response to sodium lactate and calcium lactate during lactic acid production.

    PubMed

    Qin, Jiayang; Wang, Xiuwen; Wang, Landong; Zhu, Beibei; Zhang, Xiaohua; Yao, Qingshou; Xu, Ping

    2015-01-01

    Lactate production is enhanced by adding calcium carbonate or sodium hydroxide during fermentation. However, Bacillus coagulans 2-6 can produce more than 180 g/L L-lactic acid when calcium lactate is accumulated, but less than 120 g/L L-lactic acid when sodium lactate is formed. The molecular mechanisms by which B. coagulans responds to calcium lactate and sodium lactate remain unclear. In this study, comparative transcriptomic methods based on high-throughput RNA sequencing were applied to study gene expression changes in B. coagulans 2-6 cultured in non-stress, sodium lactate stress and calcium lactate stress conditions. Gene expression profiling identified 712 and 1213 significantly regulated genes in response to calcium lactate stress and sodium lactate stress, respectively. Gene ontology assignments of the differentially expressed genes were performed. KEGG pathway enrichment analysis revealed that 'ATP-binding cassette transporters' were significantly affected by calcium lactate stress, and 'amino sugar and nucleotide sugar metabolism' was significantly affected by sodium lactate stress. It was also found that lactate fermentation was less affected by calcium lactate stress than by sodium lactate stress. Sodium lactate stress had negative effect on the expression of 'glycolysis/gluconeogenesis' genes but positive effect on the expression of 'citrate cycle (TCA cycle)' genes. However, calcium lactate stress had positive influence on the expression of 'glycolysis/gluconeogenesis' genes and had minor influence on 'citrate cycle (TCA cycle)' genes. Thus, our findings offer new insights into the responses of B. coagulans to different lactate stresses. Notably, our RNA-seq dataset constitute a robust database for investigating the functions of genes induced by lactate stress in the future and identify potential targets for genetic engineering to further improve L-lactic acid production by B. coagulans.

  5. Frequency of nonalcoholic fatty liver disease and degree of hepatic steatosis in African-American patients.

    PubMed Central

    Giday, Samuel A.; Ashiny, Zelalem; Naab, Tammy; Smoot, Duane; Banks, Alpha

    2006-01-01

    BACKGROUND: This retrospective study evaluates the degree and distribution of hepatic steatosis in predominantly African-American patients who had liver biopsies over a period of five years in our institution. METHOD: A search in the pathology registry of Howard University Hospital was performed for the presence of fat in liver biopsies. Each biopsy was assessed. RESULTS: Of the 320 liver biopsies that were reviewed, 61 were found to have steatosis. Fifty-six of the 61 patients were African-American. The mean body mass index in those African-American patients was found to be 30. Grade-1 steatosis was found in 16 patients, grade 2 in 22 patients, grade 3 in 14 patients and nine patients had grade-4 steatosis. Four patients fulfilled the criteria for the diagnosis of nonalcoholic fatty liver disease (NAFLD). All four patients had simple steatosis without any inflammation. The frequency of NAFLD in our study population was found to be <2%. Nonalcoholic steatohepatitis was not found in any of our study population. Dyslipidemia was found in all four patients with steatosis. CONCLUSION: NAFLD has a low prevalence in African-American patients. Nonalcoholic steatohepatitis was not found in any of the African-American patients seen at our institution. PMID:17052050

  6. Non-invasive Diagnosis of Fibrosis in Non-alcoholic Fatty Liver Disease

    PubMed Central

    Arora, Anil; Sharma, Praveen

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed as well as in developing countries. Its prevalence continues to rise currently affecting approximately 20-30% of adults and 10% of children in the United States. Non-alcoholic fatty liver disease represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign non-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several non-invasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. There has been a substantial development of non-invasive risk scores, biomarker panels, and radiological modalities to identify at risk patients with NAFLD without recourse to liver biopsy on a routine basis. Examples include combination of serum markers like NAFLD fibrosis score (NFS), BARD score, fibrometer, FIB4, and non-invasive tools like fibroscan which assess fibrosis in patients with NAFLD. Other markers of fibrosis that have been evaluated include high-sensitivity C-reactive protein, plasma pentraxin 3, interleukin-6, and cytokeratin-18. This review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on the potential future markers under investigation. PMID:25755423

  7. Mitochondrial DNA from hepatocytes as a ligand for TLR9: Drivers of nonalcoholic steatohepatitis?

    PubMed

    Handa, Priya; Vemulakonda, Akhila; Kowdley, Kris V; Uribe, Misael; Méndez-Sánchez, Nahum

    2016-08-21

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, affecting approximately one third of the Western world. It consists of a wide spectrum of liver disorders, ranging from fatty liver to nonalcoholic steatohepatitis (NASH), which consists of steatosis, ballooning injury and inflammation. Despite an alarming growth in the statistics surrounding NAFLD, there are as yet no effective therapies for its treatment. Innate immune signaling has been thought to play a significant role in initiating and augmenting hepatic inflammation, contributing to the transition from nonalcoholic fatty liver to NASH. An immune response is triggered by countless signals called damage-associated molecular patterns (DAMPs) elicited by lipid-laden and damaged hepatocytes, which are recognized by pattern recognition receptors (PRRs) on hepatic immune cells to initiate inflammatory signaling. In this editorial, in addition to summarizing innate immune signaling in NAFLD and discussing potential therapies that target innate immune pathways, we have described a recent study that demonstrated that mitochondrial DNA serves as a DAMP activating a hepatic PRR, TLR9, in mice and in the plasma of NASH patients. In addition to identifying a new ligand for TLR9 during NASH progression, the study shows that blocking TLR9 reverses NASH, paving the way for the development of future NASH therapy. PMID:27610009

  8. Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

    PubMed Central

    Yki-Järvinen, Hannele

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance. PMID:26556368

  9. Mitochondrial DNA from hepatocytes as a ligand for TLR9: Drivers of nonalcoholic steatohepatitis?

    PubMed Central

    Handa, Priya; Vemulakonda, Akhila; Kowdley, Kris V; Uribe, Misael; Méndez-Sánchez, Nahum

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, affecting approximately one third of the Western world. It consists of a wide spectrum of liver disorders, ranging from fatty liver to nonalcoholic steatohepatitis (NASH), which consists of steatosis, ballooning injury and inflammation. Despite an alarming growth in the statistics surrounding NAFLD, there are as yet no effective therapies for its treatment. Innate immune signaling has been thought to play a significant role in initiating and augmenting hepatic inflammation, contributing to the transition from nonalcoholic fatty liver to NASH. An immune response is triggered by countless signals called damage-associated molecular patterns (DAMPs) elicited by lipid-laden and damaged hepatocytes, which are recognized by pattern recognition receptors (PRRs) on hepatic immune cells to initiate inflammatory signaling. In this editorial, in addition to summarizing innate immune signaling in NAFLD and discussing potential therapies that target innate immune pathways, we have described a recent study that demonstrated that mitochondrial DNA serves as a DAMP activating a hepatic PRR, TLR9, in mice and in the plasma of NASH patients. In addition to identifying a new ligand for TLR9 during NASH progression, the study shows that blocking TLR9 reverses NASH, paving the way for the development of future NASH therapy.

