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Sample records for acid-independent bile formation

  1. Effects of ion substitution on bile acid-dependent and -independent bile formation by rat liver.

    PubMed Central

    Van Dyke, R W; Stephens, J E; Scharschmidt, B F

    1982-01-01

    To characterize the transport mechanisms responsible for formation of canalicular bile, we have examined the effects of ion substitution on bile acid-dependent and bile acid-independent bile formation by the isolated perfused rat liver. Complete replacement of perfusate sodium with choline and lithium abolished taurocholate-induced choleresis and reduced biliary taurocholate output by greater than 70%. Partial replacement of perfusate sodium (25 of 128 mM) by choline reduced bile acid-independent bile formation by 30% and replacement of the remaining sodium (103 mM) by choline reduced bile acid-independent bile formation by an additional 64%. In contrast, replacement of the remaining sodium (103 mM) by lithium reduced bile acid-independent bile formation by only an additional 20%, while complete replacement of sodium (128 mM) by lithium reduced bile formation by only 17%, and lithium replaced sodium as the predominant biliary cation. Replacement of perfusate bicarbonate by Tricine, a zwitterionic amino acid buffer, decreased bile acid-independent bile formation by greater than or equal to 50% and decreased biliary bicarbonate output by approximately 60%, regardless of the accompanying cation. In separate experiments, replacement of sodium by lithium essentially abolished Na,K-ATPase activity measured either as ouabain-suppressible ATP hydrolysis in rat liver or kidney homogenates, or as ouabain-suppressible 86Rb uptake by cultured rat hepatocytes. These studies indicate that bile acid(taurocholate)-dependent bile formation by rat liver exhibits a specific requirement for sodium, a finding probably attributable to the role(s) of sodium in hepatic sodium-coupled taurocholate uptake and/or in maintenance of Na,K-ATPase activity. The surprising finding that bile acid-independent bile formation was substantially unaltered by complete replacement of sodium with the permeant cation lithium does not appear to be explained by Na,K-ATPase-mediated lithium transport. Although

  2. Bile Formation and Secretion

    PubMed Central

    Boyer, James L.

    2014-01-01

    Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (~1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions. PMID:23897680

  3. Physiological and molecular biochemical mechanisms of bile formation

    PubMed Central

    Reshetnyak, Vasiliy Ivanovich

    2013-01-01

    This review considers the physiological and molecular biochemical mechanisms of bile formation. The composition of bile and structure of a bile canaliculus, biosynthesis and conjugation of bile acids, bile phospholipids, formation of bile micellar structures, and enterohepatic circulation of bile acids are described. In general, the review focuses on the molecular physiology of the transporting systems of the hepatocyte sinusoidal and apical membranes. Knowledge of physiological and biochemical basis of bile formation has implications for understanding the mechanisms of development of pathological processes, associated with diseases of the liver and biliary tract. PMID:24259965

  4. History of Hepatic Bile Formation: Old Problems, New Approaches

    ERIC Educational Resources Information Center

    Javitt, Norman B.

    2014-01-01

    Studies of hepatic bile formation reported in 1958 established that it was an osmotically generated water flow. Intravenous infusion of sodium taurocholate established a high correlation between hepatic bile flow and bile acid excretion. Secretin, a hormone that stimulates bicarbonate secretion, was also found to increase hepatic bile flow. The…

  5. Focal hepatic infarction with bile lake formation

    SciTech Connect

    Peterson, I.M.; Neumann, C.H.

    1984-06-01

    Venous thrombosis associated with oral contraceptives is a well recognized phenomenon. Arterial thrombosis, while less common, is also a known risk, as evidenced by the increased incidence of cerebral vascular accidents and myocardial ischemia or infarction. The liver is relatively protected from the usual consequences of arterial thrombosis because of its dual blood supply. The authors present an unusual case of a young woman with a history of oral contraceptive and cigarette use who developed hepatic artery thrombosis and had focal liver lesions on computed tomography (CT) due to hepatic infarction and bile lake formation despite an intact portal venous system.

  6. Kinetics of formation of bile salt micelles from coarse-grained Langevin dynamics simulations.

    PubMed

    Vila Verde, Ana; Frenkel, Daan

    2016-06-21

    We examine the mechanism of formation of micelles of dihydroxy bile salts using a coarse-grained, implicit solvent model and Langevin dynamics simulations. We find that bile salt micelles primarily form via addition and removal of monomers, similarly to surfactants with typical head-tail molecular structures, and not via a two-stage mechanism - involving formation of oligomers and their subsequent aggregation to form larger micelles - originally proposed for bile salts. The free energy barrier to removal of single bile monomers from micelles is ≈2kBT, much less than what has been observed for head-tail surfactants. Such a low barrier may be biologically relevant: it allows for rapid release of bile monomers into the intestine, possibly enabling the coverage of fat droplets by bile salt monomers and subsequent release of micelles containing fats and bile salts - a mechanism that is not possible for ionic head-tail surfactants of similar critical micellar concentrations. PMID:27199094

  7. Mechanical compaction directly modulates the dynamics of bile canaliculi formation.

    PubMed

    Wang, Yan; Toh, Yi-Chin; Li, Qiushi; Nugraha, Bramasta; Zheng, Baixue; Lu, Thong Beng; Gao, Yi; Ng, Mary Mah Lee; Yu, Hanry

    2013-02-01

    Homeostatic pressure-driven compaction is a ubiquitous mechanical force in multicellular organisms and is proposed to be important in the maintenance of multicellular tissue integrity and function. Previous cell-free biochemical models have demonstrated that there are cross-talks between compaction forces and tissue structural functions, such as cell-cell adhesion. However, its involvement in physiological tissue function has yet to be directly demonstrated. Here, we use the bile canaliculus (BC) as a physiological example of a multicellular functional structure in the liver, and employ a novel 3D microfluidic hepatocyte culture system to provide an unprecedented opportunity to experimentally modulate the compaction states of primary hepatocyte aggregates in a 3D physiological-mimicking environment. Mechanical compaction alters the physical attributes of the hepatocyte aggregates, including cell shape, cell packing density and cell-cell contact area, but does not impair the hepatocytes' remodeling and functional capabilities. Characterization of structural and functional polarity shows that BC formation in compact hepatocyte aggregates is accelerated to as early as 12 hours post-seeding; whereas non-compact control requires 48 hours for functional BC formation. Further dynamic immunofluorescence imaging and gene expression profiling reveal that compaction accelerated BC formation is accompanied by changes in actin cytoskeleton remodeling dynamics and transcriptional levels of hepatic nuclear factor 4α and Annexin A2. Our report not only provides a novel strategy of modeling BC formation for in vitro hepatology research, but also shows a first instance that homeostatic pressure-driven compaction force is directly coupled to the higher-order multicellular functions. PMID:23233209

  8. Structural stability and prebiotic properties of resistant starch type 3 increase bile acid turnover and lower secondary bile acid formation.

    PubMed

    Dongowski, Gerhard; Jacobasch, Gisela; Schmiedl, Detlef

    2005-11-16

    Microbial metabolism is essential in maintaining a healthy mucosa in the large bowel, preferentially through butyrate specific mechanisms. This system depends on starch supply. Two structurally different resistant starches type 3 (RS3) have been investigated with respect to their resistance to digestion, fermentability, and their effects on the composition and turnover of bile acids in rats. RSA (a mixture of retrograded maltodextrins and branched high molecular weight polymers), which is more resistant than RSB (a retrograded potato starch), increased the rate of fermentation accompanied by a decrease of pH in cecum, colon, and feces. Because they were bound to RS3, less bile acids were reabsorbed, resulting in a higher turnover through the large bowel. Because of the rise of volume, the bile acid level was unchanged and the formation of secondary bile acids was partly suppressed. The results proved a strong relation between RS3, short chain fatty acid production, and microflora. However, butyrate specific benefits are only achieved by an intake of RS3 that result in good fermentation properties, which depend on the kind of the resistant starch structures. PMID:16277431

  9. Formation of drug-bearing vesicles in mixed colloids of bile salts and phosphatidylcholine

    SciTech Connect

    Hjelm, R.P.; Mang, J.; Hofmann, A.F.; Schteingart, C.; Alkan-Onyuksel, H.; Ayd, S.

    1997-11-01

    This is the final report of a three-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The authors used small-angle neutron scattering to study drug interactions with mixed colloids of bile salt and phosphatidylcholine. Because the mixed colloids form liposomes spontaneously, this system is a model for drug-bile interactions that are important in understanding the efficacy of oral drug formulations and in advanced applications for liposome drug delivery systems. The authors studied particle formation in incorporation of enzymatic products formed in the gut and the effects of cholesteric drugs and taxol on vesicle formation. The studies show that particle morphology is not affected by inclusion of most cholesteric drugs and taxol, and is not affected by incorporation of the products of enzymatic action. The findings suggest that particle form is important for the physiological function of bile and they are beginning to show which drugs affect liposome formation.

  10. Formation of delta 22-bile acids in rats is not gender specific and occurs in the peroxisome.

    PubMed

    Rodrigues, C M; Kren, B T; Steer, C J; Setchell, K D

    1996-03-01

    We recently demonstrated that the formation of delta 22-bile acids is a quantitatively major pathway for normal bile acid synthesis in the adult male Sprague-Dawley rat. This pathway is specific for 7 beta-hydroxy bile acids and, when ursodeoxycholic acid is administered, delta 22-ursodeoxycholic acid appears as a major metabolite in the liver tissue, bile, intestinal contents, and plasma. The aims of this study were, therefore, to determine whether this metabolic pathway was gender specific, and to establish that the peroxisome is a site of formation of delta 22-bile acids. Bile acids were determined by gas chromatography-mass spectrometry in liver tissue, jejunum, and plasma of adult female rats and in animals fed a diet containing 0.4% and 1% ursodeoxycholic acid. Bile acid metabolism in female rats was found to be similar to that of male rats, and delta 22-beta-muricholic acid, rather than beta-muricholate, was likewise confirmed as the major muricholic acid synthesized. Ursodeoxycholic acid administration resulted in the appearance of delta 22-ursodeoxycholic acid as a major metabolite. When adult male Sprague-Dawley rats were treated with clofibrate, a drug that induces peroxisomal proliferation, liver weight increased 40-60% and total bile acid synthesis decreased markedly, but the relative composition of individual bile acids was unchanged. When ursodeoxycholic acid was added to the diet, the proportion of delta 22-bile acids relative to the corresponding saturated analogues increased significantly compared with untreated rats, indicating that clofibrate had "amplified" the pathway for formation of delta 22-bile acids. When UDCA was incubated in vitro with a peroxisomal-enriched fraction from normal adult male rat liver, delta 22-ursodeoxycholic acid was formed in proportions comparable to that observed in vivo when this bile acid was given orally. These studies establish that the pathway for the formation of delta 22-bile acids is not gender specific and

  11. Biofilm Formation and Detachment in Gram-Negative Pathogens Is Modulated by Select Bile Acids.

    PubMed

    Sanchez, Laura M; Cheng, Andrew T; Warner, Christopher J A; Townsley, Loni; Peach, Kelly C; Navarro, Gabriel; Shikuma, Nicholas J; Bray, Walter M; Riener, Romina M; Yildiz, Fitnat H; Linington, Roger G

    2016-01-01

    Biofilms are a ubiquitous feature of microbial community structure in both natural and host environments; they enhance transmission and infectivity of pathogens and provide protection from human defense mechanisms and antibiotics. However, few natural products are known that impact biofilm formation or persistence for either environmental or pathogenic bacteria. Using the combination of a novel natural products library from the fish microbiome and an image-based screen for biofilm inhibition, we describe the identification of taurine-conjugated bile acids as inhibitors of biofilm formation against both Vibrio cholerae and Pseudomonas aeruginosa. Taurocholic acid (1) was isolated from the fermentation broth of the fish microbiome-derived strain of Rhodococcus erythropolis and identified using standard NMR and MS methods. Screening of the twelve predominant human steroidal bile acid components revealed that a subset of these compounds can inhibit biofilm formation, induce detachment of preformed biofilms under static conditions, and that these compounds display distinct structure-activity relationships against V. cholerae and P. aeruginosa. Our findings highlight the significance of distinct bile acid components in the regulation of biofilm formation and dispersion in two different clinically relevant bacterial pathogens, and suggest that the bile acids, which are endogenous mammalian metabolites used to solubilize dietary fats, may also play a role in maintaining host health against bacterial infection. PMID:26992172

  12. Biofilm Formation and Detachment in Gram-Negative Pathogens Is Modulated by Select Bile Acids

    PubMed Central

    Townsley, Loni; Peach, Kelly C.; Navarro, Gabriel; Shikuma, Nicholas J.; Bray, Walter M.; Riener, Romina M.; Yildiz, Fitnat H.; Linington, Roger G.

    2016-01-01

    Biofilms are a ubiquitous feature of microbial community structure in both natural and host environments; they enhance transmission and infectivity of pathogens and provide protection from human defense mechanisms and antibiotics. However, few natural products are known that impact biofilm formation or persistence for either environmental or pathogenic bacteria. Using the combination of a novel natural products library from the fish microbiome and an image-based screen for biofilm inhibition, we describe the identification of taurine-conjugated bile acids as inhibitors of biofilm formation against both Vibrio cholerae and Pseudomonas aeruginosa. Taurocholic acid (1) was isolated from the fermentation broth of the fish microbiome-derived strain of Rhodococcus erythropolis and identified using standard NMR and MS methods. Screening of the twelve predominant human steroidal bile acid components revealed that a subset of these compounds can inhibit biofilm formation, induce detachment of preformed biofilms under static conditions, and that these compounds display distinct structure-activity relationships against V. cholerae and P. aeruginosa. Our findings highlight the significance of distinct bile acid components in the regulation of biofilm formation and dispersion in two different clinically relevant bacterial pathogens, and suggest that the bile acids, which are endogenous mammalian metabolites used to solubilize dietary fats, may also play a role in maintaining host health against bacterial infection. PMID:26992172

  13. Transport systems in cholangiocytes: their role in bile formation and cholestasis.

    PubMed Central

    Strazzabosco, M.

    1997-01-01

    Formation of bile requires the coordinated function of two epithelial cell types: hepatocytes, that are responsible for secretion of the major osmolytes and biliary constituents and cholangiocytes that regulate the fluidity and alkalinity of bile through secretion of osmolytes such as Cl- and HCO3- Studies in isolated cholangiocyte preparations have elucidated the basic transport mechanisms involved in constitutive and stimulated secretory activities in the biliary epithelium. Basolateral Na+/H+ exchanger and Na+:HCO3- symporter mediate HCO3- uptake, while an apical cAMP-activated Cl-/HCO3- exchanger secretes bicarbonate into the lumen. Cholangiocytes also possess a cAMP-stimulated Cl- conductance (CFTR) and a Ca-activated Cl- channel, both likely located at the apical membrane. Cholangiocyte secretory functions are regulated by a complex network of hormones mainly acting via the cAMP system. In addition, recent data indicate that part of the regulation of ductular secretion may take place at the apical membrane of the cholangiocyte through factors present into the bile, such as ATP, bile acids and glutathione. Primary damage to the biliary epithelium is the cause of several chronic cholestatic disorders (cholangiopathies). From a pathophysiological point of view, common to all cholangiopathies is the coexistance of cholangiocyte death and proliferation and various degrees of portal inflammation and fibrosis. Cholestasis dominates the clinical picture and, pathophysiologically, may initiate or worsen the process. Alterations in biliary electrolyte transport could contribute to the pathogenesis of cholestasis in primary bile duct diseases. Cystic Fibrosis-related liver disease represents an example of biliary cirrhosis secondary to a derangement of cholangiocyte ion transport. Most primary cholangiopaties recognize an immune-mediated pathogenesis. Cytokines, chemokines, and proinflammatory mediators released in the portal spaces or produced by the cholangiocyte

  14. Matrix metalloproteinase-14 mediates formation of bile ducts and hepatic maturation of fetal hepatic progenitor cells.

    PubMed

    Otani, Satoshi; Kakinuma, Sei; Kamiya, Akihide; Goto, Fumio; Kaneko, Shun; Miyoshi, Masato; Tsunoda, Tomoyuki; Asano, Yu; Kawai-Kitahata, Fukiko; Nitta, Sayuri; Nakata, Toru; Okamoto, Ryuichi; Itsui, Yasuhiro; Nakagawa, Mina; Azuma, Seishin; Asahina, Yasuhiro; Yamaguchi, Tomoyuki; Koshikawa, Naohiko; Seiki, Motoharu; Nakauchi, Hiromitsu; Watanabe, Mamoru

    2016-01-22

    Fetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver development; however, the molecular mechanisms regulating the phenotype of these cells have not been completely elucidated. Matrix metalloproteinase (MMP)-14 is a type I transmembrane proteinase regulating pericellular proteolysis of the extracellular matrix and is essential for the activation of several MMPs and cytokines. However, the physiological functions of MMP-14 in liver development are unknown. Here we describe a functional role for MMP-14 in hepatic and biliary differentiation of mouse hepatoblasts. MMP-14 was upregulated in cells around the portal vein in perinatal stage liver. Formation of bile duct-like structures in MMP-14-deficient livers was significantly delayed compared with wild-type livers in vivo. In vitro biliary differentiation assays showed that formation of cholangiocytic cysts derived from MMP-14-deficient hepatoblasts was completely impaired, and that overexpression of MMP-14 in hepatoblasts promoted the formation of bile duct-like cysts. In contrast, the expression of molecules associated with metabolic functions in hepatocytes, including hepatic nuclear factor 4α and tryptophan 2,3-dioxygenase, were significantly increased in MMP-14-deficient livers. Expression of the epidermal growth factor receptor and phosphorylation of mitogen-activated protein kinases were significantly upregulated in MMP-14-deficient livers. We demonstrate that MMP-14-mediated signaling in fetal hepatic progenitor cells promotes biliary luminal formation around the portal vein and negatively controls the maturation of hepatocytes. PMID:26724533

  15. Epimorphin Regulates Bile Duct Formation via Effects on Mitosis Orientation in Rat Liver Epithelial Stem-Like Cells

    PubMed Central

    Qin, Lipeng; Wang, Jing; Jia, Yali; Yao, Hailei; Sang, Chen; Hu, Qinghua; Shi, Shuangshuang; Nan, Xue; Yue, Wen; Zhuang, Fengyuan; Yang, Chun; Wang, Yunfang; Pei, Xuetao

    2010-01-01

    Understanding how hepatic precursor cells can generate differentiated bile ducts is crucial for studies on epithelial morphogenesis and for development of cell therapies for hepatobiliary diseases. Epimorphin (EPM) is a key morphogen for duct morphogenesis in various epithelial organs. The role of EPM in bile duct formation (DF) from hepatic precursor cells, however, is not known. To address this issue, we used WB-F344 rat epithelial stem-like cells as model for bile duct formation. A micropattern and a uniaxial static stretch device was used to investigate the effects of EPM and stress fiber bundles on the mitosis orientation (MO) of WB cells. Immunohistochemistry of liver tissue sections demonstrated high EPM expression around bile ducts in vivo. In vitro, recombinant EPM selectively induced DF through upregulation of CK19 expression and suppression of HNF3α and HNF6, with no effects on other hepatocytic genes investigated. Our data provide evidence that EPM guides MO of WB-F344 cells via effects on stress fiber bundles and focal adhesion assembly, as supported by blockade EPM, β1 integrin, and F-actin assembly. These blockers can also inhibit EPM-induced DF. These results demonstrate a new biophysical action of EPM in bile duct formation, during which determination of MO plays a crucial role. PMID:20305811

  16. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice

    PubMed Central

    Sparks, Erin E.; Huppert, Kari A.; Brown, Melanie A.; Washington, M. Kay; Huppert, Stacey S.

    2010-01-01

    Alagille syndrome, a chronic hepatobiliary disease, is characterized by paucity of intrahepatic bile ducts (IHBDs). To determine the impact of Notch signaling specifically on IHBD arborization we studied the influence of both chronic gain and loss of Notch function on the intact three-dimensional IHBD structure using a series of mutant mouse models and a resin casting method. Impaired Notch signaling in bi-potential hepatoblast progenitor cells (BHPCs) dose-dependently decreased the density of peripheral IHBDs, whereas activation of Notch1 results in an increased density of peripheral IHBDs. While Notch2 has a dominant role in IHBD formation there is also a redundant role for other Notch receptors in determining the density of peripheral IHBDs. Since changes in IHBD density do not appear to be due to changes in cellular proliferation of bile duct progenitors, we suggest that Notch plays a permissive role in cooperation with other factors to influence lineage decisions of BHPCs and sustain peripheral IHBDs. Conclusion There is a threshold requirement for Notch signaling at multiple steps, IHBD tubulogenesis and maintenance, during hepatic development that determines the density of three-dimensional peripheral IHBD architecture. PMID:20069650

  17. Effect of ion-pair formation with bile salts on the in vitro cellular transport of berberine.

    PubMed

    Chae, Hye-Won; Kim, In-Wha; Jin, Hyo-Eon; Kim, Dae-Duk; Chung, Suk-Jae; Shim, Chang-Koo

    2008-01-01

    The objective of this study was to examine the effect of ion-pair complexation with endogenous bile salts on the transport of a quarternary ammonium organic cationic (OC) drug, berberine, across the Caco-2 and LLC-PK1 cell monolayers. The basolateral-to-apical (BL-AP) transport of berberine in Caco-2 cells was temperature dependent and 10-fold higher than that of the apical-to-basolateral (AP-BL) transport. Similar results were observed for the transport of berberine across the LLC-PK1 cells. Moreover, the BL-AP transport in the Caco-2 cells was significantly reduced by the cis-presence of P-glycoprotein (P-gp) inhibitors such as cyclosporine A, verapamil, and digoxin. These results suggest that an efflux transporter, probably P-gp, is involved in the Caco-2 cell transport. The Km and Vmax values for the carrier-mediated transport were estimated to be 83.4 mM and 7640 pmole/h/cm2, respectively. The apparent partition coefficient (APC) of berberine between n-octanol and a phosphate buffer (pH 7.4) was increased by the presence of an organic anion (OA), taurodeoxycholate (TDC, a bile salt), suggesting the formation of a lipophilic ion-pair complex between an OC (berberine) and an OA (TDC). Despite the ion-pair complexation, however, the BL-AP transport of berberine across the Caco-2 and LLC-PK1 cells was not altered by the cis-presence of bile salts or the rat bile juice. This is consistent with the reportedly unaltered secretory transport of a quarternary ammonium compound, tributylmethylammonium (TBuMA), across the Caco-2 cell monolayers in the cis-presence of bile salts or the rat bile juice, but not with our previous report in which the secretory transport of TBuMA across the LLC-PK1 cell was increased in the cis-presence of TDC. Therefore, the effect of ion-pair formation with the bile components or bile salts on the secretory transport of OCs appears to depend on the molecular properties of OCs (e.g., molecular weight, lipophilicity and affinity to relevant

  18. Mechanisms of Lithogenic Bile Formation in American Indian Women with Cholesterol Gallstones

    PubMed Central

    Grundy, Scott M.; Metzger, Allan L.; Adler, Ronald D.

    1972-01-01

    Hepatic secretions of biliary lipids were estimated in 43 patients with and without cholesterol gallstones. Studies were carried out by a marker dilution technique employing duodenal intubation with a three-lumen tube. Hourly secretion rates of cholesterol, bile acids, and phospholipids were determined during constant infusion with liquid formula. In 17 American Indian women with gallstones, hourly outputs of biliary bile acids were significantly less than those in 7 Indian men and 12 Caucasian women without gallstones. These findings suggest that a decreased hepatic secretion of bile acids contributes significantly to the production of a lithogenic bile in Indian women. However, in Indian women with gallstones, secretion of biliary cholesterol was also significantly increased, as compared with Caucasian women without stones. Therefore, lithogenic bile in Indian women was, in most cases, due to a combined decrease in bile acid output and increase in cholesterol secretion. In an attempt to determine the mechanisms for these abnormalities, cholesterol balance studies were done in Indian women with gallstones and normal Indian men. Balance data were compared with results reported previously in non-Indian patients studied by the same techniques, and in general, Indian women showed a slight increase in fecal excretion of bile acids. Since bile acids in the enterohepatic circulation were relatively depleted in Indian women, these patients had a reduced fractional reabsorption. However, previous studies have shown that Caucasians can rapidly replenish bile acid pools in the presence of much greater intestinal losses, and it is suggested that among Indian women with gallstones, reduced secretion rates of bile acids are primarily the result of defective homeostatic regulation of bile acid synthesis. In Indian women with gallstones, at least two factors may have contributed to an increased availability of cholesterol in the liver for secretion into bile. First, cholesterol

  19. Impairment of bile secretion induced by exhaustive exercise in the rat. Protective effects of S-adenosyl-L-methionine.

    PubMed

    Villa, J G; Almar, M M; Collado, P S; Llamazares, E; González-Gallego, J

    1993-05-01

    The effects of strenuous exercise on the mechanisms of bile formation were studied in rats. Animals (n = 8) were exercised to exhaustion in a rodent treadmill at a speed of 24 m/min and a 12% slope. Hepatic glutathione concentration was significantly reduced (-40%) and liver malondialdehyde content significantly increased (+37%) when compared to sedentary controls (n = 6). Both serum alkaline phosphatase level and bile acid concentration were significantly higher in runners (+81% and +85%). Bile flow and the biliary secretion of bile acids were significantly reduced both in basal conditions and following an i.v. taurocholate infusion (0.5 mumol/min/100 g body wt). Biliary glutathione secretion was also significantly decreased following exercise. Cholestasis was caused by an impairment of both bile acid-dependent (BADF) and bile acid-independent fraction (BAIF) of bile flow (-25% and -29% respectively). Exercise caused a delay in the peak appearance time and a reduced biliary secretion of horseradish peroxidase, suggesting alterations in the functional integrity of the cytoskeleton. To test the protective effects of S-adenosyl-L-methionine (SAMe), rats received the drug for ten days at a daily dose of 8 mg/kg i.p. SAMe administration prevented hepatic glutathione depletion due to exercise, normalizing both bile flow and bile acid as well as glutathione secretion. Our results suggest that both glutathione depletion and alterations in fluidity and composition of hepatocyte membranes could contribute to the development of exercise-induced cholestasis. PMID:8325715

  20. Inhibition of bile canalicular network formation in rat sandwich cultured hepatocytes by drugs associated with risk of severe liver injury.

    PubMed

    Takemura, Akinori; Izaki, Aya; Sekine, Shuichi; Ito, Kousei

    2016-09-01

    Idiosyncratic drug-induced liver injury is a clinical concern with serious consequences. Although many preclinical screening methods have been proposed, it remains difficult to identify compounds associated with this rare but potentially fatal liver condition. Here, we propose a novel assay system to assess the risk of liver injury. Rat primary hepatocytes were cultured in a sandwich configuration, which enables the formation of a typical bile canalicular network. From day 2 to 3, test drugs, mostly selected from a list of cholestatic drugs, were administered, and the length of the network was semi-quantitatively measured by immunofluorescence. Liver injury risk information was collected from drug labels and was compared with in vitro measurements. Of 23 test drugs examined, 15 exhibited potent inhibition of bile canalicular network formation (<60% of control). Effects on cell viability were negligible or minimal as confirmed by lactate dehydrogenase leakage and cellular ATP content assays. For the potent 15 drugs, IC50 values were determined. Finally, maximum daily dose divided by the inhibition constant gave good separation of the highest risk of severe liver toxicity drugs such as troglitazone, benzbromarone, flutamide, and amiodarone from lower risk drugs. In conclusion, inhibitory effect on the bile canalicular network formation observed in in vitro sandwich cultured hepatocytes evaluates a new aspect of drug toxicity, particularly associated with aggravation of liver injury. PMID:27256767

  1. Physiology of bile secretion

    PubMed Central

    Esteller, Alejandro

    2008-01-01

    The formation of bile depends on the structural and functional integrity of the bile-secretory apparatus and its impairment, in different situations, results in the syndrome of cholestasis. The structural bases that permit bile secretion as well as various aspects related with its composition and flow rate in physiological conditions will first be reviewed. Canalicular bile is produced by polarized hepatocytes that hold transporters in their basolateral (sinusoidal) and apical (canalicular) plasma membrane. This review summarizes recent data on the molecular determinants of this primary bile formation. The major function of the biliary tree is modification of canalicular bile by secretory and reabsorptive processes in bile-duct epithelial cells (cholangiocytes) as bile passes through bile ducts. The mechanisms of fluid and solute transport in cholangiocytes will also be discussed. In contrast to hepatocytes where secretion is constant and poorly controlled, cholangiocyte secretion is regulated by hormones and nerves. A short section dedicated to these regulatory mechanisms of bile secretion has been included. The aim of this revision was to set the bases for other reviews in this series that will be devoted to specific issues related with biliary physiology and pathology. PMID:18837079

  2. Bile salt–induced intermolecular disulfide bond formation activates Vibrio cholerae virulence

    PubMed Central

    Yang, Menghua; Liu, Zhi; Hughes, Chambers; Stern, Andrew M.; Wang, Hui; Zhong, Zengtao; Kan, Biao; Fenical, William; Zhu, Jun

    2013-01-01

    To be successful pathogens, bacteria must often restrict the expression of virulence genes to host environments. This requires a physical or chemical marker of the host environment as well as a cognate bacterial system for sensing the presence of a host to appropriately time the activation of virulence. However, there have been remarkably few such signal–sensor pairs identified, and the molecular mechanisms for host-sensing are virtually unknown. By directly applying a reporter strain of Vibrio cholerae, the causative agent of cholera, to a thin layer chromatography (TLC) plate containing mouse intestinal extracts, we found two host signals that activate virulence gene transcription. One of these was revealed to be the bile salt taurocholate. We then show that a set of bile salts cause dimerization of the transmembrane transcription factor TcpP by inducing intermolecular disulfide bonds between cysteine (C)-207 residues in its periplasmic domain. Various genetic and biochemical analyses led us to propose a model in which the other cysteine in the periplasmic domain, C218, forms an inhibitory intramolecular disulfide bond with C207 that must be isomerized to form the active C207–C207 intermolecular bond. We then found bile salt–dependent effects of these cysteine mutations on survival in vivo, correlating to our in vitro model. Our results are a demonstration of a mechanism for direct activation of the V. cholerae virulence cascade by a host signal molecule. They further provide a paradigm for recognition of the host environment in pathogenic bacteria through periplasmic cysteine oxidation. PMID:23341592

  3. A method for the determination of the hepatic enzyme activity catalyzing bile acid acyl glucuronide formation by high-performance liquid chromatography with pulsed amperometric detection.

    PubMed

    Ikegawa, S; Oohashi, J; Murao, N; Goto, J

    2000-05-01

    A method for the determination of the activity of hepatic glucuronyltransferase catalyzing formation of bile acid 24-glucuronides using high-performance liquid chromatography (HPLC) with pulsed amperometric detection (PAD) has been developed. Bile acid 24-glucuronides were simultaneously separated on a semimicrobore column, Capcell Pak C18UG120, using 20 mM ammonium phosphate (pH 6.0)-acetonitrile (27:10 and 16:10) as the mobile phase in the stepwise gradient elution mode. A 1 M potassium hydroxide solution for the hydrolysis of the 24-glucuronides, which liberates the corresponding bile acids and glucuronic acid, was mixed with the mobile phase in a post-column mode, and the resulting eluant was heated at 90 degrees C, the 24-glucuronides being monitored using a pulsed amperometric detector; the limit of detection was 10 ng. The proposed method was applied to the determination of the hepatic enzyme activity catalyzing bile acid 24-glucuronide formation and the result exhibited the efficient 24-glucuronide formation of the monohydroxylated bile acid, lithocholic acid. PMID:10850616

  4. Metastable and equilibrium phase diagrams of unconjugated bilirubin IXα as functions of pH in model bile systems: Implications for pigment gallstone formation

    PubMed Central

    Berman, Marvin D.

    2014-01-01

    Metastable and equilibrium phase diagrams for unconjugated bilirubin IXα (UCB) in bile are yet to be determined for understanding the physical chemistry of pigment gallstone formation. Also, UCB is a molecule of considerable biomedical importance because it is a potent antioxidant and an inhibitor of atherogenesis. We employed principally a titrimetric approach to obtain metastable and equilibrium UCB solubilities in model bile systems composed of taurine-conjugated bile salts, egg yolk lecithin (mixed long-chain phosphatidylcholines), and cholesterol as functions of total lipid concentration, biliary pH values, and CaCl2 plus NaCl concentrations. Metastable and equilibrium precipitation pH values were obtained, and average pKa values of the two carboxyl groups of UCB were calculated. Added lecithin and increased temperature decreased UCB solubility markedly, whereas increases in bile salt concentrations and molar levels of urea augmented solubility. A wide range of NaCl and cholesterol concentrations resulted in no specific effects, whereas added CaCl2 produced large decreases in UCB solubilities at alkaline pH values only. UV-visible absorption spectra were consistent with both hydrophobic and hydrophilic interactions between UCB and bile salts that were strongly influenced by pH. Reliable literature values for UCB compositions of native gallbladder biles revealed that biles from hemolytic mice and humans with black pigment gallstones are markedly supersaturated with UCB and exhibit more acidic pH values, whereas biles from nonstone control animals and patients with cholesterol gallstone are unsaturated with UCB. PMID:25359538

  5. Metastable and equilibrium phase diagrams of unconjugated bilirubin IXα as functions of pH in model bile systems: Implications for pigment gallstone formation.

    PubMed

    Berman, Marvin D; Carey, Martin C

    2015-01-01

    Metastable and equilibrium phase diagrams for unconjugated bilirubin IXα (UCB) in bile are yet to be determined for understanding the physical chemistry of pigment gallstone formation. Also, UCB is a molecule of considerable biomedical importance because it is a potent antioxidant and an inhibitor of atherogenesis. We employed principally a titrimetric approach to obtain metastable and equilibrium UCB solubilities in model bile systems composed of taurine-conjugated bile salts, egg yolk lecithin (mixed long-chain phosphatidylcholines), and cholesterol as functions of total lipid concentration, biliary pH values, and CaCl2 plus NaCl concentrations. Metastable and equilibrium precipitation pH values were obtained, and average pKa values of the two carboxyl groups of UCB were calculated. Added lecithin and increased temperature decreased UCB solubility markedly, whereas increases in bile salt concentrations and molar levels of urea augmented solubility. A wide range of NaCl and cholesterol concentrations resulted in no specific effects, whereas added CaCl2 produced large decreases in UCB solubilities at alkaline pH values only. UV-visible absorption spectra were consistent with both hydrophobic and hydrophilic interactions between UCB and bile salts that were strongly influenced by pH. Reliable literature values for UCB compositions of native gallbladder biles revealed that biles from hemolytic mice and humans with black pigment gallstones are markedly supersaturated with UCB and exhibit more acidic pH values, whereas biles from nonstone control animals and patients with cholesterol gallstone are unsaturated with UCB. PMID:25359538

  6. Migration of vessel clip into the common bile duct and late formation of choledocholithiasis after laparoscopic cholecystectomy.

    PubMed

    Gonzalez, Francisco Javier; Dominguez, Elias; Lede, Angel; Jose, Portela; Miguel, Piñon

    2011-10-01

    Since the first silk suture material acting as a nidus for the development of subsequent common bile duct stones after cholecystectomy was described in 1897, several investigators have reported that suture materials may cause choledocholithiasis. Silk, chromic catgut, parasites, and other foreign bodies are known occasionally to form such niduses in the common bile duct. Surgical hemostatic clips have been used widely and generally are considered very safe. The first case of postcholecystectomy clip migration was reported in 1979. Its exact pathogenesis remains unknown; it generally is agreed that bile duct injuries, inappropriate clip placements, subclinical bile leak, and infections also have been postulated to contribute to clip migration. We report an unusual case in which the core of a biliary calculus in the common bile duct was found to contain a surgical clip. This case illustrates the potentially abrupt and late development of clip-related gallstones and highlights the need for long-term follow-up evaluation. PMID:21943951

  7. Roles of myofibroblasts and notch and hedgehog signaling pathways in the formation of intrahepatic bile duct lesions in polycystic kidney rats.

    PubMed

    Furubo, Shinichi; Sato, Yasunori; Harada, Kenichi; Nakanuma, Yasuni

    2013-01-01

    Polycystic kidney (PCK) rats, an animal model of Caroli's disease, show a dilatation of intrahepatic bile ducts (IHBD) called "ductal plate malformation." Mesenchymal cells and the Notch and Hedgehog signaling pathways in portal tracts are reportedly involved in the normal development of IHBD, although there have been no studies on the roles of these signaling pathways in PCK rats. We immunohistochemically examined the expression of the molecules related to these signaling pathways in portal tracts. All molecules related to these signaling pathways expressed in portal tracts in Sprague Dawley (SD) rats (control) were also expressed in PCK rats. Mesenchymal cells (myofibroblasts) were frequently found in the connective tissue of portal tracts of 20 embryonic-day-old (E20D), 1-day-old (1D), and 1-week-old (1W) SD and PCK rats and were abundant in PCK rats. Interestingly, myofibroblasts almost disappeared at in both strains of 3W rats. Jagged1 was expressed in mesenchymal cells in portal tracts and was abundant in PCK rats. Double immunostaining showed that Jagged1-positive cells were myofibroblasts. Notch2 and HES1 were expressed in cholangiocytes of the bile ducts of both rats. Sonic Hedgehog was similarly expressed in the bile ducts of both rats. A well-balanced and time-sequential expression of the Notch and Hedgehog family in portal tracts might be essential for the normal development of IHBD in E20D to 1W SD rats, and an imbalanced interaction of these molecules, particularly increased Jagged1 expression in periductal and periportal myofibroblasts and Notch2 expressed in cholangiocytes, may be involved in the formation of bile duct lesions in PCK rats. PMID:23331119

  8. Partial replacement of bile salts causes marked changes of cholesterol crystallization in supersaturated model bile systems.

    PubMed Central

    Nishioka, T; Tazuma, S; Yamashita, G; Kajiyama, G

    1999-01-01

    Cholesterol crystallization is a key step in gallstone formation and is influenced by numerous factors. Human bile contains various bile salts having different hydrophobicity and micelle-forming capacities, but the importance of lipid composition to bile metastability remains unclear. This study investigated the effect of bile salts on cholesterol crystallization in model bile (MB) systems. Supersaturated MB systems were prepared with an identical composition on a molar basis (taurocholate/phosphatidylcholine/cholesterol, 152 mM:38 mM: 24 mM), except for partial replacement of taurocholate (10, 20, and 30%) with various taurine-conjugated bile salts. Cholesterol crystallization was quantitatively estimated by spectrophotometrically measuring crystal-related turbidity and morphologically scanned by video-enhanced microscopy. After partial replacement of taurocholate with hydrophobic bile salts, cholesterol crystallization increased dose-dependently without changing the size of vesicles or crystal morphology and the rank order of crystallization was deoxycholate>chenodeoxycholate>cholate (control MB). All of the hydrophilic bile salts (ursodeoxycholate, ursocholate and beta-muricholate) inhibited cholesterol precipitation by forming a stable liquid-crystal phase, and there were no significant differences among the hydrophilic bile-salt species. Cholesterol crystallization was markedly altered by partial replacement of bile salts with a different hydrophobicity. Thus minimal changes in bile-salt composition may dramatically alter bile lipid metastability. PMID:10333488

  9. Cholesterol Solubility in Bile. EVIDENCE THAT SUPERSATURATED BILE IS FREQUENT IN HEALTHY MAN

    PubMed Central

    Holzbach, R. Thomas; Marsh, Mitsuko; Olszewski, Monica; Holan, Keith

    1973-01-01

    The development and validation of a direct method for measuring maximum cholesterol solubility in bile is described. Application of this method to five large mammalian species, including man, produced a micellar zone significantly smaller than that previously reported. Further studies on in vitro model solutions patterned after bile confirmed this new micellar zone. Thus, direct evidence demonstrates that the micellar zone boundary derived in vitro from model solutions is applicable to human gallbladder bile. Using the present criteria, normal human bile, in contrast to bile from other mammalian species, is commonly supersaturated with cholesterol. A male-female difference in bile composition is not demonstrable despite the well-established female preponderance of cholelithiasis. Bile from patients with cholesterol cholelithiasis has a micellar zone similar to normals but differs compositionally in that there is a greater excess of cholesterol above saturation. We conclude that cholesterol supersaturation may be a necessary but not solely sufficient cause for gallstone formation. PMID:4703231

  10. Characterization of bile acids and fatty acids from ox bile in oil paintings by gas chromatography-mass spectrometry.

    PubMed

    Casas-Catalán, M J; Doménech-Carbó, M T; Mateo-Castro, R; Gimeno-Adelantado, J V; Bosch-Reig, F

    2004-02-01

    Characterization of ox bile, traditionally used in painting, is of interest in the fields of archaeometry and conservation and restoration of works of art. Bile acids, fatty acids (F), and cholesterol found in ox bile have been identified using a derivatization method that combines the formation of ethyl esters from the carboxylic groups and the trimethylsilyl ethers from hydroxyl groups. This method of analysis is consistent with these others proposed by the authors to analyze drying oils, proteins, and diterpenic resins usually used as binders and varnishes by the painters. Bile acids from binary samples such as animal glue/ox bile, casein/ox bile and Arabic gum/ox bile have been successfully analyzed using the proposed method. Finally, a method of analysis of mixtures of drying oil and ox bile has been also proposed attempting to quantitatively characterize samples in which ox bile was added to the drying oil for increasing the surfactant properties. PMID:14763811

  11. [Dietary modification of bile lipids].

    PubMed

    Wechsler, J G; Wenzel, H; Swobodnik, W; Splitt, S; Janowitz, P; Ditschuneit, H

    1988-02-01

    The average incidence of gallstones in european countries is about 25%. Excessive secretion of cholesterol into the bile can predispose to saturation and gallstone-formation. Obesity, overnutrition, diets rich in refined carbohydrates, diets high in cholesterol intake and poor in dietary fibre, lipid lowering drugs, age and female sex hormones are recognized causing increased cholesterol secretion into the bile. These metabolic consequences may predispose to a higher incidence of cholesterol gallstone than in normal persons. Taking all the results of the literature together patients with gallstones should be encouraged to take a low cholesterol, low calorie, low refined carbohydrate and high polyunsaturated fat diet rich in bran und vegetable fibre. Obese patients should reduce their body weight. These dietary recommendations should be given for patients with gallstones during bile acid therapy and after successful dissolution in order to prevent gallstone recurrence. PMID:3280933

  12. Bile duct obstruction

    MedlinePlus

    ... the liver. It contains cholesterol, bile salts, and waste products such as bilirubin . Bile salts help your ... can lead to life-threatening infection and a dangerous buildup of bilirubin. If the blockage lasts a ...

  13. Human liver steroid sulphotransferase sulphates bile acids.

    PubMed Central

    Radominska, A; Comer, K A; Zimniak, P; Falany, J; Iscan, M; Falany, C N

    1990-01-01

    The sulphation of bile acids is an important pathway for the detoxification and elimination of bile acids during cholestatic liver disease. A dehydroepiandrosterone (DHEA) sulphotransferase has been purified from male and female human liver cytosol using DEAE-Sepharose CL-6B and adenosine 3',5'-diphosphate-agarose affinity chromatography [Falany, Vazquez & Kalb (1989) Biochem. J. 260, 641-646]. Results in the present paper show that the DHEA sulphotransferase, purified to homogeneity, is also reactive towards bile acids, including lithocholic acid and 6-hydroxylated bile acids, as well as 3-hydroxylated short-chain bile acids. The highest activity towards bile acids was observed with lithocholic acid (54.3 +/- 3.6 nmol/min per mg of protein); of the substrates tested, the lowest activity was detected with hyodeoxycholic acid (4.2 +/- 0.01 nmol/min per mg of protein). The apparent Km values for the enzyme are 1.5 +/- 0.31 microM for lithocholic acid and 4.2 +/- 0.73 microM for taurolithocholic acid. Lithocholic acid also competitively inhibits DHEA sulphation by the purified sulphotransferase (Ki 1.4 microM). No evidence was found for the formation of bile acid sulphates by sulphotransferases different from the DHEA sulphotransferase during purification work. The above results suggest that a single steroid sulphotransferase with broad specificity encompassing neutral steroids and bile acids exists in human liver. PMID:2268288

  14. Liposome formation from bile salt-lipid micelles in the digestion and drug delivery model FaSSIF(mod) estimated by combined time-resolved neutron and dynamic light scattering.

    PubMed

    Nawroth, Thomas; Buch, Philipp; Buch, Karl; Langguth, Peter; Schweins, Ralf

    2011-12-01

    The flow of bile secretion into the human digestive system was simulated by the dilution of a bile salt-lipid micellar solution. The structural development upon the dilution of the fed state bile model FeSSIF(mod6.5) to the fasted state bile model FaSSIF(mod) was investigated by small-angle neutron scattering (SANS) and dynamic light scattering (DLS) in crossed beam experiments to observe small and large structures in a size range of 1 nm to 50 μm in parallel. Because of the physiologically low lipid and surfactant concentrations of 2.625 mM egg-phosphatidylcholine and 10.5 mM taurocholate the sensitivity of the neutron-structural investigations was improved by partial solvent deuteration with 71% D(2)O, with control experiments in H(2)O. Static experiments of initial and end state systems after 6 days of development revealed the presence of mixed bile salt-lipid micelles of 5.1 nm size in the initial state model FeSSIF(mod6.5), and large liposomes in FaSSIF(mod), which represent the late status after dilution of bile secretion in the intestine in the fasted state. The liposomes depicted a size of 34.39 nm with a membrane thickness of 4.75 nm, which indicates medium to large size unilamellar vesicles. Crossed beam experiments with time-resolved neutron and light scattering experiments after fast mixing with a stopped-flow device revealed a stepwise structural dynamics upon dilution by a factor of 3.5. The liposome formation was almost complete five minutes after bile dilution. The liposomes 30 min after dilution resembled the liposomes found after 6 days and depicted a size of 44.56 nm. In the time regime between 3 and 100 s a kinetic intermediate was observed. In a further experiment the liposome formation was abolished when the dilution was conducted with a surfactant solution containing sodium dodecyl sulfate. PMID:21988605

  15. Bile acid transporters

    PubMed Central

    Dawson, Paul A.; Lan, Tian; Rao, Anuradha

    2009-01-01

    In liver and intestine, transporters play a critical role in maintaining the enterohepatic circulation and bile acid homeostasis. Over the past two decades, there has been significant progress toward identifying the individual membrane transporters and unraveling their complex regulation. In the liver, bile acids are efficiently transported across the sinusoidal membrane by the Na+ taurocholate cotransporting polypeptide with assistance by members of the organic anion transporting polypeptide family. The bile acids are then secreted in an ATP-dependent fashion across the canalicular membrane by the bile salt export pump. Following their movement with bile into the lumen of the small intestine, bile acids are almost quantitatively reclaimed in the ileum by the apical sodium-dependent bile acid transporter. The bile acids are shuttled across the enterocyte to the basolateral membrane and effluxed into the portal circulation by the recently indentified heteromeric organic solute transporter, OSTα-OSTβ. In addition to the hepatocyte and enterocyte, subgroups of these bile acid transporters are expressed by the biliary, renal, and colonic epithelium where they contribute to maintaining bile acid homeostasis and play important cytoprotective roles. This article will review our current understanding of the physiological role and regulation of these important carriers. PMID:19498215

  16. [Structure and Activity of Fungal Lipases in Bile Salt Solutions].

    PubMed

    Bogdanova, L R; Bakirova, D R; Valiullina, Yu A; Idiyatullin, B Z; Faizullin, D A; Zueva, O S; Zuev, Yu F

    2016-01-01

    The changes in structure and catalytic properties of fungal lipases (Candida rugosa, Rhizomucor miehei, Mucor javanicus) were investigated in micellar solutions of bile salts that differ in hydrophilic-lypophilic balance and reaction medium properties. The methods of circular dichroism and tryptophan fluorescence were applied to estimate the changes in peptide structure within complexes with bile salt micelles. Bile salts do not exert a significant influence on the structure of the enzymes under study: in Rh. miehei and M. javanicus lipases the alpha helix content slightly decreased, the influence of bile salts on the C. rugosa structure was not revealed. Despite negligible structural modifications in the enzymes, in bile salt solutions a considerable change in their catalytic properties was observed: an abrupt decrease in catalytic effectiveness. Substrate-bile salts micelles complex formation was demonstrated by the NMR self-diffusion method. The model of a regulation of fungal lipase activity was proposed. PMID:27192825

  17. Bile culture (image)

    MedlinePlus

    ... tract. A specimen of bile is placed in culture media and observed for growth of microorganisms. If there ... no infection. If there is growth in the culture media, the growth is then isolated and identified to ...

  18. Bile duct obstruction

    MedlinePlus

    ... bile builds up in the liver, and jaundice (yellow color of the skin) develops due to the increasing ... upper right side Dark urine Fever Itching Jaundice (yellow skin color) Nausea and vomiting Pale-colored stools

  19. Respiratory Pathogens Adopt a Chronic Lifestyle in Response to Bile

    PubMed Central

    Reen, F. Jerry; Woods, David F.; Mooij, Marlies J.; Adams, Claire; O'Gara, Fergal

    2012-01-01

    Chronic respiratory infections are a major cause of morbidity and mortality, most particularly in Cystic Fibrosis (CF) patients. The recent finding that gastro-esophageal reflux (GER) frequently occurs in CF patients led us to investigate the impact of bile on the behaviour of Pseudomonas aeruginosa and other CF-associated respiratory pathogens. Bile increased biofilm formation, Type Six Secretion, and quorum sensing in P. aeruginosa, all of which are associated with the switch from acute to persistent infection. Furthermore, bile negatively influenced Type Three Secretion and swarming motility in P. aeruginosa, phenotypes associated with acute infection. Bile also modulated biofilm formation in a range of other CF-associated respiratory pathogens, including Burkholderia cepacia and Staphylococcus aureus. Therefore, our results suggest that GER-derived bile may be a host determinant contributing to chronic respiratory infection. PMID:23049911

  20. Bile acids: analysis in biological fluids and tissues

    PubMed Central

    Griffiths, William J.; Sjövall, Jan

    2010-01-01

    The formation of bile acids/bile alcohols is of major importance for the maintenance of cholesterol homeostasis. Besides their functions in lipid absorption, bile acids/bile alcohols are regulatory molecules for a number of metabolic processes. Their effects are structure-dependent, and numerous metabolic conversions result in a complex mixture of biologically active and inactive forms. Advanced methods are required to characterize and quantify individual bile acids in these mixtures. A combination of such analyses with analyses of the proteome will be required for a better understanding of mechanisms of action and nature of endogenous ligands. Mass spectrometry is the basic detection technique for effluents from chromatographic columns. Capillary liquid chromatography-mass spectrometry with electrospray ionization provides the highest sensitivity in metabolome analysis. Classical gas chromatography-mass spectrometry is less sensitive but offers extensive structure-dependent fragmentation increasing the specificity in analyses of isobaric isomers of unconjugated bile acids. Depending on the nature of the bile acid/bile alcohol mixture and the range of concentration of individuals, different sample preparation sequences, from simple extractions to group separations and derivatizations, are applicable. We review the methods currently available for the analysis of bile acids in biological fluids and tissues, with emphasis on the combination of liquid and gas phase chromatography with mass spectrometry. PMID:20008121

  1. Modern management of common bile duct stones.

    PubMed

    Buxbaum, James

    2013-04-01

    It is imperative for gastroenterologists to understand the different formations of bile duct stones and the various medical treatments available. To minimize the complications of endoscopic retrograde cholangiopancreatography (ERCP), it is critical to appropriately assess the risk of bile duct stones before intervention. Biliary endoscopists should be comfortable with the basic techniques of stone removal, including sphincterotomy, mechanical lithotripsy, and stent placement. It is important to be aware of advanced options, including laser and electrohydraulic stone fragmentation, and papillary dilatation for problematic cases. The timing and need for ERCP in those who require a cholecystectomy is also a consideration. PMID:23540960

  2. [Isolated neurofibroma of the common bile duct].

    PubMed

    Carbia, S; Pagola, J; Flaster, N; Guida, A; Jufe, L; González, B; Caniparoli, A

    1995-01-01

    The neurogenic tumors in the biliary tract are rare and usually are amputation neuroma that occur after cholecystectomy. We describe a case of isolated neurofibroma of the common bile duct in a young man not cholecystectomized. The patient suffered recurrent episodes of abdominal pain, vomiting and weight loss without clinical signs of Von Recklinghausen's disease or jaundice. The hepatogram was normal. The echography indicated a solid formation with obstruction of the proximal common bile duct. In the ERCP the stenosis was found. Surgical excision of the tumor and anastomosis of bilateral hepatic ducts and jejunum were carried out. At microscopic examination intraparietal neurofibroma of the common bile duct was found. As isolated entity, we know of only one reported case. PMID:8731581

  3. Bile acid sequestrants for cholesterol

    MedlinePlus

    Bile acid sequestrants are medicines that help lower your LDL (bad) cholesterol . Too much cholesterol in your blood can ... block them. These medicines work by blocking bile acid in your stomach from being absorbed in your ...

  4. What Is Bile Duct Cancer?

    MedlinePlus

    ... of bile duct cancer. The rest of this document refers only to cholangiocarcinomas. Benign bile duct tumors ... tumors, which aren’t discussed further in this document. Other cancers in the liver The most common ...

  5. Bile Acid Synthesis in the Isolated, Perfused Rabbit Liver

    PubMed Central

    Mosbach, E. H.; Rothschild, M. A.; Bekersky, I.; Oratz, M.; Mongelli, J.

    1971-01-01

    These experiments were carried out to demonstrate the usefulness of the perfused rabbit liver for studies of bile acid metabolism, and to determine the rate-limiting enzyme of bile acid synthesis. Rabbits were fed a semisynthetic diet, with or without the addition of 1% cholestyramine, under controlled conditions. At the end of 2-5 wk, the livers were removed and perfused for 2.5 hr employing various 14C-labeled precursors to measure de novo cholic acid synthesis. The livers were then analyzed for cholesterol, and the bile collected during the perfusion was analyzed for cholesterol and bile acids. Control bile contained, on the average, 0.34 mg of glycocholate, 7.4 mg of glycodeoxycholate, and 0.06 mg of cholesterol. After cholestyramine treatment of the donor rabbits, the bile contained 3.3 mg of glycocholate, 3.7 mg of glycodeoxycholate, and 0.05 mg of cholesterol. It was assumed that in cholestyramine-treated animals the enterohepatic circulation of the bile acids had been interrupted sufficiently to release the feedback inhibition of the rate-controlling enzyme of bile acid synthesis. Therefore, a given precursor should be incorporated into bile acids at a more rapid rate in livers of cholestyramine-treated animals, provided that the precursor was acted upon by the rate-controlling enzyme. It was found that the incorporation of acetate-14C, mevalonolactone-14C, and cholesterol-14C into cholate was 5-20 times greater in the livers of cholestyramine-treated animals than in the controls. In contrast, there was no difference in the incorporation of 7α-hydroxycholesterol-14C into cholate regardless of dietary pretreatment. It was concluded that given an adequate precursor pool, the 7α-hydroxylation of cholesterol is the rate-limiting step in bile acid formation. PMID:5097576

  6. Complicated bile duct stones.

    PubMed

    Roy, Ashwin; Martin, Derrick

    2013-01-01

    Common bile duct stones (CBDSs) are solid deposits that can either form within the gallbladder or migrate to the common bile duct (CBD), or form de novo in the biliary tree. In the USA around 15% of the population have gallstones and of these, 3% present with symptoms annually. Because of this, there have been major advancements in the management of gallstones and related conditions. Management is based on the patient's risk profile; young and healthy patients are likely to be recommended for surgery and elderly patients with comorbidities are usually recommended for endoscopic procedures. Imaging of gallstones has advanced in the last 30 years with endoscopic retrograde cholangiopancreatography evolving from a diagnostic to a therapeutic procedure in removing CBDSs. We present a complicated case of a patient with a CBDS and periampullary diverticulum and discuss the techniques used to diagnose and remove the stone from the biliary system. PMID:23946532

  7. Complicated bile duct stones

    PubMed Central

    Roy, Ashwin; Martin, Derrick

    2013-01-01

    Common bile duct stones (CBDSs) are solid deposits that can either form within the gallbladder or migrate to the common bile duct (CBD), or form de novo in the biliary tree. In the USA around 15% of the population have gallstones and of these, 3% present with symptoms annually. Because of this, there have been major advancements in the management of gallstones and related conditions. Management is based on the patient's risk profile; young and healthy patients are likely to be recommended for surgery and elderly patients with comorbidities are usually recommended for endoscopic procedures. Imaging of gallstones has advanced in the last 30 years with endoscopic retrograde cholangiopancreatography evolving from a diagnostic to a therapeutic procedure in removing CBDSs. We present a complicated case of a patient with a CBDS and periampullary diverticulum and discuss the techniques used to diagnose and remove the stone from the biliary system. PMID:23946532

  8. Bile acids: emerging role in management of liver diseases.

    PubMed

    Asgharpour, Amon; Kumar, Divya; Sanyal, Arun

    2015-10-01

    Bile acids are well known for their effects on cholesterol homeostasis and lipid digestion. Since the discovery of bile acid receptors, of which there are farnesoid X receptor (FXR), a nuclear receptor, and the plasma membrane G-protein receptor, as well as Takeda G-protein coupled receptor clone 5, further roles have been elucidated for bile acids including glucose and lipid metabolism as well as inflammation. Additionally, treatment with bile acid receptor agonists has shown a decrease in the amount of atherosclerosis plaque formation and decreased portal vascular resistance and portal hypotension in animal models. Furthermore, rodent models have demonstrated antifibrotic activity using bile acid receptor agonists. Early human data using a FXR agonist, obeticholic acid, have shown promising results with improvement of histological activity and even a reduction of fibrosis. Human studies are ongoing and will provide further information on bile acid receptor agonist therapies. Thus, bile acids and their derivatives have the potential for management of liver diseases and potentially other disease states including diabetes and the metabolic syndrome. PMID:26320013