  10. Role of diet and nutritional management in non-alcoholic fatty liver disease.

    PubMed

    Fan, Jian-Gao; Cao, Hai-Xia

    2013-12-01

    Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis, which causes an increased risk of cirrhosis, type 2 diabetes, and cardiovascular complications. With the worldwide growing incidence of obesity, sedentary lifestyle, and unhealthy dietary pattern, NAFLD has currently been recognized as a major health burden. Dietary patterns and nutrients are the important contributors to the development, progression, and treatment of NAFLD and associated metabolic comorbidities. Generally, hypercaloric diet, especially rich in trans/saturated fat and cholesterol, and fructose-sweetened beverages seem to increase visceral adiposity and stimulate hepatic lipid accumulation and progression into non-alcoholic steatohepatitis, whereas reducing caloric intake, increasing soy protein and whey consumption, and supplement of monounsaturated fatty acids, omega-3 fatty acids, and probiotics have preventive and therapeutic effects. In addition, choline, fiber, coffee, green tea, and light alcohol drinking might be protective factors for NAFLD. Based on available data, at least 3-5% of weight loss, achieved by hypocaloric diet alone or in conjunction with exercise and behavioral modification, generally reduces hepatic steatosis, and up to 10% weight loss may be needed to improve hepatic necroinflammation. A sustained adherence to diet rather than the actual diet type is a major predictor of successful weight loss. Moreover, a healthy diet has benefits beyond weight reduction on NAFLD patients whether obese or of normal weight. Therefore, nutrition serves as a major route of prevention and treatment of NAFLD, and patients with NAFLD should have an individualized diet recommendation.

  11. Mitochondrial DNA from hepatocytes as a ligand for TLR9: Drivers of nonalcoholic steatohepatitis?

    PubMed Central

    Handa, Priya; Vemulakonda, Akhila; Kowdley, Kris V; Uribe, Misael; Méndez-Sánchez, Nahum

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, affecting approximately one third of the Western world. It consists of a wide spectrum of liver disorders, ranging from fatty liver to nonalcoholic steatohepatitis (NASH), which consists of steatosis, ballooning injury and inflammation. Despite an alarming growth in the statistics surrounding NAFLD, there are as yet no effective therapies for its treatment. Innate immune signaling has been thought to play a significant role in initiating and augmenting hepatic inflammation, contributing to the transition from nonalcoholic fatty liver to NASH. An immune response is triggered by countless signals called damage-associated molecular patterns (DAMPs) elicited by lipid-laden and damaged hepatocytes, which are recognized by pattern recognition receptors (PRRs) on hepatic immune cells to initiate inflammatory signaling. In this editorial, in addition to summarizing innate immune signaling in NAFLD and discussing potential therapies that target innate immune pathways, we have described a recent study that demonstrated that mitochondrial DNA serves as a DAMP activating a hepatic PRR, TLR9, in mice and in the plasma of NASH patients. In addition to identifying a new ligand for TLR9 during NASH progression, the study shows that blocking TLR9 reverses NASH, paving the way for the development of future NASH therapy. PMID:27610009

  12. Simple Resistance Exercise helps Patients with Non-alcoholic Fatty Liver Disease.

    PubMed

    Takahashi, A; Abe, K; Usami, K; Imaizumi, H; Hayashi, M; Okai, K; Kanno, Y; Tanji, N; Watanabe, H; Ohira, H

    2015-10-01

    To date, only limited evidence has supported the notion that resistance exercise positively impacts non-alcoholic fatty liver disease. We evaluated the effects of resistance exercise on the metabolic parameters of non-alcoholic fatty liver disease (NAFLD) in 53 patients who were assigned to either a group that performed push-ups and squats 3 times weekly for 12 weeks (exercise group; n=31) or a group that did not (control; n=22). Patients in the control group proceeded with regular physical activities under a restricted diet throughout the study. The effects of the exercise were compared between the 2 groups after 12 weeks. Fat-free mass and muscle mass significantly increased, whereas hepatic steatosis grade, mean insulin and ferritin levels, and the homeostasis model assessment-estimated insulin resistance index were significantly decreased in the exercise group. Compliance with the resistance exercise program did not significantly correlate with patient background characteristics such as age, sex, BMI and metabolic complications. These findings show that resistance exercise comprising squats and push-ups helps to improve the characteristics of metabolic syndrome in patients with non-alcoholic fatty liver disease.

  13. Macrophage Activation in Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) Correlates with Hepatic Progenitor Cell Response via Wnt3a Pathway

    PubMed Central

    Renzi, Anastasia; De Stefanis, Cristiano; Stronati, Laura; Franchitto, Antonio; Alisi, Anna; Onori, Paolo; De Vito, Rita; Alpini, Gianfranco; Gaudio, Eugenio

    2016-01-01

    Non-alcoholic fatty liver disease is one of the most important causes of liver-related morbidity in children. In non-alcoholic fatty liver disease, the activation of liver resident macrophage pool is a central event in the progression of liver injury. The aims of the present study were to evaluate the polarization of liver macrophages and the possible role of Wnt3a production by macrophages in hepatic progenitor cell response in the progression of pediatric non-alcoholic fatty liver disease. 32 children with biopsy-proven non-alcoholic fatty liver disease were included. 20 out of 32 patients were treated with docosahexaenoic acid for 18 months and biopsies at the baseline and after 18 months were included. Hepatic progenitor cell activation, macrophage subsets and Wnt/β-catenin pathway were evaluated by immunohistochemistry and immunofluorescence. Our results indicated that in pediatric non-alcoholic fatty liver disease, pro-inflammatory macrophages were the predominant subset. Macrophage polarization was correlated with Non-alcoholic fatty liver disease Activity Score, ductular reaction, and portal fibrosis; docosahexaenoic acid treatment determined a macrophage polarization towards an anti-inflammatory phenotype in correlation with the reduction of serum inflammatory cytokines, with increased macrophage apoptosis, and with the up-regulation of macrophage Wnt3a expression; macrophage Wnt3a expression was correlated with β-catenin phosphorylation in hepatic progenitor cells and signs of commitment towards hepatocyte fate. In conclusion, macrophage polarization seems to have a key role in the progression of pediatric non-alcoholic fatty liver disease; the modulation of macrophage polarization could drive hepatic progenitor cell response by Wnt3a production. PMID:27310371