  9. Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis

    PubMed Central

    Payne, Claire M; Bernstein, Carol; Dvorak, Katerina; Bernstein, Harris

    2008-01-01

    Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer. PMID:21677822

  10. Bile acids: emerging role in management of liver diseases

    PubMed Central

    Asgharpour, Amon; Kumar, Divya

    2016-01-01

    Bile acids are well known for their effects on cholesterol homeostasis and lipid digestion. Since the discovery of bile acid receptors, of which there are farnesoid X receptor (FXR), a nuclear receptor, and the plasma membrane G-protein receptor, as well as Takeda G-protein coupled receptor clone 5, further roles have been elucidated for bile acids including glucose and lipid metabolism as well as inflammation. Additionally, treatment with bile acid receptor agonists has shown a decrease in the amount of atherosclerosis plaque formation and decreased portal vascular resistance and portal hypotension in animal models. Furthermore, rodent models have demonstrated antifibrotic activity using bile acid receptor agonists. Early human data using a FXR agonist, obeticholic acid, have shown promising results with improvement of histological activity and even a reduction of fibrosis. Human studies are ongoing and will provide further information on bile acid receptor agonist therapies. Thus, bile acids and their derivatives have the potential for management of liver diseases and potentially other disease states including diabetes and the metabolic syndrome. PMID:26320013

  11. Boldine enhances bile production in rats via osmotic and Farnesoid X receptor dependent mechanisms

    SciTech Connect

    Cermanova, Jolana; Kadova, Zuzana; Zagorova, Marie; Hroch, Milos; Tomsik, Pavel; Nachtigal, Petr; Kudlackova, Zdenka; Pavek, Petr; Dubecka, Michaela; Ceckova, Martina; Staud, Frantisek; Laho, Tomas; Micuda, Stanislav

    2015-05-15

    Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine. - Highlights: • Boldine may increase bile production by direct as well as indirect mechanisms. • Biliary concentrations of boldine above 10 μM directly stimulate bile production. • Long-term oral boldine administration increases bile acid (BA) biliary secretion. • Boldine

  12. Bile duct malignancies.

    PubMed

    Tucek, S; Tomasek, J; Halámkova, J; Kiss, I; Andrasina, T; Hemmelová, B; Adámková-Krákorová, D; Vyzula, R

    2010-01-01

    Bile duct malignancies include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gall bladder carcinoma (GC) and carcinoma of Vater's ampulla (ampulloma). Bile duct neoplasms are rare tumours with overall poor prognosis. The overall incidence affects up to 12.5 per 100,000 persons in the Czech Republic. The mortality rate has risen recently to 9.5 per 100,000 persons. The incidence and mortality have been remarkably stable over the past 3 decades. The survival rate of patients with these tumours is poor, usually not exceeding 12 months. The diagnostic process is complex, uneasy and usually late. Most cases are diagnosed when unresectable, and palliative treatment is the main approach of medical care for these tumours. The treatment remains very challenging. New approaches have not brought much improvement in this field. Standards of palliative care are lacking and quality of life assessments are surprisingly not common. From the scarce data it seems, however, that multimodal individually tailored treatment can prolong patients'survival and improve the health-related quality of life. The care in specialized centres offers methods of surgery, interventional radiology, clinical oncology and high quality supportive care. These methods are discussed in the article in greater detail. Improvements in this field can be sought in new diagnostic methods and new procedures in surgery and interventional radiology. Understanding the tumour biology on the molecular level could shift the strategy to a more successful one, resulting in more cured patients. Further improvements in palliative care can be sought by defining new targets and new drug development. The lack of patients with bile duct neoplasms has been the limiting factor for any improvements. A new design of larger randomized international multicentric clinical trials with prompt data sharing could help to overcome this major problem. Defining standards of palliative care is a necessity

  13. Intrahepatic Transposition of Bile Ducts

    PubMed Central

    Delić, Jasmin; Savković, Admedina; Isaković, Eldar; Marković, Sergije; Bajtarevic, Alma; Denjalić, Amir

    2012-01-01

    Objective. To describe the intrahepatic bile duct transposition (anatomical variation occurring in intrahepatic ducts) and to determine the frequency of this variation. Material and Methods. The researches were performed randomly on 100 livers of adults, both sexes. Main research methods were anatomical macrodissection. As a criterion for determination of variations in some parts of bile tree, we used the classification of Segmentatio hepatis according to Couinaud (1957) according to Terminologia Anatomica, Thieme Stuugart: Federative Committee on Anatomical Terminology, 1988. Results. Intrahepatic transposition of bile ducts was found in two cases (2%), out of total examined cases (100): right-left transposition (right segmental bile duct, originating from the segment VIII, joins the left liver duct-ductus hepaticus sinister) and left-right intrahepatic transposition (left segmental bile duct originating from the segment IV ends in right liver duct-ductus hepaticus dexter). Conclusion. Safety and success in liver transplantation to great extent depends on knowledge of anatomy and some common embryological anomalies in bile tree. Variations in bile tree were found in 24–43% of cases, out of which 1–22% are the variations of intrahepatic bile ducts. Therefore, good knowledge on ductal anatomy enables good planning, safe performance of therapeutic and operative procedures, and decreases the risk of intraoperative and postoperative complications. PMID:22550601

  14. Nasal Absorption of Insulin: Enhancement by Hydrophobic Bile Salts

    NASA Astrophysics Data System (ADS)

    Gordon, G. S.; Moses, A. C.; Silver, R. D.; Flier, J. S.; Carey, M. C.

    1985-11-01

    We demonstrate that therapeutically useful amounts of insulin are absorbed by the nasal mucosa of human beings when administered as a nasal spray with the common bile salts. By employing a series of bile salts with subtle differences in the number, position, and orientation of their nuclear hydroxyl functions and alterations in side chain conjugation, we show that adjuvant potency for nasal insulin absorption correlates positively with increasing hydrophobicity of the bile salts' steroid nucleus. As inferred from studies employing various concentrations of unconjugated deoxycholate and a constant dose of insulin, insulin absorption begins at the aqueous critical micellar concentration of the bile salt and becomes maximal when micelle formation is well established. These and other data are consistent with the complementary hypotheses that bile salts act as absorption adjuvants by (i) producing high juxtamembrane concentrations of insulin monomers via solubilization in mixed bile salt micelles and (ii) forming reverse micelles within nasal membranes, through which insulin monomers can diffuse through polar channels from the nares into the blood stream.

  15. Gelation of self-assembed bile acid-PEG conjugates

    NASA Astrophysics Data System (ADS)

    Strandman, Satu; Le Devedec, Frantz; Zhu, X. X.

    2012-02-01

    The aggregation of macromolecules and low-molar-mass compounds into elongated self-assemblies such as wormlike micelles, fibers, or tubules increases the viscosity of the solutions and often leads to gelation due to network formation, even in organic solvents. Such one-dimensional nanostructures are promising candidates for drug delivery vehicles, packing materials for separation, templates for metal nanowires, biocides, and photo- or biocatalysis. An interesting group of compounds capable of this type of self-organization are bile acids, which are endogeneous steroids known to form gels at high concentrations and appropriate pH conditions. Grafting poly(ethylene oxide) on bile acids via anionic polymerization brings along thermoresponsiveness represented by lower critical solution temperature (LCST), while self-assembling occurs below another threshold temperature leading to a gelation at high concentrations, as shown by rheological experiments. The latter transition is assigned to the nanotube formation of pegylated bile acids, visualized by electron microscopy.

  16. Bile acid sequestrants for cholesterol

    MedlinePlus

    ... ency/patientinstructions/000787.htm Bile acid sequestrants for cholesterol To use the sharing features on this page, ... are medicines that help lower your LDL (bad) cholesterol . Too much cholesterol in your blood can stick ...

  17. Oxidation of Fe III porphyrins by peroxyl radicals derived from 2-propanol and methanol. Evidence for acid-dependent and acid-independent pathways

    NASA Astrophysics Data System (ADS)

    Brault, D.; Neta, P.

    1985-11-01

    Iron(III) deuteroporphyrin dimethyl ester is oxidized to the radical cation form by the peroxyl radicals CH 2(OH)O 2- and (CH 3) 2C(OH)O 2- generated by pulse radiolysis of air saturated aqueous solutions of methanol and 2-propanol, respectively. Oxidation by CH 2(OH)O 2- radicals proceeds with k = 1×10 7 M -1 s -1 independent of pH. In contrast, the electron-transfer reaction of (CH 3) 2C(OH)O 2-1 is pH-dependent. A reaction scheme, which may apply to all peroxyl radicals depending on relative rate constants, is proposed. It involves the formation of an iron porphyrin peroxyl radical adduct that decays by acid-dependent and acid-independent routes.

  18. Bile acids as metabolic regulators

    PubMed Central

    Li, Tiangang; Chiang, John Y. L.

    2015-01-01

    Summary Small molecule ligands that target to TGR5 and FXR have shown promise in treating various metabolic and inflammation-related human diseases. New insights into the mechanisms underlying the bariatric surgery and bile acid sequestrant treatment suggest that targeting the enterohepatic circulation to modulate gut-liver bile acid signaling, incretin production and microbiota represents a new strategy to treat obesity and type-2 diabetes. PMID:25584736

  19. COMPLEX EVOLUTION OF BILE SALTS IN BIRDS

    PubMed Central

    Hagey, Lee R.; Vidal, Nicolas; Hofmann, Alan F.; Krasowski, Matthew D.

    2010-01-01

    Bile salts are the major end-metabolites of cholesterol and are important in lipid digestion and shaping of the gut microflora. There have been limited studies of bile-salt variation in birds. The purpose of our study was to determine bile-salt variation among birds and relate this variation to current avian phylogenies and hypotheses on the evolution of bile salt pathways. We determined the biliary bile-salt composition of 405 phylogenetically diverse bird species, including 7 paleognath species. Bile salt profiles were generally stable within bird families. Complex bile-salt profiles were more common in omnivores and herbivores than in carnivores. The structural variation of bile salts in birds is extensive and comparable to that seen in surveys of bile salts in reptiles and mammals. Birds produce many of the bile salts found throughout nonavian vertebrates and some previously uncharacterized bile salts. One difference between birds and other vertebrates is extensive hydroxylation of carbon-16 of bile salts in bird species. Comparison of our data set of bird bile salts with that of other vertebrates, especially reptiles, allowed us to infer evolutionary changes in the bile salt synthetic pathway. PMID:21113274

  20. Boldine enhances bile production in rats via osmotic and farnesoid X receptor dependent mechanisms.

    PubMed

    Cermanova, Jolana; Kadova, Zuzana; Zagorova, Marie; Hroch, Milos; Tomsik, Pavel; Nachtigal, Petr; Kudlackova, Zdenka; Pavek, Petr; Dubecka, Michaela; Ceckova, Martina; Staud, Frantisek; Laho, Tomas; Micuda, Stanislav

    2015-05-15

    Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine. PMID:25771127

  1. Development of a differential medium for bile salt hydrolase-active Lactobacillus spp.

    PubMed Central

    Dashkevicz, M P; Feighner, S D

    1989-01-01

    An agar plate assay was developed to detect bile salt hydrolase activity in lactobacilli. On Lactobacillus-selective MRS or Rogosa SL medium supplemented with taurodeoxycholic, taurocholic, or taurochenodeoxycholic acids, bile salt hydrolysis was manifested at two intensities: (i) the formation of precipitate halos around colonies or (ii) the formation of opaque granular white colonies. Sixty-six lactobacilli were tested for bile salt hydrolase activity by both the plate assay and a sensitive radiochemical assay. No false-positive or false-negative results were detected by the plate assay. Based on results of experiments with Eubacterium lentum and Bacteroides species, the plate assay was dependent on two factors: (i) the presence of bile salt hydrolytic activity and (ii) the ability of the organism to sufficiently acidify the medium to protonate free bile acids. The availability of a differential medium for determination of bile salt hydrolase activity will provide a rapid method for determining shifts in a specific functional activity of intestinal Lactobacillus species and provide a rapid screening capability for identifying bile salt hydrolase-deficient mutants. The latter application should allow bile salt hydrolase activity to be used as a marker enzyme in genetic experiments. Images PMID:2705765

  2. Calcium signaling and the secretory activity of bile duct epithelia.

    PubMed

    Amaya, Maria Jimena; Nathanson, Michael H

    2014-06-01

    Cytosolic calcium (Cai(2+)) is a second messenger that is important for the regulation of secretion in many types of tissues. Bile duct epithelial cells, or cholangiocytes, are polarized epithelia that line the biliary tree in liver and are responsible for secretion of bicarbonate and other solutes into bile. Cai(2+) signaling plays an important role in the regulation of secretion by cholangiocytes, and this review discusses the machinery involved in the formation of Ca(2+) signals in cholangiocytes, along with the evidence that these signals regulate ductular secretion. Finally, this review discusses the evidence that impairments in cholangiocyte Ca(2+) signaling play a primary role in the pathogenesis of cholestatic disorders, in which hepatic bile secretion is impaired. PMID:24612866

  3. Laparoscopic common bile duct exploration.

    PubMed

    Vecchio, Rosario; MacFadyen, Bruce V

    2002-04-01

    In recent years, laparoscopic common bile duct exploration has become the procedure of choice in the management of choledocholithiasis in several laparoscopic centers. The increasing interest for this laparoscopic approach is due to the development of instrumentation and technique, allowing the procedure to be performed safely, and it is also the result of the revised role of endoscopic retrograde cholangiopancreatography, which has been questioned because of its cost, risk of complications and effectiveness. Many surgeons, however, are still not familiar with this technique. In this article we discuss the technique and results of laparoscopic common bile duct exploration. Both the laparoscopic transcystic approach and choledochotomy are discussed, together with the results given in the literature. When one considers the costs, morbidity, mortality and the time required before the patient can return to work, it would appear that laparoscopic cholecystectomy with common bile duct exploration is more favorable than open surgery or laparoscopic cholecystectomy with preoperative or postoperative endoscopic sphincterotomy. However, the technique requires advanced laparoscopic skills, including suturing, knot tying, the use of a choledochoscope, guidewire, dilators and balloon stone extractor. Although laparoscopic common bile duct exploration appears to be the most cost-effective method to treat common bile duct stones, it should be emphasized that this procedure is very challenging, and it should be performed by well-trained laparoscopic surgeons with experience in biliary surgery. PMID:11981684

  4. Fifty years with bile acids and steroids in health and disease.

    PubMed

    Sjövall, Jan

    2004-08-01

    Cholesterol and its metabolites, e.g., steroid hormones and bile acids, constitute a class of compounds of great biological importance. Their chemistry, biochemistry, and regulation in the body have been intensely studied for more than two centuries. The author has studied aspects of the biochemistry and clinical chemistry of steroids and bile acids for more than 50 years, and this paper, which is an extended version of the Schroepfer Medal Award lecture, reviews and discusses part of this work. Development and application of analytical methods based on chromatography and mass spectrometry (MS) have been a central part of many projects, aiming at detailed characterization and quantification of metabolic profiles of steroids and bile acids under different conditions. In present terminology, much of the work may be termed steroidomics and cholanoidomics. Topics discussed are bile acids in human bile and feces, bile acid production, bacterial dehydroxylation of bile acids and steroids during the enterohepatic circulation, profiles of steroid sulfates in plasma of humans and other primates, development of neutral and ion-exchanging lipophilic derivatives of Sephadex for sample preparation and group separation of steroid and bile acid conjugates, profiles of steroids and bile acids in human urine under different conditions, hydroxylation of bile acids in liver disease, effects of alcohol-induced redox changes on steroid synthesis and metabolism, alcohol-induced changes of bile acid biosynthesis, compartmentation of bile acid synthesis studied with 3H-labeled ethanol, formation and metabolism of sulfated metabolites of progesterone in human pregnancy, abnormal patterns of these in patients with intrahepatic cholestasis of pregnancy corrected by ursodeoxycholic acid, inherited and acquired defects of bile acid biosynthesis and their treatment, conjugation of bile acids and steroids with N-acetylglucosamine, sulfate-glucuronide double conjugates of hydroxycholesterols

  5. What Are the Key Statistics about Bile Duct Cancer?

    MedlinePlus

    ... for bile duct cancer? What are the key statistics about bile duct cancer? Bile duct cancer is ... it is when it is found. For survival statistics, see the section “ Survival statistics for bile duct ...

  6. What's New in Bile Duct Cancer Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for bile duct cancer What’s new in bile duct cancer research and treatment? Bile ... is tumor blood vessels. Bile duct tumors need new blood vessels to grow beyond a certain size. ...

  7. Bile Stress Response in Listeria monocytogenes LO28: Adaptation, Cross-Protection, and Identification of Genetic Loci Involved in Bile Resistance

    PubMed Central

    Begley, Máire; Gahan, Cormac G. M.; Hill, Colin

    2002-01-01

    Bile is one of many barriers that Listeria monocytogenes must overcome in the human gastrointestinal tract in order to infect and cause disease. We demonstrated that stationary-phase cultures of L. monocytogenes LO28 were able to tolerate concentrations of bovine, porcine, and human bile and bile acids well in excess of those encountered in vivo. Strain LO28 was relatively bile resistant compared with other clinical isolates of L. monocytogenes, as well as with Listeria innocua, Salmonella enterica serovar Typhimurium LT2, and Lactobacillus sakei. While exponential-phase L. monocytogenes LO28 cells were exquisitely sensitive to unconjugated bile acids, prior adaptation to sublethal levels of bile acids or heterologous stresses, such as acid, heat, salt, or sodium dodecyl sulfate (SDS), significantly enhanced bile resistance. This adaptive response was independent of protein synthesis, and in the cases of bile and SDS adaptation, occurred in seconds. In order to identify genetic loci involved in the bile tolerance phenotype of L. monocytogenes LO28, transposon (Tn917) and plasmid (pORI19) integration banks were screened for bile-sensitive mutants. The disrupted genes included a homologue of the capA locus required for capsule formation in Bacillus anthracis; a gene encoding the transcriptional regulator ZurR; a homologue of an Escherichia coli gene, lytB, involved in isoprenoid biosynthesis; a gene encoding a homologue of the Bacillus subtilis membrane protein YxiO; and a gene encoding an amino acid transporter with a putative role in pH homeostasis, gadE. Interestingly, all of the identified loci play putative roles in maintenance of the cell envelope or in stress responses. PMID:12450822

  8. Bile stress response in Listeria monocytogenes LO28: adaptation, cross-protection, and identification of genetic loci involved in bile resistance.

    PubMed

    Begley, Máire; Gahan, Cormac G M; Hill, Colin

    2002-12-01

    Bile is one of many barriers that Listeria monocytogenes must overcome in the human gastrointestinal tract in order to infect and cause disease. We demonstrated that stationary-phase cultures of L. monocytogenes LO28 were able to tolerate concentrations of bovine, porcine, and human bile and bile acids well in excess of those encountered in vivo. Strain LO28 was relatively bile resistant compared with other clinical isolates of L. monocytogenes, as well as with Listeria innocua, Salmonella enterica serovar Typhimurium LT2, and Lactobacillus sakei. While exponential-phase L. monocytogenes LO28 cells were exquisitely sensitive to unconjugated bile acids, prior adaptation to sublethal levels of bile acids or heterologous stresses, such as acid, heat, salt, or sodium dodecyl sulfate (SDS), significantly enhanced bile resistance. This adaptive response was independent of protein synthesis, and in the cases of bile and SDS adaptation, occurred in seconds. In order to identify genetic loci involved in the bile tolerance phenotype of L. monocytogenes LO28, transposon (Tn917) and plasmid (pORI19) integration banks were screened for bile-sensitive mutants. The disrupted genes included a homologue of the capA locus required for capsule formation in Bacillus anthracis; a gene encoding the transcriptional regulator ZurR; a homologue of an Escherichia coli gene, lytB, involved in isoprenoid biosynthesis; a gene encoding a homologue of the Bacillus subtilis membrane protein YxiO; and a gene encoding an amino acid transporter with a putative role in pH homeostasis, gadE. Interestingly, all of the identified loci play putative roles in maintenance of the cell envelope or in stress responses. PMID:12450822

  9. General Information about Extrahepatic Bile Duct Cancer

    MedlinePlus

    ... Bile Duct Cancer Treatment (PDQ®)–Patient Version General Information About Bile Duct Cancer Go to Health Professional ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  10. Effects of cholecystectomy on the kinetics of primary and secondary bile acids.

    PubMed Central

    Berr, F; Stellaard, F; Pratschke, E; Paumgartner, G

    1989-01-01

    Removal of the gallbladder is thought to increase formation and pool size of secondary bile acids, mainly deoxycholic acid (DCA), by increased exposure of primary bile acids (cholic acid [CA], chenodeoxycholic acid [CDCA]) to bacterial dehydroxylation in the intestine. We have tested this hypothesis by simultaneous determination of pool size and turnover of DCA, CA, and CDCA in nine women before and at various intervals after removal of a functioning gallbladder. An isotope dilution technique using marker bile acids labeled with stable isotopes (2H4-DCA, 13C-CA, 13C-CDCA) was used. After cholecystectomy, concentration and output of bile acids relative to bilirubin increased (P less than 0.02) in fasting duodenal bile and cholesterol saturation decreased by 27% (P less than 0.05) consistent with enhanced enterohepatic cycling of bile acids. Three months after removal of the gallbladder bile acid kinetics were in a new steady state: pool size and turnover of CDCA were unchanged. Synthesis of CA, the precursor of DCA, was diminished by 37% (P = 0.05), probably resulting from feedback inhibition by continuous transhepatic flux of bile acids. The fraction of CA transferred after 7 alpha-dehydroxylation to the DCA pool increased from 46 +/- 16 to 66 +/- 32% (P less than 0.05). However, this enhanced transfer did not lead to increased input or size of the DCA pool, because synthesis of the precursor CA had decreased. PMID:2708522

  11. The metabolism of primary, 7-oxo, and 7 beta-hydroxy bile acids by Clostridium absonum.

    PubMed

    Sutherland, J D; Macdonald, I A

    1982-07-01

    Clostridium absonum was shown to metabolize primary bile acids to give rise to both 7-oxo bile acids and 7 beta-hydroxy (urso) bile acids. At relatively low redox potential (Eh) values, high yields of urso bile acids were achieved (60-75%). If, however, the Eh value of the culture was allowed to rise above approximately -100 mv, the 7-oxo bile acid would tend to predominate (more than 75%) and the "death phase" was accelerated. Growth of C. absonum in sterile graduated cylinders instead of in conventional Erlenmeyer flasks was effective in delaying the rise in Eh value with time (which appears largely due to diffusion of atmospheric oxygen into the medium) and in preserving a higher viable count of organisms. It is proposed that the formation of excess amounts of 7-oxo bile acid is a manifestation of oxygen toxicity and that it could be mediated by an increasing intracellular NADP:NADPH ratio. Additionally, the reaction: primary bile acid in equilibrium oxo bile acid in equilibrium urso bile acid was shown to be partially reversible. When the organisms were grown with [24-(14)C]chenodeoxycholic, -cholic, or -7-keto-lithocholic acid, this reaction could be clearly demonstrated. The addition of an equimolar concentration of deoxycholic acid (which itself is not metabolized) effectively enhanced the rate of bioconversion of cholate and 7-keto-lithocholic, but not chenodeoxycholate (whose rate of bioconversion was the fastest of the three). When the organisms were grown with urso bile acids (ursocholic or ursodeoxycholic) or with 7-keto-deoxycholic acid, very little metabolism occurred unless deoxycholic acid was added which induced formation of primary and keto bile acids. In all cases, formation of oxo bile acid from primary or urso bile acid occurred as the Eh value of the medium rose with time and could thus be delayed by the use of a cylinder instead of a flask for growing the culture. These results were rationalized by demonstrating that induction of 7 alpha- and

  12. Bile salts as semiochemicals in fish

    USGS Publications Warehouse

    Buchinger, Tyler J.; Li, Weiming; Johnson, Nicholas S.

    2014-01-01

    Bile salts are potent olfactory stimuli in fishes; however the biological functions driving such sensitivity remain poorly understood. We provide an integrative review of bile salts as semiochemicals in fish. First, we present characteristics of bile salt structure, metabolism, and function that are particularly relevant to chemical communication. Bile salts display a systematic pattern of structural variation across taxa, are efficiently synthesized, and are stable in the environment. Bile salts are released into the water via the intestine, urinary tract, or gills, and are highly water soluble. Second, we consider the potential role of bile salts as semiochemicals in the contexts of detecting nearby fish, foraging, assessing risk, migrating, and spawning. Lastly, we suggest future studies on bile salts as semiochemicals further characterize release into the environment, behavioral responses by receivers, and directly test the biological contexts underlying olfactory sensitivity.

  13. Potential diagnostic and prognostic biomarkers for cholangiocarcinoma in serum and bile.

    PubMed

    Wang, Bin; Chen, Liang; Chang, Hao-Teng

    2016-06-01

    Cholangiocarcinoma (CCA) is a devastating malignancy that is difficult to treat because of its insensitivity to conventional therapies and the inability to detect early tumor formation. Novel molecular techniques have enabled the use of serum and bile markers for CCA diagnosis and prognosis. Herein, we summarize the principal characteristics of serum and bile markers of CCA. Biomarkers such as interleukin-6, matrix metalloproteinases, serotonin (5-hydroxytryptamine) and bile acids have shown promise for improving CCA diagnosis. Several markers such as CYFRA 21-1, MK-1 and C-reactive protein were recently shown to be effective for CCA prognosis. PMID:27232281

  14. Distribution of free and conjugated cannabinoids in human bile samples.

    PubMed

    Fabritius, Marie; Staub, Christian; Mangin, Patrice; Giroud, Christian

    2012-11-30

    The metabolism of Δ(9)-tetrahydrocannabinol (THC) is relatively complex, and over 80 metabolites have been identified. However, much less is known about the formation and fate of cannabinoid conjugates. Bile excretion is known to be an important route for the elimination of phase II metabolites. A liquid chromatography-tandem mass spectrometry LC-MS/MS procedure for measuring cannabinoids in oral fluid was adapted, validated and applied to 10 bile samples. THC, 11-hydroxy-Δ(9)-tetrahydrocannabinol (11-OH-THC), 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol (THCCOOH), cannabinol (CBN), cannabidiol (CBD), Δ(9)-tetrahydrocannabinolic acid A (THC-A), 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol glucuronide (THCCOOH-gluc) and Δ(9)-tetrahydrocannabinol glucuronide (THC-gluc) were determined following solid-phase extraction and LC-MS/MS. High concentrations of THCCOOH-gluc were found in bile samples (range: 139-21,275 ng/mL). Relatively high levels of THCCOOH (7.7-1548 ng/mL) and THC-gluc (38-1366 ng/mL) were also measured. THC-A, the plant precursor of THC, was the only cannabinoid that was not detected. These results show that biliary excretion is an important route of elimination for cannabinoids conjugates and that their enterohepatic recirculation is a significant factor to consider when analyzing blood elimination profiles of cannabinoids. Furthermore, we suggest that the bile is the matrix of choice for the screening of phase II cannabinoid metabolites. PMID:22980143

  15. Intestinal GPS: bile and bicarbonate control cyclic di-GMP to provide Vibrio cholerae spatial cues within the small intestine

    PubMed Central

    Koestler, Benjamin J; Waters, Christopher M

    2014-01-01

    The second messenger cyclic di-GMP (c-di-GMP) regulates numerous phenotypes in response to environmental stimuli to enable bacteria to transition between different lifestyles. Here we discuss our recent findings that the human pathogen Vibrio cholerae recognizes 2 host-specific signals, bile and bicarbonate, to regulate intracellular c-di-GMP. We have demonstrated that bile acids increase intracellular c-di-GMP to promote biofilm formation. We have also shown that this bile-mediated increase of intracellular c-di-GMP is negated by bicarbonate, and that this interaction is dependent on pH, suggesting that V. cholerae uses these 2 environmental cues to sense and adapt to its relative location in the small intestine. Increased intracellular c-di-GMP by bile is attributed to increased c-di-GMP synthesis by 3 diguanylate cyclases (DGCs) and decreased expression of one phosphodiesterase (PDE) in the presence of bile. The molecular mechanisms by which bile controls the activity of the 3 DGCs and the regulators of bile-mediated transcriptional repression of the PDE are not yet known. Moreover, the impact of varying concentrations of bile and bicarbonate at different locations within the small intestine and the response of V. cholerae to these cues remains unclear. The native microbiome and pharmaceuticals, such as omeprazole, can impact bile and pH within the small intestine, suggesting these are potential unappreciated factors that may alter V. cholerae pathogenesis. PMID:25621620

  16. Intestinal GPS: bile and bicarbonate control cyclic di-GMP to provide Vibrio cholerae spatial cues within the small intestine.

    PubMed

    Koestler, Benjamin J; Waters, Christopher M

    2014-01-01

    The second messenger cyclic di-GMP (c-di-GMP) regulates numerous phenotypes in response to environmental stimuli to enable bacteria to transition between different lifestyles. Here we discuss our recent findings that the human pathogen Vibrio cholerae recognizes 2 host-specific signals, bile and bicarbonate, to regulate intracellular c-di-GMP. We have demonstrated that bile acids increase intracellular c-di-GMP to promote biofilm formation. We have also shown that this bile-mediated increase of intracellular c-di-GMP is negated by bicarbonate, and that this interaction is dependent on pH, suggesting that V. cholerae uses these 2 environmental cues to sense and adapt to its relative location in the small intestine. Increased intracellular c-di-GMP by bile is attributed to increased c-di-GMP synthesis by 3 diguanylate cyclases (DGCs) and decreased expression of one phosphodiesterase (PDE) in the presence of bile. The molecular mechanisms by which bile controls the activity of the 3 DGCs and the regulators of bile-mediated transcriptional repression of the PDE are not yet known. Moreover, the impact of varying concentrations of bile and bicarbonate at different locations within the small intestine and the response of V. cholerae to these cues remains unclear. The native microbiome and pharmaceuticals, such as omeprazole, can impact bile and pH within the small intestine, suggesting these are potential unappreciated factors that may alter V. cholerae pathogenesis. PMID:25621620

  17. Intestinal transport and metabolism of bile acids

    PubMed Central

    Dawson, Paul A.; Karpen, Saul J.