  14. Imperfect asymmetry of life: earth microbial communities prefer D-lactate but can use L-lactate also.

    PubMed

    Moazeni, Faegheh; Zhang, Gaosen; Sun, Henry J

    2010-05-01

    Asymmetrical utilization of chiral compounds has been sought on Mars as evidence for biological activity. This method was recently validated in glucose. Earth organisms utilize D-glucose, not L-glucose, a perfect asymmetry. In this study, we tested the method in lactate and found utilization of both enantiomers. Soil-, sediment-, and lake-borne microbial communities prefer D-lactate but can consume L-lactate if given extra time to acclimate. This situation is termed imperfect asymmetry. Future life-detection mission investigators need to be aware of imperfect asymmetry so as not to miss relatively subtle signs of life. PMID:20528194

  15. Nutritional status and behavior during lactation.

    PubMed

    Pachón, H; McGuire, M K; Rasmussen, K M

    1995-08-01

    Effects of chronic maternal food restriction and time of day on maternal and pup behaviors were examined in ovariectomized Sprague-Dawley rats (n = 26). Dams were fed ad lib (AL) or were restricted to 85% (85 AL) or 70% (70 AL) of ad lib intake. Dams and their 5-pup litters were observed for 45 min at night on days 9, 14, and 19 of lactation and during the day on day 14. A novel behavioral instrument was used to observe maternal and pup behaviors. At night, food-restricted animals engaged in more nursing behaviors than AL animals. Differential pup stimuli may account for this difference. AL animals engaged in more nursing behaviors during the day than night, whereas 70 AL animals demonstrated the opposite diurnal pattern. Time of feeding may explain this difference. On the other hand, 85 AL animals behaved similarly during the day and at night. Therefore, alterations in circadian behavior patterns are less pronounced in rats mildly restricted (85 AL) than in rats more food restricted (70 AL).

  16. Maximal lactate steady state in Judo

    PubMed Central

    de Azevedo, Paulo Henrique Silva Marques; Pithon-Curi, Tania; Zagatto, Alessandro Moura; Oliveira, João; Perez, Sérgio

    2014-01-01

    Summary Background: the purpose of this study was to verify the validity of respiratory compensation threshold (RCT) measured during a new single judo specific incremental test (JSIT) for aerobic demand evaluation. Methods: to test the validity of the new test, the JSIT was compared with Maximal Lactate Steady State (MLSS), which is the gold standard procedure for aerobic demand measuring. Eight well-trained male competitive judo players (24.3 ± 7.9 years; height of 169.3 ± 6.7cm; fat mass of 12.7 ± 3.9%) performed a maximal incremental specific test for judo to assess the RCT and performed on 30-minute MLSS test, where both tests were performed mimicking the UchiKomi drills. Results: the intensity at RCT measured on JSIT was not significantly different compared to MLSS (p=0.40). In addition, it was observed high and significant correlation between MLSS and RCT (r=0.90, p=0.002), as well as a high agreement. Conclusions: RCT measured during JSIT is a valid procedure to measure the aerobic demand, respecting the ecological validity of Judo. PMID:25332923

  17. Mood stabilizers in pregnancy and lactation

    PubMed Central

    Grover, Sandeep; Avasthi, Ajit

    2015-01-01

    Management of bipolar during pregnancy and postpartum is very challenging. The treating clinicians have to take into account various factors like current mental state, longitudinal history of the patient, past history of relapse while off medication, response to medication, time of pregnancy at which patient presents to the clinician, etc. The choice of drug should depend on the balance between safety and efficacy profile. Whenever patient is on psychotropic medication, close and intensive monitoring should be done. Among the various mood stabilizers, use of lithium during the second and third trimester appears to be safe. Use of valproate during first trimester is associated with major malformation and long-term sequalae in the form of developmental delay, lower intelligence quotient, and higher risk of development of autism spectrum disorder. Similarly use of carbamazepine in first trimester is associated with higher risk of major congenital malformation and its use in first trimester is contraindicated. Data for lamotrigine (LTG) appears to be more favorable than other antiepileptics. During lactation, use of valproate and LTG is reported to be safe. Use of typical and/atypical antipsychotic is a good option during pregnancy in women with bipolar disorder. PMID:26330649

  18. Lack of Influence of the Menstrual Cycle on Blood Lactate.

    ERIC Educational Resources Information Center

    Lamont, Linda S.

    1986-01-01

    Nine healthy women were tested before, during, and after exercise during the follicular and luteal phases of their menstrual cycles to determine the effect of menstruation on blood lactate levels. Findings are discussed. (Author/MT)

  19. Pregnant & Lactating Populations Research - NCS Dietary Assessment Literature Review

    Cancer.gov

    Identifying and studying additional biomarkers of energy and nutrient intake will advance validation efforts and lead to a better understanding of the biases and sources of measurement error in dietary assessment instruments in pregnant or lactating populations.

  20. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

    PubMed Central

    Sumida, Yoshio; Nakajima, Atsushi; Itoh, Yoshito

    2014-01-01

    It is estimated that 30% of the adult population in Japan is affected by nonalcoholic fatty liver disease (NAFLD). Fatty changes of the liver are generally diagnosed using imaging methods such as abdominal ultrasonography (US) and computed tomography (CT), but the sensitivity of these imaging techniques is low in cases of mild steatosis. Alanine aminotransferase levels may be normal in some of these patients, warranting the necessity to establish a set of parameters useful for detecting NAFLD, and the more severe form of the disease, nonalcoholic steatohepatitis (NASH). Although liver biopsy is currently the gold standard for diagnosing progressive NASH, it has many drawbacks, such as sampling error, cost, and risk of complications. Furthermore, it is not realistic to perform liver biopsies on all NAFLD patients. Diagnosis of NASH using various biomarkers, scoring systems and imaging methods, such as elastography, has recently been attempted. The NAFIC score, calculated from the levels of ferritin, fasting insulin, and type IV collagen 7S, is useful for the diagnosis of NASH, while the NAFLD fibrosis score and the FIB-4 index are useful for excluding NASH in cases of advanced fibrosis. This article reviews the limitations and merits of liver biopsy and noninvasive diagnostic tests in the diagnosis of NAFLD/NASH. PMID:24574716