    2015-01-01

    In addition to their classical roles as detergents to aid in the process of digestion, bile acids have been identified as important signaling molecules that function through various nuclear and G protein-coupled receptors to regulate a myriad of cellular and molecular functions across both metabolic and nonmetabolic pathways. Signaling via these pathways will vary depending on the tissue and the concentration and chemical structure of the bile acid species. Important determinants of the size and composition of the bile acid pool are their efficient enterohepatic recirculation, their host and microbial metabolism, and the homeostatic feedback mechanisms connecting hepatocytes, enterocytes, and the luminal microbiota. This review focuses on the mammalian intestine, discussing the physiology of bile acid transport, the metabolism of bile acids in the gut, and new developments in our understanding of how intestinal metabolism, particularly by the gut microbiota, affects bile acid signaling. PMID:25210150

  18. Limy bile syndrome complicated by obstructive jaundice.

    PubMed

    Sasaki, Takamitsu; Kato, Daisuke; Matsuoka, Nobuhide; Yamashita, Yuichi

    2010-01-01

    Limy bile syndrome is a rare condition in which the gallbladder is filled with a paste-like radiopaque material. The presence of limy bile in the common bile duct is rare. A 72-year-old woman was admitted to our hospital with epigastric pain and jaundice. Plain abdominal radiography on admission showed a radiopaque material in the gallbladder. Computed tomography also showed that the gallbladder and the common bile duct were filled with a radiopaque material. The patient had never received any cholecystographic contrast agents. As a result, a diagnosis of obstructive jaundice due to choledocholithiasis, which includes limy bile, was made. We herein report the process by which limy bile syndrome, complicated by obstructive jaundice, was successfully treated through combined treatment via endoscopic sphincterotomy and laparoscopic cholecystectomy. PMID:20480840

  19. CDDO-9,11-dihydro-trifluoroethyl amide (CDDO-dhTFEA) induces hepatic cytoprotective genes and increases bile flow in rats.

    PubMed

    Reisman, Scott A; Ward, Keith W; Klaassen, Curtis D; Meyer, Colin J

    2013-07-01

    1. The transcription factor Nrf2 is important for hepatoprotection against oxidative stress, as it regulates many cytoprotective genes, including several important for glutathione (GSH) homeostasis. In addition to being an important endogenous antioxidant, GSH is also critical for the maintenance of bile acid-independent bile flow. While it has been well-established that synthetic oleanane triterpenoids pharmacologically activate Nrf2, their effects on bile flow and hepatic cytoprotective capacity have not been fully explored. 2. The present studies were conducted to evaluate the effects of a compound in this class, CDDO-9,11-dihydro-trifluoroethyl amide (CDDO-dhTFEA), on these parameters. CDDO-dhTFEA at 3, 10 or 30 mg/kg was orally administered to bile duct-cannulated rats once daily for 7 days, with bile collected 5 h after each dose for 1 h. Livers were harvested after the final bile collection for the evaluation of histology and Nrf2 targets. 3. CDDO-dhTFEA did not affect liver histology. CDDO-dhTFEA markedly and dose-dependently increased bile flow, as well as the biliary excretion of GSH, cholesterol and phospholipids without affecting biliary excretion of bile acids. This was accompanied by dose-dependent increases in mRNA expression and/or enzyme activity of a broad panel of cytoprotective Nrf2 target genes, including NAD(P)H quinone oxidoreductase 1 (Nqo1), thioredoxin reductase (Txnrd), sulfiredoxin 1(Srxn1), glutamate cysteine ligase catalytic and modifier subunits (Gclc and Gclm), glutathione reductase (Gsr), gamma-glutamyl transpeptidase 1 (Ggt1), heme oxygenase-1 (Ho-1) and epoxide hydrolase-1 (Eh-1). 4. These data further demonstrate the important hepatobiliary attributes of oleanane synthetic triterpenoids and support their continued investigation for liver diseases. PMID:23244591

  20. The role of bile carcinoembryonic antigen in diagnosing bile duct cancer.

    PubMed Central

    Joo, Kwang Ro; Kim, Do Ha; Park, Jong Ho; Bang, Sung-Jo; Shin, Jung Woo; Park, Neung Hwa; Park, Jae Hoo

    2003-01-01

    It is known that the fluids bathing tumors might contain a higher level of the carcinoembryonic antigen (CEA) than those found in the blood. Therefore, we evaluated the role of bile CEA in diagnosing bile duct cancer. One hundred and thirty two patients were prospectively studied. The patients were divided into 3 groups: the bile duct cancer (n=32), pancreatic cancer (n=16), and benign biliary diseases (n=84) groups. Bile samples were obtained on the next day of the biliary drainage procedures. The mean bile CEA level in those with bile duct cancer (120.6 +/- 156.9 ng/mL) was significantly higher than those with pancreatic cancer and benign biliary diseases (32.0 +/- 28.5 ng/mL, 29.3 +/- 56.3 ng/mL). Using the level of 20 ng/mL, the sensitivity and specificity of bile CEA in the diagnosis of bile duct cancer from benign biliary diseases were 65.6% and 66.7%, respectively. Both the bile CEA and total bilirubin level were found to be an independent factor linked to bile duct cancer. This study result suggests that bile CEA level is a useful supplementary test for diagnosing bile duct cancer. PMID:14676443

  1. Genetics Home Reference: congenital bile acid synthesis defect type 1

    MedlinePlus

    ... bile acid synthesis defect type 1 congenital bile acid synthesis defect type 1 Enable Javascript to view ... PDF Open All Close All Description Congenital bile acid synthesis defect type 1 is a disorder characterized ...

  2. Genetics Home Reference: congenital bile acid synthesis defect type 2

    MedlinePlus

    ... bile acid synthesis defect type 2 congenital bile acid synthesis defect type 2 Enable Javascript to view ... PDF Open All Close All Description Congenital bile acid synthesis defect type 2 is a disorder characterized ...

  3. Bile salts of the West Indian manatee, Trichechus manatus latirostris: novel bile alcohol sulfates and absence of bile acids.

    PubMed

    Kuroki, S; Schteingart, C D; Hagey, L R; Cohen, B I; Mosbach, E H; Rossi, S S; Hofmann, A F; Matoba, N; Une, M; Hoshita, T

    1988-04-01

    The bile salts present in gallbladder bile of the West Indian manatee, Trichechus manatus latirostris, an herbivorous marine mammal of the tropical and subtropical margins of the Atlantic Ocean, were found to consist of a mixture of bile alcohol sulfates. Bile acids, previously believed to be present in all mammals, were not detected. Using chromatography, mass spectrometry, and 1H- and 13C-nuclear magnetic resonance spectroscopy, the major bile alcohol was identified as 5 beta-cholestane-3 alpha,6 beta,7 alpha-25,26-pentol; that is, it had the nuclear structure of alpha-muricholic acid and the side chain structure of bufol. This compound has not been described previously and the trivial name "alpha-trichechol" is proposed. The second most abundant compound was 5 beta-cholestane-3 alpha,7 alpha,25,26-tetrol. Other bile alcohols were tentatively identified as 5 beta-cholestane-3 alpha,6 beta,7 beta,25,26-pentol (named beta-trichechol), 3 alpha,6 alpha,7 beta, 25-26-pentol (named omega-trichechol) and 5 beta-cholestane-3 alpha,6 beta,7 alpha,26-tetrol. The 1H and 13C NMR spectra of the four 6,7 epimers of 3,6,7 trihydroxy bile acids are described and discussed. All bile alcohols were present as ester sulfates, the sulfate group being tentatively assigned to the 26-hydroxy group. 12-Hydroxy compounds were not detected. The manatee is the first mammal found to lack bile acids, presumably because it lacks the enzymes required for oxidation of the 26-hydroxy group to a carboxylic acid. Trichechols, like other bile salts, are water-soluble end products of cholesterol metabolism; whether they also function as biological surfactants in promoting biliary cholesterol secretion or lipid digestion is unknown. PMID:3392467

  4. Protection of live bacteria from bile acid toxicity using bile acid adsorbing resins.

    PubMed

    Edwards, Alexander D; Slater, Nigel K H

    2009-06-12

    We previously demonstrated that a dry, room temperature stable formulation of a live bacterial vaccine was highly susceptible to bile, and suggested that this will lead to significant loss of viability of any live bacterial formulation released into the intestine using an enteric coating or capsule. We found that bile and acid tolerance is very rapidly recovered after rehydration with buffer or water, raising the possibility that rehydration in the absence of bile prior to release into the intestine might solve the problem of bile toxicity to dried cells. We describe here a novel formulation that combines extensively studied bile acid adsorbent resins with the dried bacteria, to temporarily adsorb bile acids and allow rehydration and recovery of bile resistance of bacteria in the intestine before release. Tablets containing the bile acid adsorbent cholestyramine release 250-fold more live bacteria when dissolved in a bile solution, compared to control tablets without cholestyramine or with a control resin that does not bind bile acids. We propose that a simple enteric coated oral dosage form containing bile acid adsorbent resins will allow improved live bacterial delivery to the intestine via the oral route, a major step towards room temperature stable, easily administered and distributed vaccine pills and other bacterial therapeutics. PMID:19490986

  5. Circadian dysregulation disrupts bile acid homeostasis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bile acids are potentially toxic compounds and their levels of hepatic production, uptake, and export are tightly regulated by many inputs, including circadian rhythm. We tested the impact of disrupting the peripheral circadian clock on integral steps of bile acid homeostasis. Both restricted feedi...

  6. Bile Flow Phantom Model and Animal Bile Duct Dilation Model for Evaluating Biliary Plastic Stents with Advanced Hydrophilic Coating

    PubMed Central

    Kwon, Chang-Il; Kim, Gwangil; Jeong, Seok; Lee, Won Seop; Lee, Don Haeng; Ko, Kwang Hyun; Hong, Sung Pyo; Hahm, Ki Baik

    2016-01-01

    Background/Aims The efforts to improve biliary plastic stents (PSs) for decreasing biofilm formation and overcome short patency time have been continued. The aim of this study is to evaluate the effect of advanced hydrophilic coating for patency and biodurability of PS. Methods Using an in vitro bile flow phantom model, we compared patency between prototype PS with hydrophilic coating (PS+HC) and prototype PS without hydrophilic coating (PS−HC). We performed an analysis of the degree of luminal narrowing by microscopic examination. Using an in vivo swine bile duct dilation model made by endoscopic papillary closure and stent insertion, we evaluated biodurability of hydrophilic coating. Results In the phantom model, PS+HC showed less biofilm formation and luminal narrowing than PS−HC at 8 weeks (p<0.05). A total of 31 stents were inserted into the dilated bile duct of seven swine models, and 24 stents were successfully retrieved 8 weeks later. There was no statistical difference of stent patency between the polyethylene PS+HC and the polyurethane PS+HC. The biodurability of hydrophilic coating was sustained up to 8 weeks, when assessing the coating layer by scanning electron microscopy examination. Conclusions Advanced hydrophilic coating technology may extend the patency of PS compared to uncoated PS. PMID:27021507

  7. Acute bile nephropathy secondary to anabolic steroids.

    PubMed

    Alkhunaizi, Ahmed M; ElTigani, Mohamed A; Rabah, Rola S; Nasr, Samih H

    2016-02-01

    Renal dysfunction in cholestatic liver disease is multifactorial. Acute kidney injury may develop secondary to renal vasoconstriction in the setting of peripheral vasodilation and relative hypovolemia, tubular obstruction by bile casts, and direct tubular toxicity from bile. Anabolic steroids are frequently used by athletes to boost endurance and increase muscle mass. These agents are a recently recognized cause of hepatotoxicity and jaundice and may lead to acute kidney injury. To increase awareness about this growing problem and to characterize the pathology of acute kidney injury in this setting, we report on a young male who developed acute kidney injury in the setting of severe cholestatic jaundice related to ingestion of anabolic steroids used for bodybuilding. Kidney biopsy showed bile casts within distal tubular lumina, filamentous bile inclusions within tubular cells, and signs of acute tubular injury. This report supports the recently re-emerged concept of bile nephropathy cholemic nephrosis. PMID:26587777

  8. Bile acids in radiation-induced diarrhea

    SciTech Connect

    Arlow, F.L.; Dekovich, A.A.; Priest, R.J.; Beher, W.T.

    1987-10-01

    Radiation-induced bowel disease manifested by debilitating diarrhea is an unfortunate consequence of therapeutic irradiation for pelvic malignancies. Although the mechanism for this diarrhea is not well understood, many believe it is the result of damage to small bowel mucosa and subsequent bile acid malabsorption. Excess amounts of bile acids, especially the dihydroxy components, are known to induce water and electrolyte secretion and increase bowel motility. We have directly measured individual and total bile acids in the stool samples of 11 patients with radiation-induced diarrhea and have found bile acids elevated two to six times normal in eight of them. Our patients with diarrhea and increased bile acids in their stools had prompt improvement when given cholestyramine. They had fewer stools and returned to a more normal life-style.

  9. Bile acid dissolution therapy of gallbladder stones.

    PubMed

    Fromm, H; Malavolti, M

    1992-11-01

    Oral cholelitholytic bile acid therapy has become established treatment for selected patients with cholesterol gallstones. The treatment finds its clinical application both alone and in combination with ESWL. UDCA alone or, less commonly, a combination of this bile acid with CDCA is used. Optimal results can be expected only in carefully selected patients. Bile acid dissolution therapy is most successful in patients with radiolucent gallstones which are < or = 0.5 cm in diameter or are shown by OCG to be floating. Dissolution is seldom seen when the stones are > 1 cm in size. Cholelitholytic treatment in combination with ESWL yields optimal results in single radiolucent gallstones which are not greater than 2 cm. ESWL thus makes it possible to use medical treatment effectively in single 1-2 cm gallstones when bile acids alone would not be successful. Bile acid treatment is extremely safe, especially if UDCA is given without the addition of CDCA. PMID:1486209

  10. Bile resistance mechanisms in Lactobacillus and Bifidobacterium

    PubMed Central

    Ruiz, Lorena; Margolles, Abelardo; Sánchez, Borja

    2013-01-01

    Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Most of the probiotic bacteria currently available in the market belong to the genera Lactobacillus and Bifidobacterium, and specific health-promoting activities, such as treatment of diarrhea or amelioration of gastrointestinal discomfort, have been attributed to them. In order to be able to survive the gastrointestinal transit and transiently colonize our gut, these bacteria must be able to counteract the deleterious action of bile salts, which are the main components of bile. Bile salts are detergent-like biological substances synthesized in the liver from cholesterol. Host enzymes conjugate the newly synthesized free bile acids in the liver with the amino acids glycine or taurine, generating conjugated bile salts. These compounds are stored in the gall bladder and they are released into the duodenum during digestion to perform their physiological function, which is the solubilization of fat coming from diet. These bile salts possess strong antimicrobial activity, since they are able to disorganize the structure of the cell membrane, as well as trigger DNA damage. This means that bacteria inhabiting our intestinal tract must have intrinsic resistance mechanisms to cope with bile salts. To do that, Lactobacillus and Bifidobacterium display a variety of proteins devoted to the efflux of bile salts or protons, to modify sugar metabolism or to prevent protein misfolding. In this manuscript, we review and discuss specific bile resistance mechanisms, as well as the processes responsible for the adaptation of bifidobacteria and lactobacilli to bile. PMID:24399996

  11. Bile resistance mechanisms in Lactobacillus and Bifidobacterium.

    PubMed

    Ruiz, Lorena; Margolles, Abelardo; Sánchez, Borja

    2013-01-01

    Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Most of the probiotic bacteria currently available in the market belong to the genera Lactobacillus and Bifidobacterium, and specific health-promoting activities, such as treatment of diarrhea or amelioration of gastrointestinal discomfort, have been attributed to them. In order to be able to survive the gastrointestinal transit and transiently colonize our gut, these bacteria must be able to counteract the deleterious action of bile salts, which are the main components of bile. Bile salts are detergent-like biological substances synthesized in the liver from cholesterol. Host enzymes conjugate the newly synthesized free bile acids in the liver with the amino acids glycine or taurine, generating conjugated bile salts. These compounds are stored in the gall bladder and they are released into the duodenum during digestion to perform their physiological function, which is the solubilization of fat coming from diet. These bile salts possess strong antimicrobial activity, since they are able to disorganize the structure of the cell membrane, as well as trigger DNA damage. This means that bacteria inhabiting our intestinal tract must have intrinsic resistance mechanisms to cope with bile salts. To do that, Lactobacillus and Bifidobacterium display a variety of proteins devoted to the efflux of bile salts or protons, to modify sugar metabolism or to prevent protein misfolding. In this manuscript, we review and discuss specific bile resistance mechanisms, as well as the processes responsible for the adaptation of bifidobacteria and lactobacilli to bile. PMID:24399996

  12. Kinetic analysis of bile acid sulfation by stably expressed human sulfotransferase 2A1 (SULT2A1).

    PubMed

    Huang, J; Bathena, S P; Tong, J; Roth, M; Hagenbuch, B; Alnouti, Y

    2010-03-01

    Human sulfotransferase 2A1 (SULT2A1) is a member of the hydroxysteroid sulfotransferase (SULT2) family that mediates sulfo-conjugation of a variety of endogenous molecules including dehydroepiandrosterone (DHEA) and bile acids. In this study, we have constructed a stable cell line expressing SULT2A1 by transfection into HEK293 cells. The expression system was used to characterize and compare the sulfation kinetics of DHEA and 15 human bile acids by SULT2A1. Formation of DHEA sulfate demonstrated Michaelis-Menten kinetics with apparent K(m) and V(max) values of 3.8 muM and 130.8 pmol min(-1) mg(-1) protein, respectively. Sulfation kinetics of bile acids also demonstrated Michaelis-Menten kinetics with a marked variation in apparent K(m) and V(max) values between individual bile acids. Sulfation affinity was inversely proportional to the number of hydroxyl groups of bile acids. The monohydroxy- and most toxic bile acid (lithocholic acid) had the highest affinity, whereas the trihydroxy- and least toxic bile acid (cholic acid) had the lowest affinity to sulfation by SULT2A1. Intrinsic clearance (CL(int)) of ursodeoxycholic acid (UDCA) was approximately 1.5- and 9.0-fold higher than that of deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), respectively, despite the fact that all three are dihydroxy bile acids. PMID:20102295

  13. Novel naproxen/esomeprazole magnesium compound pellets based on acid-independent mechanism: in vitro and in vivo evaluation.

    PubMed

    Lu, Jing; Kan, Shuling; Zhao, Yi; Zhang, Wenli; Liu, Jianping

    2016-09-01

    The purpose of this study was to develop the novel naproxen/esomeprazole magnesium compound pellets (novel-NAP/EMZ) depending on EMZ acid-independent mechanism which has been proved to be predominate in the mechanism of co-therapy with nonsteroidal anti-inflammatory drug. The novel-NAP/EMZ compound pellets, composed of NAP colon-specific pellets (NAP-CSPs) and EMZ modified-release pellets (EMZ-MRPs), were prepared by fluid-bed coating technology with desired in vitro release profiles. The resulting pellets were filled into hard gelatin capsules for in vivo evaluation in rats and compared with the reference compound pellets, consisted of NAP enteric-coated pellets (NAP-ECPs) and EMZ immediate-release pellets (EMZ-IRPs). The reference compound pellets were prepared simulating the drug delivery system of VIMOVO(®). In vivo pharmacokinetics, EMZ-MRPs had significantly larger AUC0-t (p < 0.01), 1.67 times more than that of EMZ-IRPs, and prolonged mean residence time (7.55 ± 0.12 h) than that of IRPs (1.46 ± 0.39 h). NAP-CSPs and NAP-ECPs showed similar AUC0-t. Compared to the reference compound pellets, the novel-NAP/EMZ compound pellets did not show distinct differences in histological mucosal morphology. However, biochemical tests exhibited enhanced total antioxidant capacity, increased nitric oxide content and reduced malondialdehyde level for novel-NAP/EMZ compound pellets, indicating that the acid-independent action took effect. The gastric pH values of novel-NAP/EMZ compound pellets were at a low and stable level, which could ensure normal physiological range of human gastric pH. As a result, the novel-NAP/EMZ compound pellets may be a more suitable formulation with potential advantages by improving bioavailability of drug and further reducing undesirable gastrointestinal damages. PMID:26902772

  14. A simple and accurate HPLC method for fecal bile acid profile in healthy and cirrhotic subjects: validation by GC-MS and LC-MS[S

    PubMed Central

    Kakiyama, Genta; Muto, Akina; Takei, Hajime; Nittono, Hiroshi; Murai, Tsuyoshi; Kurosawa, Takao; Hofmann, Alan F.; Pandak, William M.; Bajaj, Jasmohan S.

    2014-01-01

    We have developed a simple and accurate HPLC method for measurement of fecal bile acids using phenacyl derivatives of unconjugated bile acids, and applied it to the measurement of fecal bile acids in cirrhotic patients. The HPLC method has the following steps: 1) lyophilization of the stool sample; 2) reconstitution in buffer and enzymatic deconjugation using cholylglycine hydrolase/sulfatase; 3) incubation with 0.1 N NaOH in 50% isopropanol at 60°C to hydrolyze esterified bile acids; 4) extraction of bile acids from particulate material using 0.1 N NaOH; 5) isolation of deconjugated bile acids by solid phase extraction; 6) formation of phenacyl esters by derivatization using phenacyl bromide; and 7) HPLC separation measuring eluted peaks at 254 nm. The method was validated by showing that results obtained by HPLC agreed with those obtained by LC-MS/MS and GC-MS. We then applied the method to measuring total fecal bile acid (concentration) and bile acid profile in samples from 38 patients with cirrhosis (17 early, 21 advanced) and 10 healthy subjects. Bile acid concentrations were significantly lower in patients with advanced cirrhosis, suggesting impaired bile acid synthesis. PMID:24627129

  15. Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats.

    PubMed

    Cummings, Bethany P; Bettaieb, Ahmed; Graham, James L; Kim, Jaehyoung; Ma, Fangrui; Shibata, Noreene; Stanhope, Kimber L; Giulivi, Cecilia; Hansen, Frederik; Jelsing, Jacob; Vrang, Niels; Kowala, Mark; Chouinard, Michael L; Haj, Fawaz G; Havel, Peter J

    2013-03-01

    Post-operative increases in circulating bile acids have been suggested to contribute to the metabolic benefits of bariatric surgery; however, their mechanistic contributions remain undefined. We have previously reported that ileal interposition (IT) surgery delays the onset of type 2 diabetes in UCD-T2DM rats and increases circulating bile acids, independently of effects on energy intake or body weight. Therefore, we investigated potential mechanisms by which post-operative increases in circulating bile acids improve glucose homeostasis after IT surgery. IT, sham or no surgery was performed on 2-month-old weight-matched male UCD-T2DM rats. Animals underwent an oral fat tolerance test (OFTT) and serial oral glucose tolerance tests (OGTT). Tissues were collected at 1.5 and 4.5 months after surgery. Cell culture models were used to investigate interactions between bile acids and ER stress. IT-operated animals exhibited marked improvements in glucose and lipid metabolism, with concurrent increases in postprandial glucagon-like peptide-1 (GLP-1) secretion during the OFTT and OGTTs, independently of food intake and body weight. Measurement of circulating bile acid profiles revealed increases in circulating total bile acids in IT-operated animals, with a preferential increase in circulating cholic acid concentrations. Gut microbial populations were assessed as potential contributors to the increases in circulating bile acid concentrations, which revealed proportional increases in Gammaproteobacteria in IT-operated animals. Furthermore, IT surgery decreased all three sub-arms of ER stress signaling in liver, adipose and pancreas tissues. Amelioration of ER stress coincided with improved insulin signaling and preservation of β-cell mass in IT-operated animals. Incubation of hepatocyte, adipocyte and β-cell lines with cholic acid decreased ER stress. These results suggest that postoperative increases in circulating cholic acid concentration contribute to improvements in

  16. Protection of dried probiotic bacteria from bile using bile adsorbent resins.

    PubMed

    Mahbubani, Krishnaa T; Slater, Nigel K H; Edwards, Alexander D

    2014-01-25

    Enteric coated oral tablets or capsules can deliver dried live cells directly into the intestine. Previously, we found that a live attenuated bacterial vaccine acquired sensitivity to intestinal bile when dried, raising the possibility that although gastric acid can be bypassed, significant loss of viability might occur on release from an enteric coated oral formulations. Here we demonstrate that some food-grade lyophilised preparations of Lactobacillus casei and Lactobacillus salivarius also show temporary bile sensitivity that can be rapidly reversed by rehydration. To protect dried bacterial cells from temporary bile sensitivity, we propose using bile acid adsorbing resins, such as cholestyramine, which are bile acid binding agents, historically used to lower cholesterol levels. Vcaps™ HPMC capsules alone provided up to 830-fold protection from bile. The inclusion of 50% w/w cholestyramine in Vcaps™ HPMC capsules resulted in release of up to 1700-fold more live Lactobacillus casei into simulated intestinal fluid containing 1% bile, when compared to dried cells added directly to bile. We conclude that delivery of dried live probiotic organisms to the intestine may be improved by providing protection from bile by addition of bile adsorbing resins and the use of HPMC capsules. PMID:24080386

  17. Separation by thin-layer chromatography and structure elucidation of bilirubin conjugates isolated from dog bile.

    PubMed Central

    Heirwegh, K P; Fevery, J; Michiels, R; van Hees, G P; Compernolle, F

    1975-01-01

    1. A system for separation of bile pigments by t.l.c. and for their structure elucidation is presented. Separated bile pigments are characterized by t.l.c. of derived dipyrrolic azopigments. 2. At the tetrapyrrolic stage hydrolysis in strongly alkaline medium followed by t.l.c. demonstrates the presence of bilirubin-IIIalpha, -IXalpha and -XIIIalpha and allows assessment of their relative amounts. 3. Most structural information is derived from analysis of dipyrrolic azopigments. Such derivatives, obtained by treatment of separated bile pigments with diazotized ethyl anthranilate, were separated and purified by t.l.c. Micro methods showed (a) the nature of the dipyrrolic aglycone, (b) the nature of the bonds connecting aglycone to a conjugating group, (c) the ratio of vinyl/isovinyl isomers present in the aglycone and, (d) the nature of the conjugating groups (by suitable derivative formation and t.l.c. with reference to known compounds). 4. In bile of normal dogs at least 20 tetrapyrrolic, diazo-positive bile pigments could be recognized. Except for two pigments the tetrapyrrolic nucleus corresponded predominantly to bilirubin-IXalpha. All conjugated pigments had their conjugating groups connected in ester linkage to the tetrapyrrolic aglycone, Apart from bilirubin-IXalpha, monoconjugates and homogeneous and mixed diconjugates of bilirubin were demonstrated; conjugating groups of major importance were xylose, glucose and glucuronic acid. 5. Bilirubin isomer determination on native bile and isolated bile pigments, and dipyrrole-exchange assays with [14C8]bilirubin indicated (a) that the conjugates pre-exist in bile, and (b) that no significant dipyrrole exchange occurs during isolation of the pigments. PMID:1156357

  18. Chylomicrons enhance endotoxin excretion in bile.

    PubMed Central

    Read, T E; Harris, H W; Grunfeld, C; Feingold, K R; Calhoun, M C; Kane, J P; Rapp, J H

    1993-01-01

    Chylomicrons prevent endotoxin toxicity and increase endotoxin uptake by hepatocytes. As a consequence, less endotoxin is available to activate macrophages, thereby reducing tumor necrosis factor secretion. To determine whether the chylomicron-mediated increase in hepatocellular uptake of endotoxin results in increased endotoxin excretion into bile, we examined bile after endotoxin administration. A sublethal dose (7 micrograms/kg) of 125I-endotoxin was incubated with either rat mesenteric lymph containing nascent chylomicrons (500 mg of chylomicron triglyceride per kg of body weight) or an equal volume of normal saline (controls) for 3 h and then infused into male Sprague-Dawley rats. Bile samples were collected via a common bile duct catheter for 24 h. Infusion of endotoxin incubated with chylomicrons increased biliary excretion of endotoxin by 67% at 3 h (P < or = 0.006) and by 20% at 24 h (P < or = 0.01) compared with infusion of endotoxin incubated in saline. Endotoxin activity, as measured by the Limulus assay, was not detected in the bile of test animals. However, endotoxin activity was detected after hot phenol-water extraction of bile, demonstrating that endotoxin is inactive in the presence of bile but retains bioactivity after hepatic processing. Since the majority of an intravenous endotoxin load has been shown to be cleared by the liver, acceleration of hepatocyte clearance and biliary excretion of endotoxin may represent a component of the mechanism by which chylomicrons protect against endotoxin-induced lethality. PMID:8335381

  19. Structure of plant bile pigments

    SciTech Connect

    Schoenleber, R.W.

    1983-12-01

    Selective peptide cleavage has provided a general procedure for the study of the structure, including stereochemistry, of plant bile pigments. The information derived from the synthesis and spectral analysis of a series of 2,3-dihydrodioxobilins allows the determination of the trans relative stereochemistry for ring A of the ..beta../sub 1/-phycocyanobilin from C-phycocyanin as well as for ring A of phytochrome. A complete structure proof of the five phycoerythrobilins attached to the ..cap alpha.. and ..beta.. subunits of B-phycoerythrin is described. One of these tetrapyrroles is doubly-peptide linked to a single peptide chain through two thioethers at the C-3' and C-18' positions. The four remaining phycoerythrobilins are singly-linked to the protein through thioethers at the C-3' position and all possess the probable stereochemistry C-2(R), C-3(R), C-3'(R), and C-16(R).