  1. Lactate kinetics after intermittent and continuous exercise training.

    PubMed

    Gharbi, Adnene; Chamari, Karim; Kallel, Amjad; Ahmaidi, Saîd; Tabka, Zouhair; Abdelkarim, Zbidi

    2008-01-01

    The purpose of this study was to assess, the effects of continuous and intermittent exercise training on lactate kinetic parameters and maximal aerobic speed (MAS) using field tests. Twenty-four male sport students were equally divided into continuous (CT) and intermittent (IT) physically trained groups. Another six participants acted as non-trained controls (CG). The trained participants practiced 6-days per week for 6 weeks. Before and after training, all participants completed an incremental exercise test to assess their MAS, and a 30- second supra-maximal exercise followed by 30 minutes of active recovery to determine the individual blood lactate recovery curve. It was found that exercise training has significantly increased MAS (p < 0.001), the lactate exchange and removal abilities as well as the lactate concentrations at the beginning of the recovery ([La]-(0)); for both CT and IT groups; this was accompanied by a significant reduction of the time to lactate-peak. Nevertheless, the improvement in MAS was significantly higher (p < 0.001) post-intermittent (15.1 % ± 2.4) than post-continuous (10.3 % ± 3.2) training. The lactate-exchange and removal abilities were also significantly higher for IT than for CT-group (P<0.05). Moreover, IT-group showed a significantly shorter half-time of the blood lactate (t-½-[La]) than CT-group (7.2 ± 0.5 min vs 7.7 ± 0.3 min, respectively) (p < 0.05). However, no significant differences were observed in peak blood lactate concentration ([La]peak), time to reach [La]peak (t-[La]peak), and [La]-(0) between the two physically-trained groups. We conclude that both continuous and intermittent training exercises were equally effective in improving t-[La]peak and [La]peak, although intermittent training was more beneficial in elevating MAS and in raising the lactate exchange (γ1) and removal (γ2) indexes. Key pointsCoaches and athletes need to be aware of the potentiality positive effects of exercise intensity.Improvements in

  2. Lactate Kinetics After Intermittent and Continuous Exercise Training

    PubMed Central

    Gharbi, Adnene; Chamari, Karim; Kallel, Amjad; Ahmaidi, Saîd; Tabka, Zouhair; Abdelkarim, Zbidi

    2008-01-01

    The purpose of this study was to assess, the effects of continuous and intermittent exercise training on lactate kinetic parameters and maximal aerobic speed (MAS) using field tests. Twenty-four male sport students were equally divided into continuous (CT) and intermittent (IT) physically trained groups. Another six participants acted as non-trained controls (CG). The trained participants practiced 6-days per week for 6 weeks. Before and after training, all participants completed an incremental exercise test to assess their MAS, and a 30- second supra-maximal exercise followed by 30 minutes of active recovery to determine the individual blood lactate recovery curve. It was found that exercise training has significantly increased MAS (p < 0.001), the lactate exchange and removal abilities as well as the lactate concentrations at the beginning of the recovery ([La]-(0)); for both CT and IT groups; this was accompanied by a significant reduction of the time to lactate-peak. Nevertheless, the improvement in MAS was significantly higher (p < 0.001) post-intermittent (15.1 % ± 2.4) than post-continuous (10.3 % ± 3.2) training. The lactate-exchange and removal abilities were also significantly higher for IT than for CT-group (P<0.05). Moreover, IT-group showed a significantly shorter half-time of the blood lactate (t-½-[La]) than CT-group (7.2 ± 0.5 min vs 7.7 ± 0.3 min, respectively) (p < 0.05). However, no significant differences were observed in peak blood lactate concentration ([La]peak), time to reach [La]peak (t-[La]peak), and [La]-(0) between the two physically-trained groups. We conclude that both continuous and intermittent training exercises were equally effective in improving t-[La]peak and [La]peak, although intermittent training was more beneficial in elevating MAS and in raising the lactate exchange (γ1) and removal (γ2) indexes. Key points Coaches and athletes need to be aware of the potentiality positive effects of exercise intensity. Improvements

  3. Perinatal exposure to bisphenol A exacerbates nonalcoholic steatohepatitis-like phenotype in male rat offspring fed on a high-fat diet.

    PubMed

    Wei, Jie; Sun, Xia; Chen, Yajie; Li, Yuanyuan; Song, Liqiong; Zhou, Zhao; Xu, Bing; Lin, Yi; Xu, Shunqing

    2014-09-01

    Bisphenol A (BPA) is one of the environmental endocrine disrupting chemicals, which is present ubiquitously in daily life. Accumulating evidence indicates that exposure to BPA contributes to metabolic syndrome. In this study, we examined whether perinatal exposure to BPA predisposed offspring to fatty liver disease: the hepatic manifestation of metabolic syndrome. Wistar rats were exposed to 50 μg/kg per day BPA or corn oil throughout gestation and lactation by oral gavage. Offspring were fed a standard chow diet (SD) or a high-fat diet (HFD) after weaning. Effects of BPA were assessed by examination of hepatic morphology, biochemical analysis, and the hepatic expression of genes and/or proteins involved in lipogenesis, fatty acid oxidation, gluconeogenesis, insulin signaling, inflammation, and fibrosis. On a SD, the offspring of rats exposed to BPA exhibited moderate hepatic steatosis and altered expression of insulin signaling elements in the liver, but with normal liver function. On a HFD, the offspring of rats exposed to BPA showed a nonalcoholic steatohepatitis-like phenotype, characterized by extensive accumulation of lipids, large lipid droplets, profound ballooning degeneration, impaired liver function, increased inflammation, and even mild fibrosis in the liver. Perinatal exposure to BPA worsened the hepatic damage caused by the HFD in the rat offspring. The additive effects of BPA correlated with higher levels of hepatic oxidative stress. Collectively, exposure to BPA may be a new risk factor for the development of fatty liver disease and further studies should assess whether this finding is also relevant to the human population. PMID:25112833

  4. Energy Flux, Lactate Shuttling, Mitochondrial Dynamics, and Hypoxia.

    PubMed

    Brooks, George A

    2016-01-01

    Our understanding of what happens in working muscle and at the whole-body level at sea level and at high altitude is different from that a few years ago. If dietary CHO and nutrition are adequate, at sea level metabolism shifts from a mix of lipid and CHO-derived fuels toward carbohydrate (glycogen, glucose, and lactate) oxidation at moderate and greater exercise intensities. As given by the Crossover Concept, a percentage to total energy expenditure, lipid oxidation is greatest at exercise power outputs eliciting 45-50 % of VO2max with greater intensities requiring relatively more CHO and lesser lipid oxidation. At altitude, a given exercise power output is achieved at a greater relative intensity expressed as % VO2max. Hence, exercise under conditions of hypoxia requires greater glycolytic flux, and lactate production than does the same effort at sea level, normoxic conditions. Glycolytic flux is further augmented at altitude by the effect of hypoxemia on sympathetic nervous system activity. Hence, augmented lactate production during exercise is adaptive. Over the short term, accelerated lactate flux provides ATP supporting muscle contraction and balances cytosolic redox. As well, lactate provides and energy substrate and gluconeogenic precursor. Over a longer term, via redox and ROS-generating mechanisms, lactate may affect adaptations in mitochondrial biogenesis and solute (glucose and lactate) transport. While important, the energy substrate, gluconeogenic, and signaling qualities of lactate production and disposal at altitude need to be considered within the context of overall dietary energy intake and expenditure during exercise at sea level and high altitude. PMID:27343113

  5. The promotion of breastfeeding.

    PubMed

    Tuluhungwa, R R; Yung, W

    1979-01-01

    To reverse the current trend of a significant decline worldwide in breast feeding means reeducation of medical and health personnel as well as the general public. Programs to promote breast feeding require the commitment of governments, with support from various ministries including health, education, labor, community development and judiciary. Examples of what 3 developing countries--Jamaica, Colombia and Thailand--are doing to promote breast feeding are reported. A large scale breast feeding campaign was launched in Jamaica in October 1977. The 3 phases of the campaign were: 1) preliminary surveys and research and motivation of professional, voluntary and extension groups through training seminars, panel discussions, and meetings; 2) promotion of breast feeding via mass media and motivation of target groups by trained personnel; and 3) evaluation of the campaign. A survey undertaken in 1978 showed that the breast feeding messages had achieved the desired effect--more mothers practiced breast feeding. In Colombia the breast feeding campaign emphasized non-formal education through the use of games and pictures. A game is used which is usually initiated by a health worker in the waiting room of a health center and involves the mothers, the general public, and sometimes the professional personnel. Through reading and interpreting rhymed breast feeding messages, the participants exchange opinions and experiences. Before starting a campaign to encourage low-income urban and semi-urban mothers to breast feed, the National Food and Nutrition Committee of Thailand pretested slogans and posters designed for the promotion of breast feeding. Posters develpoed in accordance with the suggestions made by the women were tested among 126 pregnant and lactating women. The Committee decided which picture to print for low-income and rural audiences and which to print for middle-class audiences. PMID:12336781

  6. D-lactate metabolism in the alga, Chlamydomonas Reinhardtii

    SciTech Connect

    Husic, D.W.; Tolbert, N.E.

    1986-05-01

    (/sup 14/C)D-lactate rapidly accumulates in Chlamydomonas cells under anaerobic conditions from the sugar-phosphate pools which are labeled during photosynthesis with /sup 14/CO/sub 2/. A soluble D-lactate dehydrogenase (30 ..mu..mol NADH oxidized/h/mg Chl), which functions only in the direction of pyruvate reduction, has been partially purified and characterized. The D-lactate is reoxidized in Chlamydomonas by a mitochondrial membrane-bound dehydrogenase. This enzyme is known in the plant literature as glycolate dehydrogenase, an enzyme of the oxidative photosynthetic carbon (C/sub 2/) cycle. This dehydrogenase may be linked to the mitochondrial electron transport chain, although the direct electron acceptor is unknown. Therefore, D-lactate accumulation may be, in part, due to the shut down of electron transport during anaerobiosis. In vivo chase experiments have shown that the D-lactate turns over rapidly when algal cells, which have been grown with air levels of CO/sub 2/ (0.04%), are returned to aerobic conditions in the light. Such turnover is not observed in cells which had been grown with 1 to 5% CO/sub 2/. Cells grown with high CO/sub 2/ have lower levels of glycolate dehydrogenase activity. They are currently using mutants of Chlamydomonas deficient in mitochondrial respiration to study the role of D-lactate oxidation in these algae.

  7. Lactational transfer of volatile chemicals in breast milk.

    PubMed

    Fisher, J; Mahle, D; Bankston, L; Greene, R; Gearhart, J

    1997-06-01

    Lactational transfer of chemicals to nursing infants is a concern for occupational physicians when women who are breast-feeding return to the workplace. Some work environments, such as paint shops, have atmospheric contamination from volatile organic chemicals (VOCs). Very little is known about the extent of exposure a nursing infant may receive from the mother's occupational exposure. A physiologically based pharmacokinetic model was developed for a lactating woman to estimate the amount of chemical that a nursing infant ingests for a given nursing schedule and maternal occupational exposure. Human blood/air and milk/air partition coefficients (PCs) were determined for 19 VOCs. Milk/blood PC values were above 3 for carbon tetrachloride, methylchloroform, perchloroethylene, and 1,4-dioxane, while the remaining 16 chemicals had milk/blood PC values of less than 3. Other model parameters, such as solid tissue PC values, metabolic rate constants, blood flow rates, and tissue volumes were taken from the literature and incorporated into the lactation model. In a simulated exposure of a lactating woman to a threshold limit value concentration of an individual chemical, only perchloroethylene, bromochloroethane, and 1,4-dioxane exceeded the U.S. Environmental Protection Agency non-cancer drinking water ingestion rates for children. Very little data exists on the pharmacokinetics of lactational transfer of volatile organics. More data are needed before the significance of the nursing exposure pathway can be adequately ascertained. Physiologically based pharmacokinetic models can play an important role in assessing lactational transfer of chemicals.

  8. Bioconversion of methane to lactate by an obligate methanotrophic bacterium

    PubMed Central

    Henard, Calvin A.; Smith, Holly; Dowe, Nancy; Kalyuzhnaya, Marina G.; Pienkos, Philip T.; Guarnieri, Michael T.