  20. Phospholipase C and diacylglycerol lipase in human gallbladder and hepatic bile.

    PubMed

    Pattinson, N R; Willis, K E

    1990-12-01

    A phospholipase C in bile, free of bacterial infection, has recently been identified from cholesterol gallstone patients. Because of the importance of phosphatidylcholine in solubilizing cholesterol in bile, this study further investigates the metabolism of phosphatidylcholine in delipidated gallbladder and common bile duct biles. Phospholipase C activity, as measured by the release of phosphoryl[3H]choline from the substrate 1,2-dipalmitoyl-sn-glycero-3-phospho [N-methyl-3H]choline, was identified in both hepatic and gallbladder biles. Similar levels of activity (nmol.h-1.mg-1 of delipidated protein) were found in common bile duct (11.25 +/- 14.23) and gallbladder bile (19.07 +/- 22.24), although per milliliter of bile, the mean gallbaldder levels were 6.4 times greater than those found in common duct bile. With the tow substrates, 1-palmitoyl-2[9,10-3H] palmitoyl-sn-glycero-3-phosphocholine and 1,2(1-14C) dipalmitoyl-sn-glycero-3-phosphocholine, the majority of organically extracted label, after thin-layer chromatography, was recovered as radiolabeled diglyceride, confirming the presence of phospholipase C. Diglyceride levels were found to be closely correlated with [3H]choline (slope, 0.9820; r = 0.9844). In addition to diglyceride, both radiolabeled free fatty acid and monoglyceride were identified in common bile duct and gallbladder biles, although their levels were an order of magnitude less than measurable phospholipase C activity. To determine whether the free fatty acid release was due to either a diacylglycerol-lipase or a phospholipase A2, the effect of adding unlabeled diglyceride on free fatty acid formation from the substrate [14C]DPPC was examined. As the concentration of unlabeled diglyceride was increased, the amount of free fatty acid and monoglyceride released were both reduced in parallel. Direct measurement of diacylglycerol-lipase activity by incubating the diglyceride, sn-2[3H]dipalmitoyl, resulted in release of both products in a ratio

  1. Nuclear receptors, bile acids and cholesterol homeostasis series - bile acids and pregnancy.

    PubMed

    Abu-Hayyeh, Shadi; Papacleovoulou, Georgia; Williamson, Catherine

    2013-04-10

    Bile acids have been traditionally thought of as having an important role in fat emulsification. It is now emerging that they act as important signalling molecules that not only autoregulate their own synthesis but also influence lipid and glucose metabolism. Although, the mechanisms that underlie the regulation of bile acid homeostasis have been well characterised in normal physiology, the impact of pregnancy on bile acid regulation is still poorly understood. This review summarises the main regulatory mechanisms underlying bile acid homeostasis and discusses how pregnancy, a unique physiological state, can modify them. The fetoplacental adaptations that protect against fetal bile acid toxicity are reviewed. We highlight the importance of bile acid regulation during gestation by discussing the liver disease of pregnancy, intrahepatic cholestasis of pregnancy (ICP) and how genetic, endocrine and environmental factors contribute to the disease aetiology at a cellular and molecular level. PMID:23159988

  2. The ulcerogenic effect of bile and bile acid in rats during immobilization stress

    NASA Technical Reports Server (NTRS)

    Weisener, J.

    1980-01-01

    The effect of different concentrations of oxen bile and individual bile acids or their sodium salts on the gastric mucosa of rats was investigated in combination with immobilization stress. A statistically significant higher frequency of ulcers was only determined in the application of 10% oxen bile. Dosages on 10% sodium glycocholic acid demonstrated strong toxic damage with atonic dilation of the stomach and extensive mucosal bleeding.

  3. How Is Bile Duct Cancer Diagnosed?

    MedlinePlus

    ... line through which a different kind of contrast dye (IV contrast) is injected. This helps better outline ... common bile duct. A small amount of contrast dye is injected through the tube to help outline ...

  4. Nuclear receptors in bile acid metabolism

    PubMed Central

    Li, Tiangang; Chiang, John Y. L.

    2013-01-01

    Bile acids are signaling molecules that activate nuclear receptors, such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism. These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system. Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity. Bile-acid–based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease. PMID:23330546

  5. Treatment Options for Extrahepatic Bile Duct Cancer

    MedlinePlus

    ... checked to measure the amounts of bilirubin and alkaline phosphatase released into the blood by the liver. ... which a stent (a thin, flexible tube or metal tube) is placed in the bile duct to ...

  6. Treatment Option Overview (Extrahepatic Bile Duct Cancer)

    MedlinePlus

    ... checked to measure the amounts of bilirubin and alkaline phosphatase released into the blood by the liver. ... which a stent (a thin, flexible tube or metal tube) is placed in the bile duct to ...

  7. Stages of Extrahepatic Bile Duct Cancer

    MedlinePlus

    ... checked to measure the amounts of bilirubin and alkaline phosphatase released into the blood by the liver. ... which a stent (a thin, flexible tube or metal tube) is placed in the bile duct to ...

  8. Bile Duct (Cholangiocarcinoma) Cancer: Radiation Therapy

    MedlinePlus

    ... form of radiation for bile duct cancer. External beam radiation therapy (EBRT) This type of radiation therapy ... determine the correct angles for aiming the radiation beams and the proper dose of radiation. The treatment ...

  9. Intraoperative cholangiography and bile duct injury.

    PubMed

    Sarli, L; Costi, R; Roncoroni, L

    2006-01-01

    We are not in agreement with the opinion that the credit for excellent results after laparoscopic cholecystectomy is to be attributed to the routine performing of intraoperative cholangiography. We performed 2538 laparoscopic cholecystectomies without routine intraoperative cholangiography and we obtained very low rate and severity of common bile duct injuries: there was a total of four common bile duct injuries (0.16%), in no case was the injury a major transaction, and injuries were detected intraoperatively and easily repaired with a T-tube. Cholangiography could prevent bile duct transaction, but that it is not necessary for intraoperative cholangiography to be routinely performed for this purpose. It is sufficient for intraoperative cholangiography to be performed whenever the surgeon is in doubt as to the biliary anatomy or common bile duct clearance, and that when dissection of the cholecystic peduncle proves difficult he does not hesitate to convert to open access. PMID:16333543

  10. Bile acid signaling and biliary functions

    PubMed Central

    Jones, Hannah; Alpini, Gianfranco; Francis, Heather

    2015-01-01

    This review focuses on various components of bile acid signaling in relation to cholangiocytes. Their roles as targets for potential therapies for cholangiopathies are also explored. While many factors are involved in these complex signaling pathways, this review emphasizes the roles of transmembrane G protein coupled receptor (TGR5), farnesoid X receptor (FXR), ursodeoxycholic acid (UDCA) and the bicarbonate umbrella. Following a general background on cholangiocytes and bile acids, we will expand the review and include sections that are most recently known (within 5–7 years) regarding the field of bile acid signaling and cholangiocyte function. These findings all demonstrate that bile acids influence biliary functions which can, in turn, regulate the cholangiocyte response during pathological events. PMID:26579437

  11. The role of peroxisomal fatty acyl-CoA beta-oxidation in bile acid biosynthesis

    SciTech Connect

    Hayashi, H.; Miwa, A. )

    1989-11-01

    The physiological role of the peroxisomal fatty acyl-CoA beta-oxidizing system (FAOS) is not yet established. We speculated that there might be a relationship between peroxisomal degradation of long-chain fatty acids in the liver and the biosynthesis of bile acids. This was investigated using (1-{sup 14}C)butyric acid and (1-{sup 14}C)lignoceric acid as substrates of FAOS in mitochondria and peroxisomes, respectively. The incorporation of ({sup 14}C)lignoceric acid into primary bile acids was approximately four times higher than that of ({sup 14}C)butyric acid (in terms of C-2 units). The pools of these two fatty acids in the liver were exceedingly small. The incorporations of radioactivity into the primary bile acids were strongly inhibited by administration of aminotriazole, which is a specific inhibitor of peroxisomal FAOS in vivo. Aminotriazole inhibited preferentially the formation of cholate, the major primary bile acid, from both ({sup 14}C)lignoceric acid and ({sup 14}C)butyric acid, rather than the formation of chenodeoxycholate. The former inhibition was about 70% and the latter was approximately 40-50%. In view of reports that cholate is biosynthesized from endogenous cholesterol, the above results indicate that peroxisomal FAOS may have an anabolic function, supplying acetyl CoA for bile acid biosynthesis.

  12. Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion

    PubMed Central

    Martin, Gregory G.; Atshaves, Barbara P.; Landrock, Kerstin K.; Landrock, Danilo; Storey, Stephen M.; Howles, Philip N.; Kier, Ann B.

    2014-01-01

    On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In contrast, LKO increased biliary bile acid, while DKO and TKO had no effect on biliary bile acid levels. LKO and DKO also altered biliary bile acid composition to increase bile acid hydrophobicity. Furthermore, LKO and TKO decreased hepatic uptake and biliary secretion of high-density lipoprotein (HDL)-derived 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol), while DKO alone had no effect. Finally, LKO and, to a lesser extent, DKO decreased most indexes contributing to cholesterol solubility in biliary bile. These results suggest different, but complementary, roles for L-FABP and SCP-2/SCP-x in biliary bile acid and cholesterol formation. L-FABP appears to function more in hepatic retention of bile acids as well as hepatic uptake and biliary secretion of HDL-cholesterol. Conversely, SCP-2/SCP-x may function more in formation and biliary secretion of bile acid, with less impact on hepatic uptake or biliary secretion of HDL-cholesterol. PMID:25277800

  13. Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion.

    PubMed

    Martin, Gregory G; Atshaves, Barbara P; Landrock, Kerstin K; Landrock, Danilo; Storey, Stephen M; Howles, Philip N; Kier, Ann B; Schroeder, Friedhelm

    2014-12-01

    On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In contrast, LKO increased biliary bile acid, while DKO and TKO had no effect on biliary bile acid levels. LKO and DKO also altered biliary bile acid composition to increase bile acid hydrophobicity. Furthermore, LKO and TKO decreased hepatic uptake and biliary secretion of high-density lipoprotein (HDL)-derived 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol), while DKO alone had no effect. Finally, LKO and, to a lesser extent, DKO decreased most indexes contributing to cholesterol solubility in biliary bile. These results suggest different, but complementary, roles for L-FABP and SCP-2/SCP-x in biliary bile acid and cholesterol formation. L-FABP appears to function more in hepatic retention of bile acids as well as hepatic uptake and biliary secretion of HDL-cholesterol. Conversely, SCP-2/SCP-x may function more in formation and biliary secretion of bile acid, with less impact on hepatic uptake or biliary secretion of HDL-cholesterol. PMID:25277800

  14. Limy Bile Syndrome Complicated with Primary Hyperparathyroidism

    PubMed Central

    Koca, Yavuz Savas; Koca, Tugba; Barut, Ibrahim

    2015-01-01

    Limy bile is a relatively rare condition, in which a radiopaque material is visible in the gallbladder on plain radiography or computerized tomography. Cases of complicated hyperparathyroidism are extremely rare. We report a patient with right upper quadrant and epigastric pain and extremity weakness in whom abdominal tomography showed limy bile in the gallbladder and laboratory values showed high levels of serum calcium and parathormone. PMID:25821626

  15. Ion pairing with bile salts modulates intestinal permeability and contributes to food-drug interaction of BCS class III compound trospium chloride.

    PubMed

    Heinen, Christian A; Reuss, Stefan; Amidon, Gordon L; Langguth, Peter

    2013-11-01

    In the current study the involvement of ion pair formation between bile salts and trospium chloride (TC), a positively charged Biopharmaceutical Classification System (BCS) class III substance, showing a decrease in bioavailability upon coadministration with food (negative food effect) was investigated. Isothermal titration calorimetry provided evidence of a reaction between TC and bile acids. An effect of ion pair formation on the apparent partition coefficient (APC) was examined using (3)H-trospium. The addition of bovine bile and bile extract porcine led to a significant increase of the APC. In vitro permeability studies of trospium were performed across Caco-2-monolayers and excised segments of rat jejunum in a modified Ussing chamber. The addition of bile acids led to an increase of trospium permeation across Caco-2-monolayers and rat excised segments by approximately a factor of 1.5. The addition of glycochenodeoxycholate (GCDC) was less effective than taurodeoxycholate (TDOC). In the presence of an olive oil emulsion, a complete extinction of the permeation increasing effects of bile salts was observed. Thus, although there are more bile acids in the intestine in the fed state compared to the fasted state, these are not able to form ion pairs with trospium in fed state, because they are involved in the emulsification of dietary fats. In conclusion, the formation of ion pairs between trospium and bile acids can partially explain its negative food effect. Our results are presumably transferable to other organic cations showing a negative food effect. PMID:23750707

  16. Pharmacology of bile acid receptors: Evolution of bile acids from simple detergents to complex signaling molecules.

    PubMed

    Copple, Bryan L; Li, Tiangang

    2016-02-01

    For many years, bile acids were thought to only function as detergents which solubilize fats and facilitate the uptake of fat-soluble vitamins in the intestine. Many early observations; however, demonstrated that bile acids regulate more complex processes, such as bile acids synthesis and immune cell function through activation of signal transduction pathways. These studies were the first to suggest that receptors may exist for bile acids. Ultimately, seminal studies by many investigators led to the discovery of several bile acid-activated receptors including the farnesoid X receptor, the vitamin D receptor, the pregnane X receptor, TGR5, α5 β1 integrin, and sphingosine-1-phosphate receptor 2. Several of these receptors are expressed outside of the gastrointestinal system, indicating that bile acids may have diverse functions throughout the body. Characterization of the functions of these receptors over the last two decades has identified many important roles for these receptors in regulation of bile acid synthesis, transport, and detoxification; regulation of glucose utilization; regulation of fatty acid synthesis and oxidation; regulation of immune cell function; regulation of energy expenditure; and regulation of neural processes such as gastric motility. Through these many functions, bile acids regulate many aspects of digestion ranging from uptake of essential vitamins to proper utilization of nutrients. Accordingly, within a short time period, bile acids moved beyond simple detergents and into the realm of complex signaling molecules. Because of the important processes that bile acids regulate through activation of receptors, drugs that target these receptors are under development for the treatment of several diseases, including cholestatic liver disease and metabolic syndrome. In this review, we will describe the various bile acid receptors, the signal transduction pathways activated by these receptors, and briefly discuss the physiological processes that

  17. Bile Acids Regulate Cardiovascular Function

    PubMed Central

    Khurana, Sandeep; Raufman, Jean-Pierre; Pallone, Thomas L.

    2011-01-01

    Research over the last decade has uncovered roles for bile acids (BAs) that extend beyond their traditional functions in regulating lipid digestion and cholesterol metabolism. BAs are now recognized as signaling molecules that interact with both plasma membrane and nuclear receptors. Emerging evidence indicates that by interacting with these receptors BAs regulate their own synthesis, glucose and energy homeostasis, and other important physiological events. Herein, we provide a comprehensive review of the actions of BAs on cardiovascular function. In the heart and the systemic circulation, BAs interact with plasma membrane G-protein coupled receptors, e.g. TGR5 and muscarinic receptors, and nuclear receptors, e.g. the farnesoid (FXR) and pregnane (PXR) xenobiotic receptors. BA receptors are expressed in cardiovascular tissue, however, the mechanisms underlying BA-mediated regulation of cardiovascular function remain poorly understood. BAs reduce heart rate by regulating channel conductance and calcium dynamics in sino-atrial and ventricular cardiomyocytes, and regulate vascular tone via both endothelium-dependent and -independent mechanisms. End-stage-liver disease, obstructive jaundice and intrahepatic cholestasis of pregnancy are prominent conditions in which elevated serum BAs alter vascular dynamics. This review focuses on BAs as newly-recognized signaling molecules that modulate cardiovascular function. PMID:21707953

  18. Slc10a2-null mice uncover colon cancer-promoting actions of endogenous fecal bile acids.

    PubMed

    Raufman, Jean-Pierre; Dawson, Paul A; Rao, Anuradha; Drachenberg, Cinthia B; Heath, Jonathon; Shang, Aaron C; Hu, Shien; Zhan, Min; Polli, James E; Cheng, Kunrong

    2015-10-01

    Although epidemiological evidence in humans and bile acid feeding studies in rodents implicate bile acids as tumor promoters, the role of endogenous bile acids in colon carcinogenesis remains unclear. In this study, we exploited mice deficient in the ileal apical sodium-dependent bile acid transporter (ASBT, encoded by SLC10A2) in whom fecal bile acid excretion is augmented more than 10-fold. Wild-type and Asbt-deficient (Slc10a2 (-/-) ) male mice were treated with azoxymethane (AOM) alone to examine the development of aberrant crypt foci, the earliest histological marker of colon neoplasia and a combination of AOM and dextran sulfate sodium to induce colon tumor formation. Asbt-deficient mice exhibited a 54% increase in aberrant crypt foci, and 70 and 59% increases in colon tumor number and size, respectively. Compared to littermate controls, Asbt-deficient mice had a striking, 2-fold increase in the number of colon adenocarcinomas. Consistent with previous studies demonstrating a role for muscarinic and epidermal growth factor receptor signaling in bile acid-induced colon neoplasia, increasing bile acid malabsorption was associated with M3 muscarinic and epidermal growth factor receptor expression, and activation of extracellular signal-related kinase, a key post-receptor signaling molecule. PMID:26210740

  19. Importance of bicarbonate in bile salt independent fraction of bile flow.

    PubMed

    Hardison, W G; Wood, C A

    1978-08-01

    The bile salt independent fraction (BSIF) of canalicular bile flow from the isolated rat liver perfused with bicarbonate-free perfusate is 50% of that from the liver perfused with bicarbonate-containing perfusate. HCO3-excretion is nearly eliminated and Na+ and Cl- excretion is reduced 50%. Replacement of HCO3- into perfusate increased bile flow by 0.3 microliter/g.min without changing bile acid excretion rate. 5.5-Dimethyl-2,4-oxazolidinedione (DMO) produced a similar effect. DMO was passively distributed between bile and plasma. The data indicate that a bicarbonate transport mechanism is responsible for production of up to 50% of the BSIF. Another weak acid, N-5[5-(2-methoxyethoxy)-2-pyrimidinyl]sulfamoylbenzene (glymidine), was rapidly excreted into bile and increased bile flow by over 2.0 microliter/g.min. Glymidine is probably excreted by an independent organic anion transport mechanism, and any effect on the bicarbonate transport mechanism is obscured. Canaliculus-enriched hepatocyte membrane fractions contained no HCO3-stimulated ATPase activity. Either this enzyme is unimportant in hepatocyte bicarbonate transport or transport occurs across membranes other than the bile canalicular membrane. PMID:150796

  20. Effect of dietary fenugreek seeds on biliary proteins that influence nucleation of cholesterol crystals in bile.

    PubMed

    Reddy, Raghunatha R L; Srinivasan, Krishnapura

    2011-04-01

    Formation of cholesterol gallstones in gallbladder is controlled by procrystallising and anticrystallising factors present in bile. Dietary fenugreek seed has been recently observed to possess anti-lithogenic potential in experimental mice. In the current animal study, we evaluated the effect of dietary fenugreek on the compositional changes in the bile, particularly its effect on glycoproteins, low-molecular-weight (LMW) and high-molecular-weight (HMW) proteins, cholesterol nucleation time and cholesterol crystal growth. Groups of Wistar rats were fed for 10 weeks with diets: (1) basal control (C), (2) C+fenugreek (12%), (3) high cholesterol diet (HCD) and (4) HCD+fenugreek (12%). Feeding of HCD containing 0.5% cholesterol for 10 weeks rendered the bile lithogenic. Incorporation of fenugreek into HCD decreased the cholesterol content (70.5%), total protein (58.3%), glycoprotein (27.5%), lipid peroxides (13.6%) and cholesterol saturation index (from 1.98 to 0.75) in bile, increased the bile flow rate (19.5%), prolonged the cholesterol nucleation time and reduced the vesicular form of cholesterol (65%), which was accompanied with an increase in smaller vesicular form (94%). There was an increase in biliary phospholipid (33%) and total bile acid (49%) contents in the HCD+fenugreek group as compared with the HCD group. Electrophoretic separation of biliary LMW proteins showed the presence of a high concentration of 28-kDa protein, which might be responsible for the prolongation of cholesterol nucleation time in the fenugreek-fed groups. These findings indicate that the beneficial anti-lithogenic effect of dietary fenugreek, which primarily is due to reduction in the cholesterol content in bile, was additionally affected through a modulation of the nucleating and anti-nucleating proteins, which, in turn, affect cholesterol crystallisation. PMID:21215764

  1. Constitutive androstane receptor-mediated changes in bile acid composition contributes to hepatoprotection from lithocholic acid-induced liver injury in mice.

    PubMed

    Beilke, Lisa D; Aleksunes, Lauren M; Holland, Ricky D; Besselsen, David G; Beger, Rick D; Klaassen, Curtis D; Cherrington, Nathan J

    2009-05-01

    Pharmacological activation of the constitutive androstane receptor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice before and during induction of intrahepatic cholestasis using the secondary bile acid, lithocholic acid (LCA). In LCA-treated WT and all the CAR-null groups (excluding controls), histology revealed severe multifocal necrosis. This pathology was absent in WT mice pretreated with PB and TCPOBOP, indicating CAR-dependent hepatoprotection. Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and trihydroxy bile acids in PB- and TCPOBOP-pretreated WT mice correlated with hepatoprotection. In comparison, concentrations of monohydroxylated and dihydroxylated bile acids were increased in all the treated CAR-null mice compared with CO controls. Along with several other enzymes (Cyp7b1, Cyp27a1, Cyp39a1), Cyp8b1 expression was increased in hepatoprotected mice, which could be suggestive of a shift in the bile acid biosynthesis pathway toward the formation of less toxic bile acids. In CAR-null mice, these changes in gene expression were not different among treatment groups. These results suggest CAR mediates a shift in bile acid biosynthesis toward the formation of less toxic bile acids, as well as a decrease in hepatic bile acid concentrations. We propose that these combined CAR-mediated effects may contribute to the hepatoprotection observed during LCA-induced liver injury. PMID:19196849

  2. Analysis of the Bile Salt Export Pump (ABCB11) Interactome Employing Complementary Approaches

    PubMed Central

    Przybylla, Susanne; Stindt, Jan; Kleinschrodt, Diana; Schulte am Esch, Jan; Häussinger, Dieter; Keitel, Verena; Smits, Sander H.; Schmitt, Lutz

    2016-01-01

    The bile salt export pump (BSEP, ABCB11) plays an essential role in the formation of bile. In hepatocytes, BSEP is localized within the apical (canalicular) membrane and a deficiency of canalicular BSEP function is associated with severe forms of cholestasis. Regulation of correct trafficking to the canalicular membrane and of activity is essential to ensure BSEP functionality and thus normal bile flow. However, little is known about the identity of interaction partners regulating function and localization of BSEP. In our study, interaction partners of BSEP were identified in a complementary approach: Firstly, BSEP interaction partners were co-immunoprecipitated from human liver samples and identified by mass spectrometry (MS). Secondly, a membrane yeast two-hybrid (MYTH) assay was used to determine protein interaction partners using a human liver cDNA library. A selection of interaction partners identified both by MYTH and MS were verified by in vitro interaction studies using purified proteins. By these complementary approaches, a set of ten novel BSEP interaction partners was identified. With the exception of radixin, all other interaction partners were integral or membrane-associated proteins including proteins of the early secretory pathway and the bile acyl-CoA synthetase, the second to last, ER-associated enzyme of bile salt synthesis. PMID:27472061

  3. Analysis of the Bile Salt Export Pump (ABCB11) Interactome Employing Complementary Approaches.

    PubMed

    Przybylla, Susanne; Stindt, Jan; Kleinschrodt, Diana; Schulte Am Esch, Jan; Häussinger, Dieter; Keitel, Verena; Smits, Sander H; Schmitt, Lutz

    2016-01-01

    The bile salt export pump (BSEP, ABCB11) plays an essential role in the formation of bile. In hepatocytes, BSEP is localized within the apical (canalicular) membrane and a deficiency of canalicular BSEP function is associated with severe forms of cholestasis. Regulation of correct trafficking to the canalicular membrane and of activity is essential to ensure BSEP functionality and thus normal bile flow. However, little is known about the identity of interaction partners regulating function and localization of BSEP. In our study, interaction partners of BSEP were identified in a complementary approach: Firstly, BSEP interaction partners were co-immunoprecipitated from human liver samples and identified by mass spectrometry (MS). Secondly, a membrane yeast two-hybrid (MYTH) assay was used to determine protein interaction partners using a human liver cDNA library. A selection of interaction partners identified both by MYTH and MS were verified by in vitro interaction studies using purified proteins. By these complementary approaches, a set of ten novel BSEP interaction partners was identified. With the exception of radixin, all other interaction partners were integral or membrane-associated proteins including proteins of the early secretory pathway and the bile acyl-CoA synthetase, the second to last, ER-associated enzyme of bile salt synthesis. PMID:27472061

  4. CAV1 Prevents Gallbladder Cholesterol Crystallization by Regulating Biosynthesis and Transport of Bile Salts.

    PubMed

    Xu, Guoqiang; Li, Yiqiao; Jiang, Xin; Chen, Hongtan

    2016-09-01

    Cholesterol gallstone disease (CGD) is a hepatobiliary disorder which results from a biochemical imbalance in the gallbladder bile. Here we show that loss of CAV1 sensitized mice to lithogenic diet-induced gallbladder cholesterol crystallization, which was associated with dysregulation of several hepatic transporters that efflux cholesterol, phospholipids, and bile salts. The combined effect of increased biliary cholesterol concentration and decreased biliary bile salt secretion in CAV1(-/-) mice led to an increased cholesterol saturation index and the formation of cholesterol crystals. At the signaling level, the ERK/AP-1 pathway seems to mediate the effects of CAV1 on biliary BA homeostasis and might be developed as a therapeutic target for CGD. We propose that CAV1 is an anti-lithogenic factor and that the CAV1(-/-) mice may offer a convenient CGD model to develop therapeutic interventions for this disease. J. Cell. Biochem. 117: 2118-2127, 2016. © 2016 Wiley Periodicals, Inc. PMID:26875794

  5. Bile acids are nutrient signaling hormones.

    PubMed

    Zhou, Huiping; Hylemon, Phillip B

    2014-08-01

    Bile salts play crucial roles in allowing the gastrointestinal system to digest, transport and metabolize nutrients. They function as nutrient signaling hormones by activating specific nuclear receptors (FXR, PXR, Vitamin D) and G-protein coupled receptors [TGR5, sphingosine-1 phosphate receptor 2 (S1PR2), muscarinic receptors]. Bile acids and insulin appear to collaborate in regulating the metabolism of nutrients in the liver. They both activate the AKT and ERK1/2 signaling pathways. Bile acid induction of the FXR-α target gene, small heterodimer partner (SHP), is highly dependent on the activation PKCζ, a branch of the insulin signaling pathway. SHP is an important regulator of glucose and lipid metabolism in the liver. One might hypothesize that chronic low grade inflammation which is associated with insulin resistance, may inhibit bile acid signaling and disrupt lipid metabolism. The disruption of these signaling pathways may increase the risk of fatty liver and non-alcoholic fatty liver disease (NAFLD). Finally, conjugated bile acids appear to promote cholangiocarcinoma growth via the activation of S1PR2. PMID:24819989

  6. Bile acid metabolism and signaling in cholestasis, inflammation and cancer

    PubMed Central

    Apte, Udayan

    2015-01-01

    Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid soluble vitamins. Bile acid synthesis, transport and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration and carcinogenesis. PMID:26233910

  7. Bile acids conjugation in human bile is not random: new insights from (1)H-NMR spectroscopy at 800 MHz.

    PubMed

    Nagana Gowda, G A; Shanaiah, Narasimhamurthy; Cooper, Amanda; Maluccio, Mary; Raftery, Daniel

    2009-06-01

    Bile acids constitute a group of structurally closely related molecules and represent the most abundant constituents of human bile. Investigations of bile acids have garnered increased interest owing to their recently discovered additional biological functions including their role as signaling molecules that govern glucose, fat and energy metabolism. Recent NMR methodological developments have enabled single-step analysis of several highly abundant and common glycine- and taurine- conjugated bile acids, such as glycocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, and taurochenodeoxycholic acid. Investigation of these conjugated bile acids in human bile employing high field (800 MHz) (1)H-NMR spectroscopy reveals that the ratios between two glycine-conjugated bile acids and their taurine counterparts correlate positively (R2 = 0.83-0.97; p = 0.001 x 10(-2)-0.006 x 10(-7)) as do the ratios between a glycine-conjugated bile acid and its taurine counterpart (R2 = 0.92-0.95; p = 0.004 x 10(-3)-0.002 x 10(-10)). Using such correlations, concentration of individual bile acids in each sample could be predicted in good agreement with the experimentally determined values. These insights into the pattern of bile acid conjugation in human bile between glycine and taurine promise useful clues to the mechanism of bile acids' biosynthesis, conjugation and enterohepatic circulation, and may improve our understanding of the role of individual conjugated bile acids in health and disease. PMID:19373503

  8. What Should You Ask Your Doctor about Bile Duct Cancer?

    MedlinePlus

    ... treatment for bile duct cancer? What should you ask your doctor about bile duct cancer? It is ... your own. For instance, you might want to ask about clinical trials for which you may qualify. ...