    2016-01-01

    Methane is the second most abundant greenhouse gas (GHG), with nearly 60% of emissions derived from anthropogenic sources. Microbial conversion of methane to fuels and value-added chemicals offers a means to reduce GHG emissions, while also valorizing this otherwise squandered high-volume, high-energy gas. However, to date, advances in methane biocatalysis have been constrained by the low-productivity and limited genetic tractability of natural methane-consuming microbes. Here, leveraging recent identification of a novel, tractable methanotrophic bacterium, Methylomicrobium buryatense, we demonstrate microbial biocatalysis of methane to lactate, an industrial platform chemical. Heterologous overexpression of a Lactobacillus helveticus L-lactate dehydrogenase in M. buryatense resulted in an initial titer of 0.06 g lactate/L from methane. Cultivation in a 5 L continuously stirred tank bioreactor enabled production of 0.8 g lactate/L, representing a 13-fold improvement compared to the initial titer. The yields (0.05 g lactate/g methane) and productivity (0.008 g lactate/L/h) indicate the need and opportunity for future strain improvement. Additionally, real-time analysis of methane utilization implicated gas-to-liquid transfer and/or microbial methane consumption as process limitations. This work opens the door to develop an array of methanotrophic bacterial strain-engineering strategies currently employed for biocatalytic sugar upgrading to “green” chemicals and fuels. PMID:26902345

  9. Lactation management clinic-positive reinforcement to hospital breastfeeding practices.

    PubMed

    Nanavati, R N; Mondkar, J A; Fernandez, A R; Raghavan, K R

    1994-11-01

    Supportive breastfeeding policies in the hospital constitute the foundation for initiation of successful breastfeeding by mothers, constant reinforcement and support to all lactating mothers is however essential to maintain lactation. The objective, methodology and outcome of the Lactation Management Clinic which constitutes a hospital-based mother support group is described. The study was carried out over a period of 2 1/2 years and 519 mothers had attended this clinic. Analysis of the data revealed that at the time of the 1st visit to the clinic, 65.9% mothers had already started supplementary top feeds and the commonest reason encountered was mother's own assessment of inadequate milk seen in 73.6% mothers. Two-thirds (66.9%) of babies in our study were roomed in right from the first day of life, 75.3% of babies had received colostrum and 67.1% babies had not received any prelacteal feeds and yet faced problems at lactation. Mother and infant evaluation revealed no complications with 86.5% mothers and with 54.5% babies. Local breast problems were detected in 19.3% mothers. Faulty positioning was observed in 47.2% patients. Psychological support to mothers was the most important form of therapy given. Seventy eight per cent mothers practiced exclusive breastfeeding subsequently while 21.2% of mothers were partially successful in lactation. Only 3 mothers had lactation failure.

  10. Effects of Pregnancy and Lactation on Iron Metabolism in Rats

    PubMed Central

    Gao, Guofen; Liu, Shang-Yuan; Wang, Hui-Jie; Zhang, Tian-Wei; Yu, Peng; Duan, Xiang-Lin; Zhao, Shu-E; Chang, Yan-Zhong

    2015-01-01

    In female, inadequate iron supply is a highly prevalent problem that often leads to iron-deficiency anemia. This study aimed to understand the effects of pregnancy and lactation on iron metabolism. Rats with different days of gestation and lactation were used to determine the variations in iron stores and serum iron level and the changes in expression of iron metabolism-related proteins, including ferritin, ferroportin 1 (FPN1), ceruloplasmin (Cp), divalent metal transporter 1 (DMT1), transferrin receptor 1 (TfR1), and the major iron-regulatory molecule—hepcidin. We found that iron stores decline dramatically at late-pregnancy period, and the low iron store status persists throughout the lactation period. The significantly increased FPN1 level in small intestine facilitates digestive iron absorption, which maintains the serum iron concentration at a near-normal level to meet the increase of iron requirements. Moreover, a significant decrease of hepcidin expression is observed during late-pregnancy and early-lactation stages, suggesting the important regulatory role that hepcidin plays in iron metabolism during pregnancy and lactation. These results are fundamental to the understanding of iron homeostasis during pregnancy and lactation and may provide experimental bases for future studies to identify key molecules expressed during these special periods that regulate the expression of hepcidin, to eventually improve the iron-deficiency status. PMID:26788496

  11. Bioconversion of methane to lactate by an obligate methanotrophic bacterium

    DOE PAGESBeta

    Henard, Calvin A.; Smith, Holly; Dowe, Nancy; Kalyuzhnaya, Marina G.; Pienkos, Philip T.; Guarnieri, Michael T.

    2016-02-23

    Methane is the second most abundant greenhouse gas (GHG), with nearly 60% of emissions derived from anthropogenic sources. Microbial conversion of methane to fuels and value-added chemicals offers a means to reduce GHG emissions, while also valorizing this otherwise squandered high-volume, high-energy gas. However, to date, advances in methane biocatalysis have been constrained by the low-productivity and limited genetic tractability of natural methane-consuming microbes. Here, leveraging recent identification of a novel, tractable methanotrophic bacterium, Methylomicrobium buryatense, we demonstrate microbial biocatalysis of methane to lactate, an industrial platform chemical. Heterologous overexpression of a Lactobacillus helveticus L-lactate dehydrogenase in M. buryatense resultedmore » in an initial titer of 0.06 g lactate/L from methane. Cultivation in a 5 L continuously stirred tank bioreactor enabled production of 0.8 g lactate/L, representing a 13-fold improvement compared to the initial titer. The yields (0.05 g lactate/g methane) and productivity (0.008 g lactate/L/h) indicate the need and opportunity for future strain improvement. Additionally, real-time analysis of methane utilization implicated gas-to-liquid transfer and/or microbial methane consumption as process limitations. This work opens the door to develop an array of methanotrophic bacterial strain-engineering strategies currently employed for biocatalytic sugar upgrading to “green” chemicals and fuels.« less

  12. Heart rate & blood lactate response in amateur competitive boxing.

    PubMed

    Ghosh, A K; Goswami, A; Ahuja, A

    1995-10-01

    The heart rate (HR) and blood lactate response were studied on 26 senior national level boxers in competitive bouts to explore the aerobic-anaerobic metabolism as well as the training status of the players. The aerobic capacity (VO2 max) of the players were determined using graded running protocol on a treadmill. Heart rate and blood lactate concentration were measured during warm up and boxing rounds. The mean relative VO2 max of the heavy weight category boxers was lower (P < 0.05) than the other two weight categories. No interweight category as well as inter-round differences were observed in the heart rate and blood lactate concentration of the boxers, excepting in the 48-57 kg category, the mean lactate levels in the second and third rounds were higher (P < 0.05) than in the first round. When all weight categories were pooled the mean HR and blood lactate levels were 178 beats/min and 8.24 mMol/l respectively. The study highlights that in amateur boxing, irrespective of the weight category and aerobic capacity, the anaerobic adaptability of the boxers was the same. The training requirements of the boxers demand that they should be also to tolerate a high blood lactate level (approx. 9.0 mMol/l) and a high HR (approx. 180 beats/min) over a total duration of one bout.