  9. Do We Know What Causes Bile Duct Cancer?

    MedlinePlus

    ... duct cancer be prevented? Do we know what causes bile duct cancer? We don’t know the exact cause of ... to top » Guide Topics What Is Bile Duct Cancer? Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and ...

  10. The effect of dietary psyllium hydrocolloid and lignin on bile.

    PubMed

    Brydon, W G; Borup-Christensen, S; Van der Linden, W; Eastwood, M A

    1979-07-01

    Animal experiments suggest that supplementing the diet with either psyllium seed husk or lignin alters the ratio of deoxycholic acid to chenodeoxycholic in bile. In this study dosages of psyllium seed husk or lignin acceptable to patients with gallstones do not appear to alter the relative amounts of cholesterol, or individual bile acids in the bile. PMID:524929

  11. Effect of cholestyramine on bile acid metabolism in normal man

    PubMed Central

    Garbutt, J. T.; Kenney, T. J.

    1972-01-01

    The effect of cholestyramine administration on the enterohepatic circulation of bile acids was studied in eight normal volunteers. In six subjects the metabolism of sodium taurocholate-14C was determined after its intravenous injection before and during the 6th wk of cholestyramine administration, 16 g/day. In two subjects, the metabolism of cholic acid-14C was observed before and during the 2nd wk of cholestyramine, 16 g/day. Bile acid sequestration resulted in a more rapid disappearance of the injected primary bile acid and its metabolic products. The composition of fasting bile acids was promptly altered by cholestyramine to predominantly glycine-conjugated trihydroxy bile acid. In four subjects, unconjugated bile acid-14C was administered during cholestyramine administration; the relative proportion of glycine-conjugated bile acid-14C before enterohepatic circulation was similar to the relative proportion of unlabeled glycine-conjugated bile acid present in duodenal contents after an overnight fast, indicating that a hepatic mechanism was responsible for the elevated ratios of glycine- to taurine-conjugated bile acid (G: T ratios) observed. The relative proportions of both dihydroxy bile acids, chenodeoxycholic and deoxycholic, were significantly reduced. Steatorrhea did not occur, and the total bile acid pool size determined after an overnight fast was unaltered by cholestyramine. These findings suggest that in normal man bile acid sequestered from the enterohepatic circulation by cholestyramine is replaced by an increase in hepatic synthesis primarily via the pathway leading to production of glycocholic acid. PMID:5080408

  12. Effect of etofibrate on bile production in the normolipidemic rat.

    PubMed

    Bocos, C; Orozco, E; Castro, M; Quack, G; Herrera, E

    1995-05-01

    1. The effect of etofibrate, the ethandiol-1,2 diester of nicotinic and clofibric acids on bile production was studied in male rats that received a daily dose of 300 mg of etofibrate/kg body weight by stomach tube for 10 days and were compared with control rats receiving the medium. 2. The bile duct was cannulated, animals were intravenously given 1 microCi (4-14C)-cholesterol/100 b.w. and bile was collected at different intervals for a total of 4 hr. 3. Etofibrate treatment decreased plasma cholesterol and triglyceride concentrations and increased the bile flow. The cummulative amount of both bile volume and total bile radioactivity secreted increased linearly in all the animals; the respective slopes being higher in etofibrate treated rats than in controls. 4. The main labelled component found in the bile was always bile acids rather than cholesterol and the proportion of each of these compounds was similar in both groups. Neither was any difference between the groups found in the concentration of bile acids, cholesterol and phospholipids nor in the cholesterol/(bile+phospholipid) ratio. 5. Besides other factors, the present results indicate that an increase in bile flow and biliary cholesterol excretion in its free form and after its conversion into bile acids should contribute to the hypocholesterolemic effect of etofibrate. PMID:7789727

  13. Clinical aspects of nonsurgical percutaneous transhepatic bile drainage in obstructive lesions of the extrahepatic bile ducts.

    PubMed Central

    Hansson, J A; Hoevels, J; Simert, G; Tylén, U; Vang, J

    1979-01-01

    Percutaneous transhepatic cholangiography (PTC) with subsequent external bile drainage by nonsurgically established percutaneous transhepatic intubation of bile ducts was performed in 105 patients with obstructive jaundice. Recovery of liver function and improvement in the patients' general condition prior to radical or palliative surgery, nonsurgical palliation in advanced cases of malignancy as well as relief of postoperative leakage from a biliodigestive anastomosis are the indications for the bile drainage technique used in the present study. Clinical aspects such as optimal period of preoperative drainage, frequency of catheter dislodgement, and rate of complications such as cholangitis, bile leakage to the abdominal cavity and risk for peritoneal hemorrhage are discussed. Two deaths occurred within this series. PMID:758865

  14. Alteration of Bile Canalicular Enzymes in Cholestasis. A POSSIBLE CAUSE OF BILE SECRETORY FAILURE

    PubMed Central

    Simon, Francis R.; Arias, Irwin M.

    1973-01-01

    Bile secretory failure (cholestasis) may result from several possible mechanisms involved in bile secretion. We have examined the possibility that abnormalities in enzyme content, composition, and turnover of liver plasma membrane constituents are altered in cholestasis. Severe and mild cholestasis were produced by 5 days of bile duct ligation and ethinyl estradiol administration, respectively. Bile duct ligation but not ethinyl estradiol treatments was associated with elevations of the serum bilirubin level and 5′-nucleotidase activity. However, basal bile flow and bilirubin transport maximum (Tm) were significantly reduced after ethinyl estradiol treatment. Liver plasma membrane fractions rich in canalicular membranes were prepared from groups of rats in each of three categories; normal, after bile duct ligation, or ethinyl estradiol administration, and their respective controls. Electron microscopy and enzyme marker studies demonstrated plasma membrane fractions free of significant contamination. Plasma membrane fractions prepared from mild as well as severe cholestasis had increased alkaline phosphatase activity, and reduced 5′-nucleotidase and Mg2+-ATPase activities. Co2+-CMPase activity was unchanged. Kinetic analysis of 5′-nucleotidase and Mg2+-ATPase activities in plasma membrane fractions demonstrated reduced Vmaz (but unaltered Km). Reducted Vmaz was unrelated to addition in vitro of di-or trihydroxy bile salts or ethinyl estradiol and, therefore, suggests that reduced activities in cholestasis are due to decreased enzyme content. Cholestasis was not associated with changes in the synthesis or degradation rate of pulse-labeled plasma membrane proteins or alterations in the major protein bands separated on sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. Plasma membrane cholesterol, phospholipid, and neutral sugar content was unaltered, but sialic acid content was significantly increased in both forms of cholestasis. Alterations in

  15. The unique ligand binding features of subfamily-II iLBPs with respect to bile salts and related drugs.

    PubMed

    Favretto, Filippo; Ceccon, Alberto; Zanzoni, Serena; D'Onofrio, Mariapina; Ragona, Laura; Molinari, Henriette; Assfalg, Michael

    2015-04-01

    Intracellular lipid binding proteins (iLBPs) are a family of evolutionarily related small cytoplasmic proteins implicated in the transcellular transport of lipophilic ligands. Subfamily-II iLBPs include the liver fatty acid binding protein (L-FABP), and the ileal and the liver and ileal bile acid binding proteins (L-BABP and I-BABP). Atomic-level investigations during the past 15-20 years have delivered relevant information on bile acid binding by this protein group, revealing unique features including binding cooperativity, promiscuity, and site selectivity. Using NMR spectroscopy and other biophysical techniques, our laboratories have contributed to an understanding of the molecular determinants of some of these properties and their generality among proteins from different animal species. We focused especially on formation of heterotypic complexes, considering the mixed compositions of physiological bile acid pools. Experiments performed with synthetic bile acid derivatives showed that iLBPs could act as targets for cell-specific contrast agents and, more generally, as effective carriers of amphiphilic drugs. This review collects the major findings related to bile salt interactions with iLBPs aiming to provide keys for a deeper understanding of protein-mediated intracellular bile salt trafficking. PMID:25468388

  16. Electrogenicity of Na(+)-coupled bile acid transporters.

    PubMed Central

    Weinman, S. A.

    1997-01-01

    The Na(+)-bile acid cotransporters NTCP and ASBT are largely responsible for the Na(+)-dependent bile acid uptake in hepatocytes and intestinal epithelial cells, respectively. This review discusses the experimental methods available for demonstrating electrogenicity and examines the accumulating evidence that coupled transport by each of these bile acid transporters is electrogenic. The evidence includes measurements of transport-associated currents by patch clamp electrophysiological techniques, as well as direct measurement of fluorescent bile acid transport rates in whole cell patch clamped, voltage clamped cells. The results support a Na+:bile acid coupling stoichiometry of 2:1. PMID:9626753

  17. Endoscopic Management of Bile Leakage after Liver Transplantation

    PubMed Central

    Oh, Dongwook; Lee, Sung Koo; Song, Tae Jun; Park, Do Hyun; Lee, Sang Soo; Seo, Dong-Wan; Kim, Myung-Hwan

    2015-01-01

    Background/Aims Endoscopic retrograde cholangiopancreatography (ERCP) can be an effective treatment for bile leakage after liver transplantation. We evaluated the efficacy of endoscopic treatment in liver transplantation in patients who developed bile leaks. Methods Forty-two patients who developed bile leaks after liver transplantation were included in the study. If a bile leak was observed on ERCP, a sphincterotomy was performed, and a nasobiliary catheter was then inserted. If a bile leak was accompanied by a bile duct stricture, either the stricture was dilated with balloons, followed by nasobiliary catheter insertion across the bile duct stricture, or endoscopic retrograde biliary drainage was performed. Results In the bile leakage alone group (22 patients), endoscopic treatment was technically successful in 19 (86.4%) and clinically successful in 17 (77.3%) cases. Among the 20 patients with bile leaks with bile duct strictures, endoscopic treatment was technically successful in 13 (65.0%) and clinically successful in 10 (50.0%) cases. Among the 42 patients who underwent ERCP, technical success was achieved in 32 (76.2%) cases and clinical success was achieved in 27 (64.3%) cases. Conclusions ERCP is an effective and safe therapeutic modality for bile leaks after liver transplantation. ERCP should be considered as an initial therapeutic modality in post-liver transplantation patients. PMID:25717048

  18. Bile Acid Signaling in Metabolic Disease and Drug Therapy

    PubMed Central

    Li, Tiangang

    2014-01-01

    Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid–activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein–coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. PMID:25073467

  19. Novel, major 2α- and 2β-hydroxy bile alcohols and bile acids in the bile of Arapaima gigas, a large South American river fish.

    PubMed

    Sato née Okihara, Rika; Saito, Tetsuya; Ogata, Hiroaki; Nakane, Naoya; Namegawa, Kazunari; Sekiguchi, Shoutaro; Omura, Kaoru; Kurabuchi, Satoshi; Mitamura, Kuniko; Ikegawa, Shigeo; Raines, Jan; Hagey, Lee R; Hofmann, Alan F; Iida, Takashi

    2016-03-01

    Bile alcohols and bile acids from gallbladder bile of the Arapaima gigas, a large South American freshwater fish, were isolated by reversed-phase high-performance liquid chromatography. The structures of the major isolated compounds were determined by electrospray-tandem mass spectrometry and nuclear magnetic resonance using (1)H- and (13)C-NMR spectra. The novel bile salts identified were six variants of 2-hydroxy bile acids and bile alcohols in the 5α- and 5β-series, with 29% of all compounds having hydroxylation at C-2. Three C27 bile alcohols were present (as ester sulfates): (24ξ,25ξ)-5α-cholestan-2α,3α,7α,12α,24,26-hexol; (25ξ)-5β-cholestan-2β,3α,7α,12α,26,27-hexol, and (25ξ)-5α-cholestan-2α,3α,7α,12α,26,27-hexol. A single C27 bile acid was identified: (25ξ)-2α,3α,7α,12α-tetrahydroxy-5α-cholestan-26-oic acid, present as its taurine conjugate. Two novel C24 bile acids were identified: the 2α-hydroxy derivative of allochenodeoxycholic acid and the 2β-hydroxy derivative of cholic acid, both occurring as taurine conjugates. These studies extend previous work in establishing the natural occurrence of novel 2α- and 2β-hydroxy-C24 and C27 bile acids as well as C27 bile alcohols in both the normal (5β) as well as the (5α) "allo" A/B-ring juncture. The bile salt profile of A. gigas appears to be unique among vertebrates. PMID:26768415

  20. The effect of bile, bile acids and detergents on calcium absorption in the chick

    PubMed Central

    Webling, D. D'A.; Holdsworth, E. S.

    1965-01-01

    1. Bile from rachitic or normal chicks causes an immediate increase in the intestinal absorption of soluble calcium in rachitic and vitamin D3-treated chicks as tested in vivo by intestinal-loop and oral-dosing methods. 2. This effect is apparently solely due to the taurine-conjugated bile acids present in the bile and is independent of the action of vitamin D. 3. Chick bile and bile acids can increase the solubility and the absorption of calcium presented as sparingly soluble calcium hydrogen phosphate. 4. In addition, bile is necessary to some extent at least for the intestinal absorption of vitamin D3 in the chick and this would indirectly enhance the absorption of calcium. 5. Thus bile is capable of a threefold action in the absorption of calcium in the chick. It is suggested that the direct action on sparingly soluble forms of calcium is of considerable physiological importance since most of the calcium in the normal bird's diet would be in this form. 6. Bile acids enhance the absorption of calcium in all regions of the small intestine of the chick. 7. Of a range of bile acids and detergents tested for enhancement of calcium absorption, various taurine-conjugated bile acids and sodium lauryl sulphate, an anionic detergent, are effective. A non-ionic detergent (Tween 80) and a cationic detergent (Zephiran) are without effect. 8. The ability of a substance to increase directly the intestinal absorption of soluble calcium appears to depend to some extent on an anionic detergent action, i.e. the ability to form a salt or complex soluble to some extent in both aqueous and lipid phases. 9. In chicks the immediate deposition of calcium (45Ca) in the bones closely reflects any increase in plasma calcium radioactivity regardless of the cause of the increase and regardless of the vitamin D3 status. Although sodium lauryl sulphate can increase markedly the calcium absorption from the gut and the immediate deposition in the bones it has no significant effect on rickets

  1. Bile salt-membrane interactions and the physico-chemical mechanisms of bile salt toxicity.

    PubMed

    Heuman, D M

    1995-09-01

    We present evidence that ursodeoxycholate prevents toxicity of more hydrophobic bile salts by inhibiting micellar solubilization of membrane lipids. Using both centrifugal ultrafiltration and gel filtration methods we studied leakage of inulin from vesicles composed of egg phosphatidylcholine and cholesterol. We observed that the addition of tauroursodeoxycholate to taurodeoxycholate reduced leakage of inulin from large unilamelar vesicles compared to that seen with taurodeoxycholate alone. This protective effect was observed only at high membrane cholesterol:phospholipid ratios (> or = 0.5). By gel filtration we found that fractional leakage of inulin from vesicles was identical to fractional phospholipid solubilization, indicating that release of inulin from vesicles results from membrane dissolution rather than from increased permeability of otherwise intact membranes. Addition of tauroursodeoxycholate to taurodeoxycholate was found to suppress the dissolution of phospholipid from cholesterol-rich vesicles. Bile salts were found to absorb to vesicles with an affinity proportional to their relative hydrophobicity, as estimated by reverse phase HPLC. Adsorption affinity decreased progressively with increasing membrane cholesterol content. Different bile salts displaced each other from membranes in proportion to their respective binding, affinities. Tauroursodeoxycholate, which absorbed to membranes with low affinity, displaced taurodeoxycholate from vesicles only weakly. Based on these findings we postulate that bile salts may damage the liver through solubilization of canalicular membrane lipids. Ursodeoxycholate may protect the liver by inhibiting dissolution of the cholesterol-rich canalicular membrane by more hydrophobic endogenous bile salts. Biliary secretion of vesicles rich in phosphatidylcholine may buffer the intermicellar concentration of bile acids at levels below those required to disrupt the cholesterol-rich canalicular membrane; thus biliary vesicle

  2. Herbert Falk: a vital force in the renaissance of bile acid research and bile acid therapy.

    PubMed

    Hofmann, Alan F

    2011-01-01

    Herbert Falk died on August 8, 2008, after a long illness. It was his vision that initiated the Bile Acid Meetings and brought to market chenodeoxycholic acid and ursodeoxycholic acid for the dissolution of cholesterol gallstones as well as the successful treatment of cholestatic liver disease. The 1st Bile Acid Meeting was a small workshop held at the University Hospital of Freiburg in 1970. Great interest in the topic was evident at that small meeting and led to a larger meeting in 1972, whose scope included both the basic and clinical aspects of bile acids. These meetings have continued at biennial intervals, the 2010 meeting being the 21st. The program has always included discussions of the most fundamental aspects of bile acid biosynthesis and metabolism as well as clinical applications of bile acid therapy. The meetings featured brief presentations, ample time for discussion, and imaginative social programs. They have always been flawlessly organized. Social programs usually included a hike through the beautiful countryside of the Black Forest followed by dinner in a rustic restaurant. Herbert Falk took part in these programs, personally welcoming every participant. In the warm glow of the 'Badische' hospitality, friendships developed, and scientific collaborations were often arranged. From a scientific standpoint, there has been enormous progress in understanding the chemistry and biology of bile acids. Herbert Falk established the Windaus Prize in 1978, and the prize has been given to individuals whose contributions moved the field forward. These bile acid meetings have been marvelous, rewarding experiences. We must all be grateful to Herbert Falk's vision in establishing the Falk Foundation that has so generously sponsored these meetings. We also express our gratitude to his widow, Ursula Falk, who continues this worthy tradition. PMID:21691101

  3. Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse.

    PubMed

    Zhang, Jie; He, Kan; Cai, Lining; Chen, Yu-Chuan; Yang, Yifan; Shi, Qin; Woolf, Thomas F; Ge, Weigong; Guo, Lei; Borlak, Jürgen; Tong, Weida

    2016-08-01

    Interference of bile salt transport is one of the underlying mechanisms for drug-induced liver injury (DILI). We developed a novel bile salt transport activity assay involving in situ biosynthesis of bile salts from their precursors in primary human, monkey, dog, rat, and mouse hepatocytes in suspension as well as LC-MS/MS determination of extracellular bile salts transported out of hepatocytes. Glycine- and taurine-conjugated bile acids were rapidly formed in hepatocytes and effectively transported into the extracellular medium. The bile salt formation and transport activities were time‒ and bile-acid-concentration‒dependent in primary human hepatocytes. The transport activity was inhibited by the bile salt export pump (BSEP) inhibitors ketoconazole, saquinavir, cyclosporine, and troglitazone. The assay was used to test 86 drugs for their potential to inhibit bile salt transport activity in human hepatocytes, which included 35 drugs associated with severe DILI (sDILI) and 51 with non-severe DILI (non-sDILI). Approximately 60% of the sDILI drugs showed potent inhibition (with IC50 values <50 μM), but only about 20% of the non-sDILI drugs showed this strength of inhibition in primary human hepatocytes and these drugs are associated only with cholestatic and mixed hepatocellular cholestatic (mixed) injuries. The sDILI drugs, which did not show substantial inhibition of bile salt transport activity, are likely to be associated with immune-mediated liver injury. Twenty-four drugs were also tested in monkey, dog, rat and mouse hepatocytes. Species differences in potency were observed with mouse being less sensitive than other species to inhibition of bile salt transport. In summary, a novel assay has been developed using hepatocytes in suspension from human and animal species that can be used to assess the potential for drugs and/or drug-derived metabolites to inhibit bile salt transport and/or formation activity. Drugs causing sDILI, except those by immune

  4. Intraductal papillary mucinous neoplasm of the bile duct with gastric and duodenal fistulas

    PubMed Central

    Hong, Man Yong; Yu, Dong Wook; Hong, Seung Goun

    2014-01-01

    Intraductal papillary mucinous neoplasm (IPMN) of the bile duct is still rare and not yet understood despite of its increased incidence and similar clinicopathologic characteristics compared with IPMN of the pancreas. The fistula formation into other organs can occur in IPMN, especially the pancreatic type. To our knowledge, only two cases of IPMN of the bile duct with a choledochoduodenal fistula were reported and we have recently experienced a case of IPMN of the bile duct penetrating into two neighboring organs of the stomach and duodenum presenting with abdominal pain and jaundice. Endoscopy showed thick mucin extruding from two openings of the fistulas. Endoscopic suction of thick mucin using direct peroral cholangioscopy with ultra-slim endoscope through choledochoduodenal fistula was very difficult and ineffective because of very thick mucin and next endoscopic suction through the stent after prior insertion of biliary metal stent into choledochogastric fistula also failed. Pathologic specimen obtained from the proximal portion of the choledochogastric fistula near left intrahepatic bile duct through the metal stent showed a low grade adenoma. The patient declined the surgical treatment due to her old age and her abdominal pain with jaundice was improved after percutaneous transhepatic biliary drainage with the irrigation of N-acetylcysteine three times daily for 10 d. PMID:25031793

  5. Observation of the seleno bis-(S-glutathionyl) arsinium anion in rat bile.

    PubMed

    George, Graham N; Gailer, Jürgen; Ponomarenko, Olena; La Porte, Paul F; Strait, Karen; Alauddin, Mohammad; Ahsan, Habibul; Ahmed, Selim; Spallholz, Julian; Pickering, Ingrid J

    2016-05-01

    Certain arsenic and selenium compounds show a remarkable mutual cancelation of toxicities, where a lethal dose of one can be voided by an equimolar and otherwise lethal dose of the other. It is now well established that the molecular basis of this antagonism is the formation and biliary excretion of seleno bis-(S-glutathionyl) arsinium anion [(GS)2AsSe](-). Previous work has definitively demonstrated the presence of [(GS)2AsSe](-) in rabbit bile, but only in the presence of other arsenic and selenium species. Rabbits have a gall bladder, which concentrates bile and lowers its pH; it seems likely that this may be responsible for the breakdown of biliary [(GS)2AsSe](-). Since rats have no gall bladder, the bile proceeds directly through the bile duct from the hepatobiliary tree. In the present work we have shown that the primary product of biliary co-excretion of arsenic and selenium in rats is [(GS)2AsSe](-), with essentially 100% of the arsenic and selenium present as this species. The chemical plausibility of the X-ray absorption spectroscopy-derived structural conclusions of this novel arsenic and selenium co-excretion product is supported by density functional theory calculations. These results establish the biomolecular basis to further explore the use of selenium dietary supplements as a possible palliative for chronic low-level arsenic poisoning of human populations. PMID:26883676

  6. Bear bile: dilemma of traditional medicinal use and animal protection.

    PubMed

    Feng, Yibin; Siu, Kayu; Wang, Ning; Ng, Kwan-Ming; Tsao, Sai-Wah; Nagamatsu, Tadashi; Tong, Yao

    2009-01-01

    Bear bile has been used in Traditional Chinese Medicine (TCM) for thousands of years. Modern investigations showed that it has a wide range of pharmacological actions with little toxicological side effect and the pure compounds have been used for curing hepatic and biliary disorders for decades. However, extensive consumption of bear bile made bears endangered species. In the 1980's, bear farming was established in China to extract bear bile from living bears with "Free-dripping Fistula Technique". Bear farming is extremely inhumane and many bears died of illness such as chronic infections and liver cancer. Efforts are now given by non-governmental organizations, mass media and Chinese government to end bear farming ultimately. At the same time, systematic research has to be done to find an alternative for bear bile. In this review, we focused on the literature, laboratory and clinical results related to bear bile and its substitutes or alternative in English and Chinese databases. We examined the substitutes or alternative of bear bile from three aspects: pure compounds derived from bear bile, biles from other animals and herbs from TCM. We then discussed the strategy for stopping the trading of bear bile and issues of bear bile related to potential alternative candidates, existing problems in alternative research and work to be done in the future. PMID:19138420

  7. Bear bile: dilemma of traditional medicinal use and animal protection

    PubMed Central

    Feng, Yibin; Siu, Kayu; Wang, Ning; Ng, Kwan-Ming; Tsao, Sai-Wah; Nagamatsu, Tadashi; Tong, Yao

    2009-01-01

    Bear bile has been used in Traditional Chinese Medicine (TCM) for thousands of years. Modern investigations showed that it has a wide range of pharmacological actions with little toxicological side effect and the pure compounds have been used for curing hepatic and biliary disorders for decades. However, extensive consumption of bear bile made bears endangered species. In the 1980's, bear farming was established in China to extract bear bile from living bears with "Free-dripping Fistula Technique". Bear farming is extremely inhumane and many bears died of illness such as chronic infections and liver cancer. Efforts are now given by non-governmental organizations, mass media and Chinese government to end bear farming ultimately. At the same time, systematic research has to be done to find an alternative for bear bile. In this review, we focused on the literature, laboratory and clinical results related to bear bile and its substitutes or alternative in English and Chinese databases. We examined the substitutes or alternative of bear bile from three aspects: pure compounds derived from bear bile, biles from other animals and herbs from TCM. We then discussed the strategy for stopping the trading of bear bile and issues of bear bile related to potential alternative candidates, existing problems in alternative research and work to be done in the future. PMID:19138420

  8. Functional genomic analysis of bile salt resistance in Enterococcus faecium

    PubMed Central

    2013-01-01

    Background Enterococcus faecium is a Gram-positive commensal bacterium of the mammalian intestinal tract. In the last two decades it has also emerged as a multi-resistant nosocomial pathogen. In order to survive in and colonize the human intestinal tract E. faecium must resist the deleterious actions of bile. The molecular mechanisms exploited by this bacterium to tolerate bile are as yet unexplored. Results In this study we used a high-throughput quantitative screening approach of transposon mutant library, termed Microarray-based Transposon Mapping (M-TraM), to identify the genetic determinants required for resistance to bile salts in E. faecium E1162. The gene gltK, which is predicted to encode a glutamate/aspartate transport system permease protein, was identified by M-TraM to be involved in bile resistance. The role of GltK in bile salt resistance was confirmed by the subsequent observation that the deletion of gltK significantly sensitized E. faecium E1162 to bile salts. To further characterize the response of E. faecium E1162 to bile salts, we performed a transcriptome analysis to identify genes that are regulated by exposure to 0.02% bile salts. Exposure to bile salts resulted in major transcriptional rearrangements, predominantly in genes involved in carbohydrate, nucleotide and coenzyme transport and metabolism. Conclusion These findings add to a better understanding of the molecular mechanisms by which E. faecium responds and resists the antimicrobial action of bile salts. PMID:23641968

  9. Advances in understanding of bile acid diarrhea

    PubMed Central

    Camilleri, Michael

    2014-01-01

    Bile acids (BA) are actively reabsorbed in the terminal ileum by the apical Na+-dependent bile salt transporter. This review addresses the epidemiology, pathophysiology, diagnosis and treatment of BA diarrhea (BAD). BAD is typically caused by ileal resection or disease; 25–33% of patients with chronic functional diarrhea or irritable bowel syndrome-diarrhea (IBS-D) have BAD, possibly from deficiency in the ileal hormone, FGF-19, which normally provides feedback inhibition of BA synthesis. Diagnosis of BAD is typically based on reduced BA retention of radiolabeled BA (75SeHCAT), increased BA synthesis (serum C4) or increased fecal BA loss. In clinical practice, diagnosis is often based on response to BA sequestrants (e.g., cholestyramine or colesevelam). Diagnostic tests for BA malabsorption (BAM) need to be used more extensively in clinical practice. In the future, farnesoid X receptor agonists that stimulate ileal production of FGF-19 may be alternative treatments of BAD. PMID:24410472

  10. Advances in understanding of bile acid diarrhea.

    PubMed

    Camilleri, Michael

    2014-01-01

    Bile acids (BA) are actively reabsorbed in the terminal ileum by the apical Na(+)-dependent bile salt transporter. This review addresses the epidemiology, pathophysiology, diagnosis and treatment of BA diarrhea (BAD). BAD is typically caused by ileal resection or disease; 25-33% of patients with chronic functional diarrhea or irritable bowel syndrome-diarrhea (IBS-D) have BAD, possibly from deficiency in the ileal hormone, FGF-19, which normally provides feedback inhibition of BA synthesis. Diagnosis of BAD is typically based on reduced BA retention of radiolabeled BA ((75)SeHCAT), increased BA synthesis (serum C4) or increased fecal BA loss. In clinical practice, diagnosis is often based on response to BA sequestrants (e.g., cholestyramine or colesevelam). Diagnostic tests for BA malabsorption (BAM) need to be used more extensively in clinical practice. In the future, farnesoid X receptor agonists that stimulate ileal production of FGF-19 may be alternative treatments of BAD. PMID:24410472

  11. Structural Determinants for Transport Across the Intestinal Bile Acid Transporter Using C-24 Bile Acid Conjugates

    PubMed Central

    Rais, Rana; Acharya, Chayan; MacKerell, Alexander D.; Polli, James E.