  13. The magnitude of blood lactate increases from high speed workouts.

    PubMed

    Caruso, J F; Kucera, S; Jackson, T; Hari, P; Olson, N; McLagan, J; Taylor, S T; Shepherd, C

    2011-05-01

    To examine blood lactate concentrations from high-speed exercise resistive exercise, subjects performed workouts on an inertial kinetic exercise (Oconomowoc, WI) device. Workouts entailed two 60-s sets of elbow flexor (curling) repetitions. Pre- and post-exercise blood lactate concentrations were measured, via a fingertip blood drop, with an analyzer. From workouts the average acceleration, maximum force and total torque were derived. Blood lactate concentrations were analyzed with a 2 (gender)×2 (time) ANOVA, with repeated measures for time. Average acceleration, maximum force and total torque were analyzed with one-way (gender) ANOVAs. With an α=0.05, blood lactate concentrations had a time (prewomen) effects. Current blood lactate concentrations were commensurate with other studies that used a modest level of resistance and engaged a small muscle mass. Given the current workout protocol and muscle mass engaged, as well as parallels to other results, our study appears to offer a valid portrayal of subsequent changes in blood lactate concentrations from high-speed resistive exercise.

  14. A novel mode of lactate metabolism in strictly anaerobic bacteria.

    PubMed

    Weghoff, Marie Charlotte; Bertsch, Johannes; Müller, Volker

    2015-03-01

    Lactate is a common substrate for major groups of strictly anaerobic bacteria, but the biochemistry and bioenergetics of lactate oxidation is obscure. The high redox potential of the pyruvate/lactate pair of E0 ' = -190 mV excludes direct NAD(+) reduction (E0 ' = -320 mV). To identify the hitherto unknown electron acceptor, we have purified the lactate dehydrogenase (LDH) from the strictly anaerobic, acetogenic bacterium Acetobacterium woodii. The LDH forms a stable complex with an electron-transferring flavoprotein (Etf) that exhibited NAD(+) reduction only when reduced ferredoxin (Fd(2-) ) was present. Biochemical analyses revealed that the LDH/Etf complex of A. woodii uses flavin-based electron confurcation to drive endergonic lactate oxidation with NAD(+) as oxidant at the expense of simultaneous exergonic electron flow from reduced ferredoxin (E0 ' ≈ -500 mV) to NAD(+) according to: lactate + Fd(2-)  + 2 NAD(+)  → pyruvate + Fd + 2 NADH. The reduced Fd(2-) is regenerated from NADH by a sequence of events that involves conversion of chemical (ATP) to electrochemical ( Δ μ ˜ Na + ) and finally redox energy (Fd(2-) from NADH) via reversed electron transport catalysed by the Rnf complex. Inspection of genomes revealed that this metabolic scenario for lactate oxidation may also apply to many other anaerobes.

  15. Blood redox status is associated with the likelihood of nonalcoholic fatty liver disease irrespectively of diet's total antioxidant capacity.

    PubMed

    Georgoulis, Michael; Fragopoulou, Elisabeth; Kontogianni, Meropi D; Margariti, Aikaterini; Boulamatsi, Olga; Detopoulou, Paraskeui; Tiniakos, Dina; Zafiropoulou, Rodessa; Papatheodoridis, George

    2015-01-01

    It is well established that oxidative stress is implicated in nonalcoholic fatty liver disease pathogenesis, whereas the dietary intake of antioxidants has been reported to be low in patients with the disease. We hypothesized that blood redox status measurements would be associated with nonalcoholic fatty liver disease presence and severity, and that diet's total antioxidant capacity could moderate the aforementioned association. The study sample consisted of 73 patients with nonalcoholic fatty liver disease, of which 58 were matched by age, sex, and body mass index with 58 controls. Diet's total antioxidant capacity was estimated through the ferric-reducing antioxidant power, the total radical-trapping antioxidant parameter, and the Trolox equivalent antioxidant capacity scores, whereas blood redox status was assessed by measuring thiobarbituric acid reactive substances levels, the enzymatic activity of glutathione peroxidase, and serum resistance to oxidation. Diet's total antioxidant capacity scores and glutathione peroxidase activity were not significantly associated with the disease presence or severity. Both thiobarbituric acid reactive substances and serum resistance to oxidation were significantly associated with the likelihood of nonalcoholic fatty liver disease (odds ratios [ORs], 7.769 [P= .007] and 0.936 [P= .033], respectively), independently of abdominal fat level, degree of insulin resistance, blood lipid levels, markers of subclinical inflammation, and diet's total antioxidant capacity, but not with the disease histologic severity or stage. Our results support the association between blood redox status and the likelihood of nonalcoholic fatty liver disease regardless of diet's total antioxidant capacity.

  16. Feeding oleamide to lactating Jersey cows 1. Effects on lactation performance and milk fatty acid composition.

    PubMed

    Jenkins, T C

    2000-02-01

    Oleamide was previously reported to resist ruminal biohydrogenation and elevate milk oleic acid concentration when fed to lactating Holstein cows. To determine if Jersey cows responded similarly to oleamide, four lactating Jersey cows (mean 417 kg of body weight and 64 days in milk) were fed four diets in a 4x4 Latin square with 2-wk periods. Diets were total mixed ration containing 47% corn silage and 53% concentrate (dry matter basis) and were supplemented with no added fat (control), or with 3.5% added fat from either higholeic canola oil, a commercial source of oleamide, or oleamide synthesized from oleic acid and urea. The canola oil supplement had no effect on milk yield or composition. Compared to canola oil, the oleamide supplements reduced milk yield, dry matter intake, and milk fat and protein contents. Milk oleic acid concentration increased from 17.4% of total fatty acids for the control diet to 22.1% for the canola oil diet. Both oleamides further increased milk oleic acid to 30.0 and 27.1% of total fatty acids for the commercial and synthesized oleamides, respectively. Milk palmitic acid was reduced and stearic acid was increased by all fat supplements but more so by the oleamides than by the canola oil. Consistent with previous reports that fatty acyl amides resist ruminal biohydrogenation, feeding oleamide to Jersey cows in this study increased milk oleic acid concentration but had negative effects on feed intake and milk yield.

  17. Elimination of tilmicosin in lactating ewes.

    PubMed

    Atef, M; Abo el-Sooud, K; Nahed, E; Tawfik, M

    1999-07-01

    Tilmicosin was injected subcutaneously to lactating ewes once at a dose of 10 mg kg-1 b.wt. to determine its plasma, milk, urine and ruminal juice concentrations. Tilmicosin could be detected in all those fluids 30 minutes after injection. Milk and urine concentrations were higher than those of plasma and ruminal juice. The drug was detectable in milk, urine and plasma for 9, 4 and 3 days after injection, respectively. No amount of tilmicosin could be detected in ruminal juice 12 hours following administration. The mean peak concentration of tilmicosin in plasma and milk (Cmax) were 1.29 and 9.5 micrograms ml-1 and were obtained at (Tmax) 5.235 and 15.093 hours, respectively. The drug was slowly eliminated from plasma and milk as indicated by its long half-life (t1/2el) of 15.4 and 26.2 hours, respectively. The mean binding of tilmicosin to plasma and milk proteins in vitro was 16.8% and 26.8%, respectively. The drug was not bound to ruminal juice at any extent. The rate of tilmicosin renal clearance revealed that it was correspondingly increased with higher blood concentrations. While creatinine clearance showed no significant change after tilmicosin administration. The ratio (fractional clearance) between tilmicosin renal clearance to creatinine clearance was less than one indicating that the glomerular filtration is the main pathway of elimination through kidneys. The rate of ruminal gas fermentation in ewes was inhibited after subcutaneous injection of tilmicosin at a dose of 10 mg kg-1 b.wt. The tested samples taken at different time intervals from the rumen of ewes showed a subsequent reduction in the rate of fermentation as compared to control samples. The reduction was correspondingly increased with the increase of tilmicosin concentration in ruminal juice and returned to normal thereafter.

  18. Using an Electronic Medical Records Database to Identify Non-Traditional Cardiovascular Risk Factors in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Corey, Kathleen E.; Kartoun, Uri; Zheng, Hui; Chung, Raymond T.; Shaw, Stanley Y.

    2016-01-01

    Among adults with nonalcoholic fatty liver disease (NAFLD), 25% of deaths are attributable to cardiovascular disease (CVD). CVD risk reduction in NAFLD requires not only modification of traditional CVD risk factors but identification of risk factors unique to NAFLD. In a NAFLD cohort, we sought to identify non-traditional risk factors associated with CVD. NAFLD was determined by a previously described algorithm and a multivariate logistic regression model determined predictors of CVD. Of the 8,409 individuals with NAFLD, 3,243 had CVD and 5,166 did not. On multivariable analysis, CVD among NAFLD patients was associated with traditional CVD risk factors including family history of CVD (OR 4.25, P=0.0007), hypertension (OR 2.54, P=0.0017), renal failure (OR 1.59, P=0.04), and age (OR 1.05, P<0.0001). Several non-traditional CVD risk factors including albumin, sodium, and Model for End-Stage Liver Disease (MELD) score were associated with CVD. On multivariable analysis, an increased MELD score (OR 1.10, P<0.0001) was associated with an increased risk of CVD. Albumin (OR 0.52, P<0.0001) and sodium (OR 0.96, P=0.037) were inversely associated with CVD. In addition, CVD was more common among those with a NAFLD fibrosis score >0.676 than those with a score ≤0.676 (39 vs. 20%, P<0.0001). CVD in NAFLD is associated with traditional CVD risk factors, as well as higher MELD scores and lower albumin and sodium levels. Individuals with evidence of advanced fibrosis were more likely to have CVD. These findings suggest that the drivers of NAFLD may also promote CVD development and progression. PMID:26925881

  19. A Fibroblast Growth Factor 21-Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease.

    PubMed

    Woolsey, Sarah J; Beaton, Melanie D; Mansell, Sara E; Leon-Ponte, Matilde; Yu, Janice; Pin, Christopher L; Adams, Paul C; Kim, Richard B; Tirona, Rommel G

    2016-10-01

    Nonalcoholic fatty liver disease (NAFLD) alters drug response. We previously reported that NAFLD is associated with reduced in vivo CYP3A drug-metabolism activity and hepatic CYP3A4 expression in humans as well as mouse and human hepatoma models of the disease. Here, we investigated the role of the lipid- and glucose-modulating hormone fibroblast growth factor 21 (FGF21) in the molecular mechanism regulating CYP3A4 expression in NAFLD. In human subjects, mouse and cellular NAFLD models with lower CYP3A4 expression, circulating FGF21, or hepatic FGF21 mRNA levels were elevated. Administration of recombinant FGF21 or transient hepatic overexpression of FGF21 resulted in reduced liver CYP3A4 luciferase reporter activity in mice and decreased CYP3A4 mRNA expression and activity in cultured Huh7 hepatoma cells. Blocking canonical FGF21 signaling by pharmacological inhibition of MEK1 kinase in Huh7 cells caused de-repression of CYP3A4 mRNA expression with FGF21 treatment. Mice with high-fat diet-induced simple hepatic steatosis and lipid-loaded Huh7 cells had reduced nuclear localization of the pregnane X receptor (PXR), a key transcriptional regulator of CYP3A4 Furthermore, decreased nuclear PXR was observed in mouse liver and Huh7 cells after FGF21 treatment or FGF21 overexpression. Decreased PXR binding to the CYP3A4 proximal promoter was found in FGF21-treated Huh7 cells. An FGF21-PXR signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in NAFLD. PMID:27482056

  20. A Fibroblast Growth Factor 21-Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease.

    PubMed

    Woolsey, Sarah J; Beaton, Melanie D; Mansell, Sara E; Leon-Ponte, Matilde; Yu, Janice; Pin, Christopher L; Adams, Paul C; Kim, Richard B; Tirona, Rommel G

    2016-10-01

    Nonalcoholic fatty liver disease (NAFLD) alters drug response. We previously reported that NAFLD is associated with reduced in vivo CYP3A drug-metabolism activity and hepatic CYP3A4 expression in humans as well as mouse and human hepatoma models of the disease. Here, we investigated the role of the lipid- and glucose-modulating hormone fibroblast growth factor 21 (FGF21) in the molecular mechanism regulating CYP3A4 expression in NAFLD. In human subjects, mouse and cellular NAFLD models with lower CYP3A4 expression, circulating FGF21, or hepatic FGF21 mRNA levels were elevated. Administration of recombinant FGF21 or transient hepatic overexpression of FGF21 resulted in reduced liver CYP3A4 luciferase reporter activity in mice and decreased CYP3A4 mRNA expression and activity in cultured Huh7 hepatoma cells. Blocking canonical FGF21 signaling by pharmacological inhibition of MEK1 kinase in Huh7 cells caused de-repression of CYP3A4 mRNA expression with FGF21 treatment. Mice with high-fat diet-induced simple hepatic steatosis and lipid-loaded Huh7 cells had reduced nuclear localization of the pregnane X receptor (PXR), a key transcriptional regulator of CYP3A4 Furthermore, decreased nuclear PXR was observed in mouse liver and Huh7 cells after FGF21 treatment or FGF21 overexpression. Decreased PXR binding to the CYP3A4 proximal promoter was found in FGF21-treated Huh7 cells. An FGF21-PXR signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in NAFLD.