    2010-01-01

    The human apical sodium dependent bile acid transporter (hASBT) re-absorbs gram quantities of bile acid daily and is a potential prodrug target to increase oral drug absorption. In the absence of a high resolution hASBT crystal structure, 3D-QSAR modeling may prove beneficial in designing prodrug targets to hASBT. The objective was to derive a conformationally sampled pharmacophore 3D–QSAR (CSP-SAR) model for the uptake of bile acid conjugates by hASBT. A series of bile acid conjugates of glutamyl chenodeoxycholate were evaluated in terms of Km and normalized Vmax(normVmax) using hASBT-MDCK cells. All mono-anionic conjugates were potent substrates. Dianions, cations and zwitterions, which bound with a high affinity, were not substrates. CSP-SAR models were derived using structural and physicochemical descriptors, and evaluated via cross-validation. The best CSP-SAR model for Km included two structural and two physiochemical descriptors, where substrate hydrophobicity enhanced affinity. A best CSP-SAR model for Km/normVmax employed one structural and three physicochemical descriptors, also indicating hydrophobicity enhanced efficiency. Overall, the bile acid C-24 region accommodated a range of substituted anilines, provided a single negative charge was present near C-24. In comparing uptake findings to prior inhibition results, increased hydrophobicity enhanced activity, with dianions and zwitterions hindering activity. PMID:20939504

  12. Bacteria, bile salts, and intestinal monosaccharide malabsorption

    PubMed Central

    Gracey, Michael; Burke, Valerie; Oshin, Ademola; Barker, Judith; Glasgow, Eric F.

    1971-01-01

    Intestinal monosaccharide transport was studied in a series of rats with a self-filling jejunal blind loop using 3mM arbutin (p-hydroxyphenyl-B-glucoside) or 1mM D-fructose as substrate in vitro and 10 mM arbutin or 5mM D-fructose in vivo. These results were compared with changes in the bacterial flora and state of conjugation of intraluminal bile salts in those animals. Observations were also made of the microscopic and ultrastructural appearances of the small-intestinal epithelium. In the small intestine of blind-loop rats intestinal monosaccharide transport is impaired, and in vitro is most marked in the blind loop, less so in the efferent jejunum, and not significantly altered in the afferent jejunum. A similar pattern of disturbed monosaccharide absorption was demonstrated by perfusions in vivo. The degree of the transport defect correlates closely with the luxuriance of the anaerobic flora, which averaged 108 per millilitre in the blind loop, 107 in the efferent jejunum, and 106 in the afferent jejunum. A similar pattern of abnormality of bile salt conjugation occurred. In the blind loop the ratio of free to conjugated bile salts was grossly abnormal; this disturbance was somewhat less marked in the efferent jejunum and considerably less in the intraluminal contents of the afferent jejunum. An irregularly distributed lesion, consisting of swelling and vacuolation of microvilli and intracellular organelles, was demonstrated in the small-intestinal epithelium of blind-loop animals. Impaired absorption of monosaccharides is a further consequence of bacterial contamination of the upper gut. It is suggested that this defect is caused by the presence of high levels of deconjugated bile salts produced by an abnormal anaerobic bacterial flora in the small intestine. ImagesFig. 3Fig. 4 PMID:4329096

  13. Biotransformation of bile acids by clostridia.

    PubMed

    Owen, R W

    1985-10-01

    The metabolism of bile acids by nuclear dehydrogenating clostridia (NDC) was studied. NDC were able to desaturate the A-ring of 5 beta-cholan-3-oxo-24-oic acid, 12 alpha-hydroxy-5 beta-cholan-3-oxo-24-oic acid, 7 alpha-hydroxy-5 beta-cholan-3-oxo-24-oic acid, 6 alpha-hydroxy-5 beta-cholan-3-oxo-24-oic acid, 7 alpha, 12 alpha-dihydroxy-5 beta-cholan-3-oxo-24-oic acid, 3,12-dioxo-5 beta-cholan-24-oic acid but not 3,6-dioxo-5 beta-cholan-24-oic acid, 3,7-dioxo-5 beta-cholan-24-oic acid and 3,7,12-trioxo-5 beta-cholan-24-oic acid. In each case the sole product possessed a 4-ene-3-one structure. Desaturation of bile acids was more efficient than that of androstanes. NDC are, therefore, capable of introducing double bonds into the nucleus of bile acids as well as that of androstanes. The physiological significance of such reactions in relation to large bowel cancer has yet to be elucidated. PMID:2864454

  14. Bile acids: Chemistry, physiology, and pathophysiology

    PubMed Central

    Monte, Maria J; Marin, Jose JG; Antelo, Alvaro; Vazquez-Tato, Jose

    2009-01-01

    The family of bile acids includes a group of molecular species of acidic steroids with very peculiar physical-chemical and biological characteristics. They are synthesized by the liver from cholesterol through several complementary pathways that are controlled by mechanisms involving fine-tuning by the levels of certain bile acid species. Although their best-known role is their participation in the digestion and absorption of fat, they also play an important role in several other physiological processes. Thus, genetic abnormalities accounting for alterations in their synthesis, biotransformation and/or transport may result in severe alterations, even leading to lethal situations for which the sole therapeutic option may be liver transplantation. Moreover, the increased levels of bile acids reached during cholestatic liver diseases are known to induce oxidative stress and apoptosis, resulting in damage to the liver parenchyma and, eventually, extrahepatic tissues. When this occurs during pregnancy, the outcome of gestation may be challenged. In contrast, the physical-chemical and biological properties of these compounds have been used as the bases for the development of drugs and as pharmaceutical tools for the delivery of active agents. PMID:19230041

  15. Effects of difructose anhydride III (DFA III) administration on bile acids and growth of DFA III-assimilating bacterium Ruminococcus productus on rat intestine.

    PubMed

    Minamida, Kimiko; Kaneko, Maki; Ohashi, Midori; Sujaya, I Nengah; Sone, Teruo; Wada, Masaru; Yokota, Atsushi; Hara, Hiroshi; Asano, Kozo; Tomita, Fusao

    2005-06-01

    The growth of DFA III-assimilating bacteria in the intestines of rats fed 3% DFA III for 2 weeks was examined. Sixty-four percent of the DFA III intake had been assimilated on day 3 of ingestion, and almost all of the DFA III was assimilated at the end of the experiment. The DFA III-assimilating bacterium, Ruminococcus productus, in DFA III-fed rats was in the stationary state of 10(8)-10(9) cells/g dry feces within a week from 10(6) cells/g dry feces on day 1 of DFA III ingestion. The number of R. productus cells was associated with the amount of DFA III excreted in the feces. The acetic acid produced from DFA III by R. productus lowered the cecal pH to 5.8. In control-fed rats and DFA III-fed rats, 94% of secondary bile acids and 94% of primary bile acids, respectively, were accounted for in the total bile acids analyzed. DFA III ingestion increased the ratio of primary bile acids and changed the composition of fecal bile acids. In conclusion, R. productus assimilated DFA III, produced short chain fatty acids, and the cecal pH was lowered. The acidification of rat intestine perhaps inhibited secondary bile acid formation and decreased the ratio of secondary bile acids. Therefore, it is expected that DFA III may prevent colorectal cancer and be a new prebiotic candidate. PMID:16233830

  16. Effect of indomethacin on bile acid-phospholipid interactions: implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs.

    PubMed

    Zhou, Yong; Dial, Elizabeth J; Doyen, Rand; Lichtenberger, Lenard M

    2010-05-01

    The injurious effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in the small intestine was not appreciated until the widespread use of capsule endoscopy. Animal studies found that NSAID-induced small intestinal injury depends on the ability of these drugs to be secreted into the bile. Because the individual toxicity of amphiphilic bile acids and NSAIDs directly correlates with their interactions with phospholipid membranes, we propose that the presence of both NSAIDs and bile acids alters their individual physicochemical properties and enhances the disruptive effect on cell membranes and overall cytotoxicity. We utilized in vitro gastric AGS and intestinal IEC-6 cells and found that combinations of bile acid, deoxycholic acid (DC), taurodeoxycholic acid, glycodeoxycholic acid, and the NSAID indomethacin (Indo) significantly increased cell plasma membrane permeability and became more cytotoxic than these agents alone. We confirmed this finding by measuring liposome permeability and intramembrane packing in synthetic model membranes exposed to DC, Indo, or combinations of both agents. By measuring physicochemical parameters, such as fluorescence resonance energy transfer and membrane surface charge, we found that Indo associated with phosphatidylcholine and promoted the molecular aggregation of DC and potential formation of larger and isolated bile acid complexes within either biomembranes or bile acid-lipid mixed micelles, which leads to membrane disruption. In this study, we demonstrated increased cytotoxicity of combinations of bile acid and NSAID and provided a molecular mechanism for the observed toxicity. This mechanism potentially contributes to the NSAID-induced injury in the small bowel. PMID:20203063

  17. Receptor-mediated uptake of low density lipoprotein stimulates bile acid synthesis by cultured rat hepatocytes

    SciTech Connect

    Junker, L.H.; Davis, R.A. )

    1989-12-01

    The cellular mechanisms responsible for the lipoprotein-mediated stimulation of bile acid synthesis in cultured rat hepatocytes were investigated. Adding 280 micrograms/ml of cholesterol in the form of human or rat low density lipoprotein (LDL) to the culture medium increased bile acid synthesis by 1.8- and 1.6-fold, respectively. As a result of the uptake of LDL, the synthesis of (14C)cholesterol from (2-14C)acetate was decreased and cellular cholesteryl ester mass was increased. Further studies demonstrated that rat apoE-free LDL and apoE-rich high density lipoprotein (HDL) both stimulated bile acid synthesis 1.5-fold, as well as inhibited the formation of (14C)cholesterol from (2-14C)acetate. Reductive methylation of LDL blocked the inhibition of cholesterol synthesis, as well as the stimulation of bile acid synthesis, suggesting that these processes require receptor-mediated uptake. To identify the receptors responsible, competitive binding studies using 125I-labeled apoE-free LDL and 125I-labeled apoE-rich HDL were performed. Both apoE-free LDL and apoE-rich HDL displayed an equal ability to compete for binding of the other, suggesting that a receptor or a group of receptors that recognizes both apolipoproteins is involved. Additional studies show that hepatocytes from cholestyramine-treated rats displayed 2.2- and 3.4-fold increases in the binding of apoE-free LDL and apoE-rich HDL, respectively. These data show for the first time that receptor-mediated uptake of LDL by the liver is intimately linked to processes activating bile acid synthesis.

  18. Disulfide bridge regulates ligand-binding site selectivity in liver bile acid-binding proteins.

    PubMed

    Cogliati, Clelia; Tomaselli, Simona; Assfalg, Michael; Pedò, Massimo; Ferranti, Pasquale; Zetta, Lucia; Molinari, Henriette; Ragona, Laura

    2009-10-01

    Bile acid-binding proteins (BABPs) are cytosolic lipid chaperones that play central roles in driving bile flow, as well as in the adaptation to various pathological conditions, contributing to the maintenance of bile acid homeostasis and functional distribution within the cell. Understanding the mode of binding of bile acids with their cytoplasmic transporters is a key issue in providing a model for the mechanism of their transfer from the cytoplasm to the nucleus, for delivery to nuclear receptors. A number of factors have been shown to modulate bile salt selectivity, stoichiometry, and affinity of binding to BABPs, e.g. chemistry of the ligand, protein plasticity and, possibly, the formation of disulfide bridges. Here, the effects of the presence of a naturally occurring disulfide bridge on liver BABP ligand-binding properties and backbone dynamics have been investigated by NMR. Interestingly, the disulfide bridge does not modify the protein-binding stoichiometry, but has a key role in modulating recognition at both sites, inducing site selectivity for glycocholic and glycochenodeoxycholic acid. Protein conformational changes following the introduction of a disulfide bridge are small and located around the inner binding site, whereas significant changes in backbone motions are observed for several residues distributed over the entire protein, both in the apo form and in the holo form. Site selectivity appears, therefore, to be dependent on protein mobility rather than being governed by steric factors. The detected properties further establish a parallelism with the behaviour of human ileal BABP, substantiating the proposal that BABPs have parallel functions in hepatocytes and enterocytes. PMID:19754879

  19. Effect of various antibiotics on modulation of intestinal microbiota and bile acid profile in mice

    SciTech Connect

    Zhang, Youcai; Limaye, Pallavi B.; Renaud, Helen J.; Klaassen, Curtis D.

    2014-06-01

    Antibiotic treatments have been used to modulate intestinal bacteria and investigate the role of intestinal bacteria on bile acid (BA) homeostasis. However, knowledge on which intestinal bacteria and bile acids are modified by antibiotics is limited. In the present study, mice were administered various antibiotics, 47 of the most abundant bacterial species in intestine, as well as individual BAs in plasma, liver, and intestine were quantified. Compared to the two antibiotic combinations (vancomycin + imipenem and cephalothin + neomycin), the three single antibiotics (metronidazole, ciprofloxacin and aztreonam) have less effect on intestinal bacterial profiles, and thus on host BA profiles and mRNA expression of genes that are important for BA homeostasis. The two antibiotic combinations decreased the ratio of Firmicutes to Bacteroidetes in intestine, as well as most secondary BAs in serum, liver and intestine. Additionally, the two antibiotic combinations significantly increased mRNA of the hepatic BA uptake transporters (Ntcp and Oatp1b2) and canalicular BA efflux transporters (Bsep and Mrp2), but decreased mRNA of the hepatic BA synthetic enzyme Cyp8b1, suggesting an elevated enterohepatic circulation of BAs. Interestingly, the two antibiotic combinations tended to have opposite effect on the mRNAs of most intestinal genes, which tended to be inhibited by vancomycin + imipenem but stimulated by cephalothin + neomycin. To conclude, the present study clearly shows that various antibiotics have distinct effects on modulating intestinal bacteria and host BA metabolism. - Highlights: • Various antibiotics have different effects on intestinal bacteria. • Antibiotics alter bile acid composition in mouse liver and intestine. • Antibiotics influence genes involved in bile acid homeostasis. • Clostridia appear to be important for secondary bile acid formation.

  20. [The physiology and pathology of bile acid metabolism].

    PubMed

    Coraggio, F; Farro, M; Spina, M

    1980-01-01

    The biochemistry and metabolism of bile acids are briefly described together with their importance in the maintenance of biliary homeostasis. An account is given os some situations in which such metabolism is impaired: in cirrhosis of the liver, an isotope technique was used to show a fall in cholic acid (expression of liver cell damage); in cholostasis, stress is laid on reduced bile acid synthesis and a simultaneous increase in sensitivity of the bile canicular epithelium to secretin stimulation. Lastly, evidence is produced to suggest that the diarrhoea which often recurs after extensive intestinal resection is secondary to an increase in intestinal AMPc cells induced by bile acids. PMID:6257207

  1. Management of excluded segmental bile duct leakage following liver resection

    PubMed Central

    Honoré, Charles; Vibert, Eric; Hoti, Emir; Azoulay, Daniel; Adam, René; Castaing, Denis

    2009-01-01

    Background: Postoperative bile leak secondary to a fistula is a known complication of hepatic surgery. Four different biliary fistula sub-types have been described: type A refers to minor leakage from the bile duct stump; type B to major leakage caused by insufficient closure of the bile duct stump; type C to major leakage caused by injury to the bile duct, and type D (the rarest) to the division and exclusion of a bile duct. This complication results from functional liver parenchyma in which bile drainage is excluded from the main duct. Methods: A retrospective review of the database for 163 patients diagnosed with post-hepatic surgery bile leak from April 1992 to June 2007 was performed. Results: Three patients were found to have type D biliary fistula, with durations of 3–21 months. The bile leak developed after a right hepatectomy in two patients and a right hepatectomy extending to segment IV in one patient. All three patients were rescheduled for surgical exploration, following failure of medical treatment. The procedure consisted of repeat resection of the independent liver parenchyma containing the fistula. One patient developed a postoperative leak from a hepaticojejunal anastomosis (treated conservatively) and the other two patients had an uneventful recovery. No recurrence of bile leak was encountered during their follow-up. Conclusions: Our experience indicates that conservative treatment is deceptive and not efficacious. For this condition, surgical intervention is the treatment of choice because it is very effective and is associated with a low morbidity. PMID:19718366

  2. In liver transplantation, T tube bile represents total bile flow: physiological and scintigraphic studies on biliary secretion of organic anions.

    PubMed

    Lenzen, R; Bähr, A; Eichstädt, H; Marschall, U; Bechstein, W O; Neuhaus, P

    1999-01-01

    The present study was performed to clarify the recovery of hepatocellular uptake and the biliary secretion of bile acids during the first 14 days after orthotopic liver transplantation (OLT) and to determine the fraction of bile flow appearing outside through the T tube and entering the duodenum. Therefore, we determined primary and secondary bile acids in bile samples obtained from the T tube at day 5 after OLT, while the T tube was permanently open, and at days 10 and 14 after OLT, i.e., 4 and 9 days after closure of the T tube, respectively, thus restoring enterohepatic bile acid circulation. In addition, we performed hepatobiliary scintigraphy using technetium 99m-labeled [2,4,6 trimethyl-3-bromo]imino-diacetic acid (technetium 99m-BRIDA) in 12 patients between days 4 and 17 after OLT. Chromatographic analyses of biliary bile acids showed no secondary bile acids during the first 5 days after OLT, as opposed to 10 and 14 days after OLT when enterohepatic circulation was restored. Eleven patients with an uncomplicated postoperative course after OLT showed a significantly reduced hepatic uptake and biliary secretion of 99mTc-BRIDA during the first days after OLT with progressive recovery. One patient with an acute allograft rejection episode showed almost no uptake and only minimal secretion. The bile fraction appearing outside through the inserted T tube represented 94.6% +/- 6.2% of the injected 99mTc-BRIDA. We conclude that OLT results in markedly impaired hepatocellular uptake and biliary secretion of organic anions. Simultaneously, bile acid synthesis is significantly reduced, which, in addition, diminishes bile secretion of the graft. We show that T tube bile is a valid tool for bile physiological studies in patients in whom transplantation was successfully performed. PMID:9873086

  3. Effect of Bile Pigments on the Compromised Gut Barrier Function in a Rat Model of Bile Duct Ligation

    PubMed Central

    Liu, Yuanli; Qu, Yilin; Shi, Guojing; Yang, Xinguang; Qin, Xiaofa; Wang, Xiuhong

    2014-01-01

    Background Studies have shown that the absence of bile in the gut lumen, either by bile duct ligation or bile diversion, induces mucosal injury. However, the mechanism remains elusive. In this study, the role of bile pigments in gut barrier function was investigated in a rat model of bile duct ligation. Methods Male Sprague Dawley (SD) rats were used in this study. After ligation of bile duct, the animals were administrated with free bilirubin, bilirubin ditaurate, or biliverdin by intragastric gavage. 1, 2, or 3 days later, the animals were sacrificed and the damage of mucosa was assessed by histological staining as well as biochemical parameters such as changes of diamine oxidase (DAO) and D-lactate (D-Lac) in the blood. Trypsin and chymotrypsin of the gut were also measured to determine how these digestive proteases may relate to the observed effects of bile pigments. Results Bile duct ligation (BDL) caused significant increases in gut trypsin and chymotrypsin along with damage of the mucosa as demonstrated by the histological findings under microscope, the reduced expression of tight junction molecules like occludin, and significant changes in DAO and D-lac in the blood. Free bilirubin but not bilirubin ditaurate or biliverdin showed significant inhibitions on trypsin and chymotrypsin as well as alleviated changes of histological and biochemical parameters related to gut barrier disruption. Conclusion Bile may protect the gut from damage through inhibiting digestive proteases like trypsin and chymotrypsin by free bilirubin. PMID:24892651

  4. Effect of ursodeoxycholic acid administration on bile acid composition in hamster bile.

    PubMed

    Matejka, M; Vescina, C; Carducci, C N; Alayón, A; Dios, A; Scarlatto, E; Mamianetti, A

    1990-01-01

    The modification in the composition of bile acids in hamster by the administration of high dose of ursodeoxycholic acid (UDCA) was investigated. Male Golden Syrian hamsters were divided into five groups: a control group, two groups that received 0.5 g of UDCA per 100 g of standard diet during 30 and 60 days and another two groups that received 1 g of UDCA per 100 g of standard diet during 30 and 60 days. After ether anaesthesia the gallbladder was removed and bile was immediately aspirated. Bile acids were determined by high performance liquid chromatography (HPLC). Taurolithocholic (TLCA) and glycolithocholic acids (GLCA) increased significantly in all treated groups. The glyco/tauro ratio of 0.69 in controls became more than 1 in treated animals except in the case of lithocholic acid (LCA) conjugates which remained less than 1. UDCA derivatives increased proportionally to the administered dose and the cholic/cheno ratio diminished significantly. A moderate increase of 3- and 7-keto derivatives of chenodeoxycholic acid (CDCA) was observed in all treated groups but the above mentioned increment was especially evident in 3-keto derivatives. A high percentage of UDCA administered in the hamster was likely transformed to CDCA and the glyco conjugates of the bile acids were the predominant species except for the LCA derivatives. PMID:2367280

  5. Postoperative Chemoradiotherapy for Extrahepatic Bile Duct Cancer

    SciTech Connect

    Park, Jin-hong; Choi, Eun Kyung; Ahn, Seung Do; Lee, Sang-wook; Song, Si Yeol; Yoon, Sang Min; Kim, Young Seok; Lee, Yu Sun; Lee, Sung-Gyu; Hwang, Shin; Lee, Young-Joo; Park, Kwang-Min; Kim, Tae Won; Chang, Heung Moon; Lee, Jae-Lyun; Kim, Jong Hoon

    2011-03-01

    Purpose: To evaluate the effect of postoperative concurrent chemoradiotherapy using three-dimensional conformal radiotherapy and to identify the prognostic factors that influence survival in patients with extrahepatic bile duct cancer. Methods and Materials: We retrospectively analyzed the data from 101 patients with extrahepatic bile duct cancer who had undergone postoperative concurrent chemoradiotherapy using three-dimensional conformal radiotherapy. Of the 101 patients, 52 (51%) had undergone complete resection (R0 resection) and 49 (49%) had microscopic or macroscopic residual tumors (R1 or R2 resection). The median radiation dose was 50 Gy. Also, 85 patients (84%) underwent concurrent chemotherapy with 5-fluorouracil. Results: The median follow-up period was 47 months for the surviving patients. The 5-year overall survival rate was 34% for all patients. A comparison between patients with R0 and R1 resection indicated no significant difference in the 5-year overall survival (44% vs. 33%, p = .2779), progression-free survival (35% vs. 22%, p = .3107), or locoregional progression-free survival (75% vs. 63%, p = .2784) rates. An analysis of the first failure site in the 89 patients with R0 or R1 resection indicated isolated locoregional recurrence in 7 patients. Elevated postoperative carbohydrate antigen 19-9 level was an independent prognostic factor for overall survival (p = .001) and progression-free survival (p = .033). A total of 3 patients developed Grade 3 or greater late toxicity. Conclusion: Adjuvant concurrent chemoradiotherapy using three-dimensional conformal radiotherapy appears to improve locoregional control and survival in extrahepatic bile duct cancer patients with R1 resection. The postoperative carbohydrate antigen 19-9 level might be a useful prognostic marker to select patients for more intensified adjuvant therapy.

  6. Predicting Infected Bile Among Patients Undergoing Percutaneous Cholecystostomy

    SciTech Connect

    Beardsley, Shannon L.; Shlansky-Goldberg, Richard D.; Patel, Aalpen; Freiman, David B.; Soulen, Michael C.; Stavropoulos, S. William; Clark, Timothy W.I.

    2005-04-15

    Purpose. Patients may not achieve a clinical benefit after percutaneous cholecystostomy due to the inherent difficulty in identifying patients who truly have infected gallbladders. We attempted to identify imaging and biochemical parameters which would help to predict which patients have infected gallbladders. Methods. A retrospective review was performed of 52 patients undergoing percutaneous cholecystostomy for clinical suspicion of acute cholecystitis in whom bile culture results were available. Multiple imaging and biochemical variables were examined alone and in combination as predictors of infected bile, using logistic regression. Results. Of the 52 patients, 25 (48%) had infected bile. Organisms cultured included Enterococcus, Enterobacter, Klebsiella, Pseudomonas, E. coli, Citrobacter and Candida. No biochemical parameters were significantly predictive of infected bile; white blood cell count >15,000 was weakly associated with greater odds of infected bile (odds ratio 2.0, p = NS). The presence of gallstones, sludge, gallbladder wall thickening and pericholecystic fluid by ultrasound or CT were not predictive of infected bile, alone or in combination, although a trend was observed among patients with CT findings of acute cholecystitis toward a higher 30-day mortality. Radionuclide scans were performed in 31% of patients; all were positive and 66% of these patients had infected bile. Since no patient who underwent a radionuclide scan had a negative study, this variable could not be entered into the regression model due to collinearity. Conclusion. No single CT or ultrasound imaging variable was predictive of infected bile, and only a weak association of white blood cell count with infected bile was seen. No other biochemical parameters had any association with infected bile. The ability of radionuclide scanning to predict infected bile was higher than that of ultrasound or CT. This study illustrates the continued challenge to identify bacterial cholecystitis

  7. [Liver, bile ducts and pancreatic diseases].

    PubMed

    Kanno, T

    1995-06-01

    A fundamental guideline for the use of test results concerning liver, bile duct and pancreatic diseases was proposed in 1991 from the Japan Society of Clinical Pathology (JSCP). This guideline was principally based on the document of 1988 from the Committee on liver function tests of the Japanese Society of Gastroenterology (JSG). The document from the JSG was revised in May, 1994. Also a guideline for selection of markers of hepatitis virus in hepatic disorders, was proposed in January, 1994 from the same Committee of JSG. Here, we reevaluated and discussed the JSCP guideline as taking into consideration the two 1994 JSG documents. PMID:7602802

  8. The Effect of Hydroxyl Moieties and Their Oxosubstitution on Bile Acid Association Studied in Floating Monolayers

    PubMed Central

    Szekeres, Márta; Viskolcz, Béla; Poša, Mihalj; Csanádi, János; Škorić, Dušan; Illés, Erzsébet; Tóth, Ildikó Y.; Tombácz, Etelka

    2014-01-01

    Bile salt aggregates are promising candidates for drug delivery vehicles due to their unique fat-solubilizing ability. However, the toxicity of bile salts increases with improving fat-solubilizing capability and so an optimal combination of efficient solubilization and low toxicity is necessary. To improve hydrophilicity (and decrease toxicity), we substituted hydroxyl groups of several natural bile acid (BA) molecules for oxogroups and studied their intrinsic molecular association behavior. Here we present the comparative Langmuir trough study of the two-dimensional (2D) association behavior of eight natural BAs and four oxoderivatives (traditionally called keto-derivatives) floated on an aqueous subphase. The series of BAs and derivatives showed systematic changes in the shape of the compression isotherms. Two types of association could be distinguished: the first transition was assigned to the formation of dimers through H-bonding and the second to the hydrophobic aggregation of BA dimers. Hydrophobic association of BA molecules in the films is linked to the ability of forming H-bonded dimers. Both H-bond formation and hydrophobic association weakened with increasing number of hydroxyl groups, decreasing distance between hydroxyl groups, and increasing oxosubstitution. The results also show that the Langmuir trough method is extremely useful in selecting appropriate BA molecules to design drug delivery systems. PMID:25685831

  9. Properties Related to Bile as Viewed in Makhzan ol-Adviya

    PubMed Central

    Mosaffa-Jahromi, Maryam

    2016-01-01

    Background: The human body has simple and compound organs that obtain their nourishment through four humors. One of them is bile (yellow bile). According to Iranian traditional medicine (ITM), there are various kinds of natural medicines with their specific mechanisms of action affecting on bile in the human body. Hakim Aghili Shirazi (18th century), one of the great scholars in ITM field, introduced all types of natural medicines influencing bile in his valuable book written in Persian, “Makhzan-ul-Adwiah”, about single herbal medicines (mofradat). The aim of this review article was to introduce all types of natural medicines influencing bile in the human body. Methods: The classification of natural medicines influencing bile was studied in this article as viewed by Hakim Aghili Shirazi in Makhzan-ul-Adwiah. Results: Reviewing Makhzan-ul-Adwiah, this natural influencing bile is defined in ten categories. These are Haabes-e Safra (obstructive of bile), Daafe-e Safra (expellant of bile), Raafe-e Safra (resolver of bile), Ghaate-e Safra (stopper of bile), Ghaame-e Safra (suppressant of bile), Kaasere-e Safra (fractionating of bile), Mohregh-e Safra (burner of bile), Moder-e Safra (bile diuretic), Mosaken-e Safra (bile reliever), and Mos’hel-e Safra (bile laxative). Conclusion: Each group has a specific function and mechanism on bile. Recognition of the precise mechanisms of these natural medicines is necessary to prescribe a suitable remedy for bilious diseases by traditional medicine specialists.

  10. Isolation and characterization of chicken bile matrix metalloproteinase

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Avian bile is rich in matrix metalloproteinases (MMP), the enzymes that cleave extracellular matrix (ECM) proteins such as collagens and proteoglycans. Changes in bile MMP expression have been correlated with hepatic and gall bladder pathologies but the significance of their expression in normal, he...

  11. Chicken bile Matrix metalloproteinase; its characterization and significance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous studies from our lab had shown that the avian bile was rich in matrix metalloproteinase (MMP), enzymes implicated in the degradation of extracellular matrices (ECM) such as collagens and proteoglycans. We hypothesized that bile MMP may be evolutionarily associated with the digestion of ECM ...

  12. Bile signalling promotes chronic respiratory infections and antibiotic tolerance

    PubMed Central

    Reen, F. Jerry; Flynn, Stephanie; Woods, David F.; Dunphy, Niall; Chróinín, Muireann Ní; Mullane, David; Stick, Stephen; Adams, Claire; O’Gara, Fergal

    2016-01-01

    Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa, while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum samples demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease. PMID:27432520

  13. A bile‐inducible membrane protein mediates bifidobacterial bile resistance

    PubMed Central

    Ruiz, Lorena; O'Connell‐Motherway, Mary; Zomer, Aldert; de los Reyes‐Gavilán, Clara G.; Margolles, Abelardo; van Sinderen, Douwe

    2012-01-01

    Summary Bbr_0838 from Bifidobacterium breve UCC2003 is predicted to encode a 683 residue membrane protein, containing both a permease domain that displays similarity to transporters belonging to the major facilitator superfamily, as well as a CBS (cystathionine beta synthase) domain. The high level of similarity to bile efflux pumps from other bifidobacteria suggests a significant and general role for Bbr_0838 in bile tolerance. Bbr_0838 transcription was shown to be monocistronic and strongly induced upon exposure to bile. Further analysis delineated the transcriptional start site and the minimal region required for promoter activity and bile regulation. Insertional inactivation of Bbr_0838 in B. breve UCC2003 resulted in a strain, UCC2003:838800, which exhibited reduced survival upon cholate exposure as compared with the parent strain, a phenotype that was reversed when a functional, plasmid‐encoded Bbr_0838 gene was introduced into UCC2003:838800. Transcriptome analysis of UCC2003:838800 grown in the presence or absence of bile demonstrated that transcription of Bbr_0832, which is predicted to encode a macrolide efflux transporter gene, was significantly increased in the presence of bile, representing a likely compensatory mechanism for bile removal in the absence of Bbr_0838. This study represents the first in‐depth analysis of a bile‐inducible locus in bifidobacteria, identifying a key gene relevant for bifidobacterial bile tolerance. PMID:22296641

  14. Bile salts are effective taste stimuli in channel catfish.

    PubMed

    Rolen, S H; Caprio, J

    2008-09-01

    Bile salts are known olfactory stimuli for teleosts, but only a single report has indicated that the taste system of a fish was sensitive to this class of stimuli. Here, gustatory responses of the channel catfish, Ictalurus punctatus, to four bile salts that included taurine-, glycine- and non-conjugated compounds along with three stimulatory amino acids as a comparison were investigated using extracellular electrophysiological techniques. Integrated multiunit responses were obtained from the branch of the facial nerve innervating taste buds on the maxillary barbel. Bile salts were shown to be highly effective facial taste stimuli, with estimated electrophysiological thresholds for three of the four tested bile salts of approximately 10(-11) mol l(-1) to 10(-10) mol l(-1), slightly lower by 1-2 log units than those to amino acids in the same species. Although the sensitivity of the facial taste system of the channel catfish to bile salts is high, the relative magnitude of the response to suprathreshold concentrations of bile salts was significantly less than that to amino acids. Multiunit cross-adaptation experiments indicate that bile salts and amino acids bind to relatively independent receptor sites; however, nerve-twig data and single-fiber recordings suggest that both independent and shared neural pathways exist for the transmission of bile salt and amino acid information to the primary gustatory nucleus of the medulla. PMID:18723536

  15. Isolation and characterization of chicken bile matrix metalloproteinase

    PubMed Central

    Packialakshmi, B.; Liyanage, R.; Rasaputra, K. S.; Lay, Jackson O.; Rath, N. C.

    2014-01-01

    Avian bile is rich in matrix metalloproteinases (MMP), the enzymes that cleave extracellular matrix proteins such as collagens and proteoglycans. Changes in bile MMP expression have been correlated with hepatic and gall bladder pathologies, but the significance of their expression in normal, healthy bile is not understood. We hypothesized that the MMP in bile may aid the digestion of native collagens that are resistant to conventional gastric proteases. Hence, the objective of this study was to characterize the bile MMP and check its regulation in association with dietary factors. We used substrate zymography, azocoll protease assay, and gelatin affinity chromatography to identify and purify the MMP from chicken bile. Using zymography and SDS PAGE, 5 bands at 70, 64, 58, 50, and 42 kDa were detected. The bands corresponding to 64, 50, and 42 kDa were identified as MMP2 using trypsin in-gel digestion and matrix-assisted laser desorption time-of-flight mass spectrometry and peptide mass fingerprinting. Chickens fed diets containing gelatin supplements showed higher levels of MMP expression in the bile by both azocoll assay and zymography. We conclude that the bile MMP may be associated with the digestion of collagens and other extracellular matrix proteins in avian diets. PMID:24879699

  16. Congenital dilatation of the intrahepatic bile ducts with cholangiocarcinoma

    PubMed Central

    Gallagher, P. J.; Millis, R. R.; Mitchinson, M. J.

    1972-01-01

    Intrahepatic cholangiocarcinomas were found at necropsy in two previously reported cases of congenital dilatation of the intrahepatic bile ducts. The nature of the developmental abnormality is discussed and compared with other forms of biliary dilatation. Slow-flowing bile for many years probably leads to cholangiocarcinoma. Images PMID:4343747

  17. Effects of bile acids on hepatocellular signaling and secretion.

    PubMed Central

    Beuers, U.

    1997-01-01

    Bile acids modulate hepatocellular signaling pathways in vitro at physiological concentrations. The present paper provides a brief overview of the effects of bile acids on three key messengers in liver cells: cytosolic free calcium, protein kinase A and protein kinase C. PMID:9626754

  18. Bile signalling promotes chronic respiratory infections and antibiotic tolerance.

    PubMed

    Reen, F Jerry; Flynn, Stephanie; Woods, David F; Dunphy, Niall; Chróinín, Muireann Ní; Mullane, David; Stick, Stephen; Adams, Claire; O'Gara, Fergal

    2016-01-01

    Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa, while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum samples demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease. PMID:27432520

  19. Impaired Bile Acid Homeostasis in Children with Severe Acute Malnutrition

    PubMed Central

    Zhang, Ling; Voskuijl, Wieger; Mouzaki, Marialena; Groen, Albert K.; Alexander, Jennifer; Bourdon, Celine; Wang, Alice; Versloot, Christian J.; Di Giovanni, Valeria; Wanders, Ronald J. A.; Bandsma, Robert

    2016-01-01

    Objective Severe acute malnutrition (SAM) is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to investigate whether SAM is associated with clinically relevant changes in bile acid homeostasis. Design An initial discovery cohort with 5 healthy controls and 22 SAM-patients was used to identify altered bile acid homeostasis. A follow up cohort of 40 SAM-patients were then studied on admission and 3 days after clinical stabilization to assess recovery in bile acid metabolism. Recruited children were 6–60 months old and admitted for SAM in Malawi. Clinical characteristics, feces and blood were collected on admission and prior to discharge. Bile acids, 7α-hydroxy-4-cholesten-3-one (C4) and FGF-19 were quantified. Results On admission, total serum bile acids were higher in children with SAM than in healthy controls and glycine-conjugates accounted for most of this accumulation with median and interquartile range (IQR) of 24.6 μmol/L [8.6–47.7] compared to 1.9 μmol/L [1.7–3.3] (p = 0.01) in controls. Total serum bile acid concentrations did not decrease prior to discharge. On admission, fecal conjugated bile acids were lower and secondary bile acids higher at admission compared to pre- discharge, suggesting increased bacterial conversion. FGF19 (Fibroblast growth factor 19), a marker of intestinal bile acid signaling, was higher on admission and was associated with decreased C4 concentrations as a marker of bile acid synthesis. Upon recovery, fecal calprotectin, a marker of intestinal inflammation, was lower. Conclusion SAM is associated with increased serum bile acid levels despite reduced synthesis rates. In SAM, there tends to be increased deconjugation of bile acids and conversion from primary to secondary bile acids, which may contribute to the

  20. Deficiency of Capicua disrupts bile acid homeostasis

    PubMed Central

    Kim, Eunjeong; Park, Sungjun; Choi, Nahyun; Lee, Jieon; Yoe, Jeehyun; Kim, Soeun; Jung, Hoe-Yune; Kim, Kyong-Tai; Kang, Hyojin; Fryer, John D.; Zoghbi, Huda Y.; Hwang, Daehee; Lee, Yoontae

    2015-01-01

    Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type 1 and cancer in mammals; however, the in vivo physiological functions of CIC remain largely unknown. Here we show that Cic hypomorphic (Cic-L-/-) mice have impaired bile acid (BA) homeostasis associated with induction of proinflammatory cytokines. We discovered that several drug metabolism and BA transporter genes were down-regulated in Cic-L-/- liver, and that BA was increased in the liver and serum whereas bile was decreased within the gallbladder of Cic-L-/- mice. We also found that levels of proinflammatory cytokine genes were up-regulated in Cic-L-/- liver. Consistent with this finding, levels of hepatic transcriptional regulators, such as hepatic nuclear factor 1 alpha (HNF1α), CCAAT/enhancer-binding protein beta (C/EBPβ), forkhead box protein A2 (FOXA2), and retinoid X receptor alpha (RXRα), were markedly decreased in Cic-L-/- mice. Moreover, induction of tumor necrosis factor alpha (Tnfα) expression and decrease in the levels of FOXA2, C/EBPβ, and RXRα were found in Cic-L-/- liver before BA was accumulated, suggesting that inflammation might be the cause for the cholestasis in Cic-L-/- mice. Our findings indicate that CIC is a critical regulator of BA homeostasis, and that its dysfunction might be associated with chronic liver disease and metabolic disorders. PMID:25653040

  1. Bile Acid diarrhea: prevalence, pathogenesis, and therapy.

    PubMed

    Camilleri, Michael

    2015-05-23

    Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn's disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as (75)selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD. PMID:25918262

  2. Bile Acid Diarrhea: Prevalence, Pathogenesis, and Therapy

    PubMed Central

    Camilleri, Michael

    2015-01-01

    Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn’s disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as 75selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD. PMID:25918262

  3. The Metabolism of Cholestanol, Cholesterol, and Bile Acids in Cerebrotendinous Xanthomatosis

    PubMed Central

    Salen, Gerald; Grundy, Scott M.

    1973-01-01

    The metabolism of cholesterol and its 5-dihydro derivative, cholestanol, was investigated by means of sterol balance and isotope kinetic techniques in 3 subjects with cerebrotendinous xanthomatosis (CTX) and 11 other individuals. All subjects were hospitalized on a metabolic ward and were fed diets practically free of cholesterol and cholestanol. After the intravenous administration of [1,2-3H]cholestanol, the radioactive sterol was transported and esterified in plasma lipoproteins in an identical manner to cholesterol. In these short-term experiments, the specific activity-time curves of plasma cholestanol conformed to two-pool models in both the CTX and control groups. However, cholestanol plasma concentrations, total body miscible pools, and daily synthesis rates were two to five times greater in the CTX than control individuals. The short-term specific activity decay curves of plasma [4-14C]cholesterol also conformed to two-pool models in both groups. However, in the CTX subjects the decay was more rapid, and daily cholesterol synthesis was nearly double that of the control subjects. Plasma concentrations and the sizes of the rapidly turning over pool of exchangeable cholesterol were apparently small in the CTX subjects, and these measurements did not correlate with the large cholesterol deposits found in tendon and tuberous xanthomas. Despite active cholesterol synthesis, bile acid formation was subnormal in the CTX subjects. However, bile acid sequestration was accompanied by a rise in plasma cholestanol levels and greatly augmented fecal cholestanol outputs. In contrast, the administration of clofibrate lowered plasma cholesterol levels 50% and presumably reduced synthesis in the CTX subjects. Plasma cholesterol concentrations and fecal steroid excretion did not change significantly during this therapy. These findings indicate that the excessive tissue deposits of cholesterol and cholestanol that characterize CTX were associated with hyperactive neutral

  4. Intestinal interaction of bile acids, phospholipids, dietary fibers, and cholestyramine.

    PubMed

    Gallaher, D; Schneeman, B O

    1986-04-01

    Binding of bile acids and phospholipids to a number of dietary fibers and cholestyramine (CH) within the small intestine was determined. The fibers used were cellulose, wheat bran, oat bran, guar gum (GG), and lignin (LG). GG, LG, and CH bound significant quantities of bile acids. However, only the CH reduced the bile acid concentration within the aqueous phase of the intestinal contents. Significant phospholipid binding was found only with CH. None of the test substances significantly reduced the quantity of solubilized lipid. Multiple regression analysis indicated that the total quantity of bile acids and phospholipids in the aqueous phase of the intestinal contents was a significant predictor of the quantity of lipid solubilized within the contents (r2 = 0.67). The failure of GG and LG to significantly decrease the amount of solubilized lipid suggests that the hypocholesterolemic effect of these fibers is due more to their bile acid binding capacity than to an effect on lipid solubilization. PMID:3008573

  5. Anicteric early bile duct carcinoma detection with magnetic resonance cholangiopancreatography.

    PubMed

    Oshikiri, Taro; Morita, Takayuki; Fujita, Miyoshi; Miyasaka, Yuji; Senmaru, Naoto; Yamada, Hidehisa; Kondo, Satoshi; Katoh, Hiroyuki

    2005-01-01

    The poor prognosis of extrahepatic bile duct carcinoma makes early detection and diagnosis essential for positive patient outcomes. We describe 2 cases of jaundice-free early extrahepatic bile duct carcinoma detected by magnetic resonance cholangiopancreatography. Extrahepatic bile duct carcinoma was discovered incidentally in patient 1 by magnetic resonance cholangiopancreatography during evaluation of a gallbladder stone. In patient 2, extrahepatic bile duct carcinoma was found during a routine health maintenance exam. Both patients underwent radical surgical intervention. Both patient 1 and 2 have remained in good health for over one year, 3.5 and one year, respectively, and have not exhibited any signs or symptoms of relapse or cancer recurrence. Based on these cases, it appears that magnetic resonance cholangiopancreatography can play a significant role in the early detection of extrahepatic bile duct carcinoma and improve disease prognosis. PMID:15816438

  6. All-trans retinoic acid regulates hepatic bile acid homeostasis

    PubMed Central

    Yang, Fan; He, Yuqi; Liu, Hui-Xin; Tsuei, Jessica; Jiang, Xiaoyue; Yang, Li; Wang, Zheng-Tao; Wan, Yu-Jui Yvonne

    2014-01-01

    Retinoic acid (RA) and bile acids share common roles in regulating lipid homeostasis and insulin sensitivity. In addition, the receptor for RA (retinoid x receptor) is a permissive partner of the receptor for bile acids, farnesoid x receptor (FXR/NR1H4). Thus, RA can activate the FXR-mediated pathway as well. The current study was designed to understand the effect of all-trans RA on bile acid homeostasis. Mice were fed an all-trans RA-supplemented diet and the expression of 46 genes that participate in regulating bile acid homeostasis was studied. The data showed that all-trans RA has a profound effect in regulating genes involved in synthesis and transport of bile acids. All-trans RA treatment reduced the gene expression levels of Cyp7a1, Cyp8b1, and Akr1d1, which are involved in bile acid synthesis. All-trans RA also decreased the hepatic mRNA levels of Lrh-1 (Nr5a2) and Hnf4α (Nr2a1), which positively regulate the gene expression of Cyp7a1 and Cyp8b1. Moreover, all-trans RA induced the gene expression levels of negative regulators of bile acid synthesis including hepatic Fgfr4, Fxr, and Shp (Nr0b2) as well as ileal Fgf15. All-trans RA also decreased the expression of Abcb11 and Slc51b, which have a role in bile acid transport. Consistently, all-trans RA reduced hepatic bile acid levels and the ratio of CA/CDCA, as demonstrated by liquid chromatography-mass spectrometry. The data suggest that all-trans RA-induced SHP may contribute to the inhibition of CYP7A1 and CYP8B1, which in turn reduces bile acid synthesis and affects lipid absorption in the gastrointestinal tract. PMID:25175738

  7. Bile and liver metallothionein behavior in copper-exposed fish.

    PubMed

    Hauser-Davis, Rachel A; Bastos, Frederico F; Tuton, Bernardo; Chávez Rocha, Rafael; Saint' Pierre, Tatiana; Ziolli, Roberta L; Arruda, Marco A Z

    2014-01-01

    The present study analyzed metallothionein (MT) excretion from liver to bile in Nile Tilapia (Oreochromis niloticus) exposed to sub-lethal copper concentrations (2mgL(-1)) in a laboratory setting. MTs in liver and bile were quantified by spectrophotometry after thermal incubation and MT metal-binding profiles were characterized by size exclusion high performance liquid chromatography coupled to ICP-MS (SEC-HPLC-ICP-MS). Results show that liver MT is present in approximately 250-fold higher concentrations than bile MT in non-exposed fish. Differences between the MT profiles from the control and exposed group were observed for both matrices, indicating differential metal-binding behavior when comparing liver and bile MT. This is novel data regarding intra-organ MT comparisons, since differences between organs are usually present only with regard to quantification, not metal-binding behavior. Bile MT showed statistically significant differences between the control and exposed group, while the same did not occur with liver MT. This indicates that MTs synthesized in the liver accumulate more slowly than MTs excreted from liver to bile, since the same fish presented significantly higher MT levels in liver when compared to bile. We postulate that bile, although excreted in the intestine and partially reabsorbed by the same returning to the liver, may also release MT-bound metals more rapidly and efficiently, which may indicate an efficient detoxification route. Thus, we propose that the analysis of bile MTs to observe recent metal exposure may be more adequate than the analysis of liver MTs, since organism responses to metals are more quickly observed in bile, although further studies are necessary. PMID:24210855

  8. BILE ACIDS REGULATE THE ONTOGENIC EXPRESSION OF ILEAL BILE ACID BINDING PROTEIN IN THE RAT VIA THE FARNESOID X RECEPTOR

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In the rat, an increase in ileal bile acid binding protein (IBABP) expression occurs during the third postnatal week. In vitro studies suggest that bile acids (BAs) increase IBABP transcription by activating the BA receptor, farnesoid X receptor (FXR). Thus, we investigated the role of BAs on the on...

  9. Rapid Determination of Bile Acids in Bile from Various Mammals by Reversed-Phase Ultra-Fast Liquid Chromatography.

    PubMed

    Si, Gu Leng Ri; Yao, Peng; Shi, Luwen

    2015-08-01

    A valid and efficient reversed-phase ultra-fast liquid chromatography method was developed for the simultaneous determination of 13 bile acids in the bile of three mammal species, including rat, pig and human gallstone patients. Chromatographic separation was performed with a Shim-pack XR-ODS column, and the mobile phase consisted of acetonitrile and potassium phosphate buffer (pH 2.6) at a flow rate of 0.5 mL min(-1). The linear detection range of most bile acids ranged from 2 to 600 ng µL(-1) with a good correlation coefficient (>0.9995). The precision of each bile acid was <1.8% for intraday and <4.8% for interday. All bile acids were separated in 15 min with satisfactory resolution, and the total analysis time was 18 min, including equilibration. The method was successfully applied in rapid screening of bile samples from the three mammals. Significant metabolic frameworks of bile acids among various species were observed, whereas considerable quantitative variations in both inter- and intraspecies were also observed, especially for gallstone patients. Our results suggest that detecting the change of bile acid profiles could be applied for the diagnosis of gallstone disease. PMID:25520305

  10. Substitutes for Bear Bile for the Treatment of Liver Diseases: Research Progress and Future Perspective

    PubMed Central

    Li, Sha; Tan, Hor Yue; Wang, Ning; Hong, Ming; Li, Lei; Cheung, Fan; Feng, Yibin

    2016-01-01

    Bear bile has been a well-known Chinese medicine for thousands of years. Because of the endangered species protection, the concept on substitutes for bear bile was proposed decades ago. Based on their chemical composition and pharmacologic actions, artificial bear bile, bile from other animals, synthetic compounds, and medicinal plants may be the promising candidates to replace bear bile for the similar therapeutic purpose. Accumulating research evidence has indicated that these potential substitutes for bear bile have displayed the same therapeutic effects as bear bile. However, stopping the use of bear bile is a challenging task. In this review, we extensively searched PubMed and CNKI for literatures, focusing on comparative studies between bear bile and its substitutes for the treatment of liver diseases. Recent research progress in potential substitutes for bear bile in the last decade is summarized, and a strategy for the use of substitutes for bear bile is discussed carefully. PMID:27087822

  11. Bile Acid-Activated Receptors, Intestinal Microbiota, and the Treatment of Metabolic Disorders.

    PubMed

    Fiorucci, Stefano; Distrutti, Eleonora

    2015-11-01

    The composition of the bile acid pool is a function of the microbial metabolism of bile acids in the intestine. Perturbations of the microbiota shape the bile acid pool and modulate the activity of bile acid-activated receptors (BARs) even beyond the gastrointestinal tract, triggering various metabolic axes and altering host metabolism. Bile acids, in turn, can also regulate the composition of the gut microbiome at the highest taxonomic levels. Primary bile acids from the host are preferential ligands for the farnesoid X receptor (FXR), while secondary bile acids from the microbiota are ligands for G-protein-coupled bile acid receptor 1 (GPBAR1). In this review, we examine the role of bile acid signaling in the regulation of intestinal microbiota and how changes in bile acid composition affect human metabolism. Bile acids may offer novel therapeutic modalities in inflammation, obesity, and diabetes. PMID:26481828

  12. Substitutes for Bear Bile for the Treatment of Liver Diseases: Research Progress and Future Perspective.

    PubMed

    Li, Sha; Tan, Hor Yue; Wang, Ning; Hong, Ming; Li, Lei; Cheung, Fan; Feng, Yibin

    2016-01-01

    Bear bile has been a well-known Chinese medicine for thousands of years. Because of the endangered species protection, the concept on substitutes for bear bile was proposed decades ago. Based on their chemical composition and pharmacologic actions, artificial bear bile, bile from other animals, synthetic compounds, and medicinal plants may be the promising candidates to replace bear bile for the similar therapeutic purpose. Accumulating research evidence has indicated that these potential substitutes for bear bile have displayed the same therapeutic effects as bear bile. However, stopping the use of bear bile is a challenging task. In this review, we extensively searched PubMed and CNKI for literatures, focusing on comparative studies between bear bile and its substitutes for the treatment of liver diseases. Recent research progress in potential substitutes for bear bile in the last decade is summarized, and a strategy for the use of substitutes for bear bile is discussed carefully. PMID:27087822

  13. Influence of Phosphatidylcholine and Calcium on Self-Association and Bile Salt Mixed Micellar Binding of the Natural Bile Pigment, Bilirubin Ditaurate.

    PubMed

    Neubrand, Michael W; Carey, Martin C; Laue, Thomas M

    2015-11-17

    Recently [Neubrand, M. W., et al. (2015) Biochemistry 54, 1542-1557], we determined a concentration-dependent monomer-dimer-tetramer equilibrium in aqueous bilirubin ditaurate (BDT) solutions and explored the nature of high-affinity binding of BDT monomers with monomers and micelles of the common taurine-conjugated bile salts (BS). We now investigate, employing complementary physicochemical methods, including fluorescence emission spectrophotometry and quasi-elastic light scattering spectroscopy, the influence of phosphatidylcholine (PC), the predominant phospholipid of bile and calcium, the major divalent biliary cation, on these self-interactions and heterointeractions. We have used short-chain, lyso and long-chain PC species as models and contrasted our results with those of parallel studies employing unconjugated bilirubin (UCB) as the fully charged dianion. Both bile pigments interacted with the zwitterionic headgroup of short-chain lecithins, forming water-soluble (BDT) and insoluble ion-pair complexes (UCB), respectively. Upon micelle formation, BDT monomers apparently remained at the headgroup mantle of short-chain PCs, but the ion pairs with UCB became internalized within the micelle's hydrophobic core. BDT interacted with the headgroups of unilamellar egg yolk (EY) PC vesicles; however, with the simultaneous addition of CaCl2, a reversible aggregation took place, but not vesicle fusion. With mixed EYPC/BS micelles, BDT became bound to the hydrophilic surface (as with simple BS micelles), and in turn, both BDT and BS bound calcium, but not other divalent cations. The calcium complexation of BDT and BS was enhanced strongly with increases in micellar EYPC, suggesting calcium-mediated cross-bridging of hydrophilic headgroups at the micelle's surface. Therefore, the physicochemical binding of BDT to BS in an artificial bile medium is influenced not only by BS species and concentration but also by long-chain PCs and calcium ions that exert a specific rather

  14. Regulation of Bile Salt Transport in Rat Liver

    PubMed Central

    Simon, Francis R.; Sutherland, Eileen M.; Gonzalez, Manuel

    1982-01-01

    Expansion of the bile salt pool size in rats increases maximum excretory capacity for taurocholate. We examined whether increased bile salt transport is due to recruitment of centrolobular transport units or rather to adaptive changes in the hepatocyte. Daily sodium cholate (100 mg/100 g body wt) was administered orally to rats. This treatment was well tolerated for at least 4 d and produced an 8.2-fold expansion of the bile salt pool. This expanded pool consisted predominently (99%) of cholic and deoxycholic acids. Significantly increased bile salt transport was not observed until 16 h after bile acid loading, and maximum elevations of transport capacity to 2.3-fold of control required ∼2 d. In contrast, maximum sulfobromophthalein excretion rates increased 2.2-fold as early as 4 h and actually fell to 1.5-fold increase at 4 d. We studied the possibility that this adaptive increase in bile salt secretory transport was due to changes in canalicular surface membrane area, lipid composition, or increased number of putative carriers. Canalicular membrane protein recovery and the specific activities of leucine aminopeptidase, Mg++-ATPase and 5′-nucleotidase activities were unaltered by bile salt pool expansion. The content of free and esterified cholesterol and total phospholipids was unchanged in liver surface membrane fractions compared with control values. In contrast, sodium cholate administration selectively increased specific [14C]cholic acid binding sites twofold in liver surface membrane fractions. Increased numbers of [14C]cholic acid receptors (a) was associated with the time-dependent increase in bile salt transport, and (b) was selective for the taurine conjugate of cholate and (c) was reduced by chenodeoxycholate. Changes in bile acid binding sites 16 h following taurocholate and chenodeoxycholate and the lack of change with glycocholate was associated with comparable changes in bile salt transport. In conclusion, selective bile salts increase bile

  15. Bile acid synthetic defects and liver disease: a comprehensive review.

    PubMed

    Bove, Kevin E; Heubi, James E; Balistreri, William F; Setchell, Kenneth D R

    2004-01-01

    Bile acid synthetic defects (BASD), uncommon genetic disorders that are responsible for approximately 2% of persistent cholestasis in infants, are reviewed with emphasis on morphology of associated liver disease. The associated liver diseases may be life threatening, and are treatable, usually by replacement of deficient primary bile acids. Specific diagnosis is made by analysis of body fluids (bile, blood, and urine) using fast atom bombardment-mass spectroscopy (FAB-MS) and gas chromatography-mass spectroscopy (GC-MS). Inborn errors have been demonstrated for four single enzymes involved in modification of the sterol nucleus and in five steps in modification of the side-chain to form cholic and chenodeoxycholic acids, the primary bile acids. With few exceptions, BASD cause liver diseases that vary from severe to mild depending on the defect. In three of four known defects of sterol nucleus modification, liver disease is progressive. Progression of liver disease is most rapid when the defect results in accumulation of toxic monohydroxy and unsaturated oxo-bile acids. Liver disease may be transient, delayed in onset and mild. Reduced bile flow caused by atypical bile acids contributes to cholestasis and may be the dominant factor in defects of side-chain synthesis, peroxisomal abiogenesis and S-L-O syndrome. Pathological findings may include intralobular cholestasis with giant cell transformation, prevalence of necrotic hepatocytes including giant cell forms, and hepatitic injury confined to the portal limiting plate where the smallest bile ductules may be injured and where fibrosis typically develops. Interlobular bile ducts are usually spared. Ultrastructure of liver reveals nonspecific changes with the possible exception of unusual canalicular morphology in some defects. The course of BASD may be modified by replacement of deficient primary bile acids, which produces beneficial feedback inhibition of abnormal bile acid production and enhances choluresis. Giant

  16. The cytotoxicity of hydrophobic bile acids is ameliorated by more hydrophilic bile acids in intestinal cell lines IEC-6 and Caco-2.

    PubMed

    Araki, Yoshio; Andoh, Akira; Bamba, Hiromichi; Yoshikawa, Kouhei; Doi, Hisakazu; Komai, Yasunobu; Higuchi, Akihiko; Fujiyama, Yoshihide

    2003-01-01

    Bile acids, especially those with hydrophobic properties, are known to possess cytotoxicity. However, the mechanisms responsible for the cytotoxicity of bile acids are still under investigation. On the other hand, the hydrophilic bile acid, ursodeoxycholic acid has been reported to exhibit therapeutic effects against cytotoxic hydrophobic bile acids. The aim of the present study was to investigate the cytotoxicity of individual bile acids and combinations of bile acids using the intestinal cell lines IEC-6 and Caco-2 cells. The cytotoxicities of individual bile acids and the effects of various bile acid combinations were evaluated using the MTS [3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. The bile acids induced cytotoxic effects depending on their hydrophobicity except for hyodeoxycholic acid. In the study for the effects of combined bile acids, not only ursodeoxycholic acid but other hydrophilic bile salts such as cholic acid and hyocholic acid exhibited cytoprotection against deoxycholic acid-induced cytotoxicity. Moreover, even some hydrophobic bile acids, such as chenodeoxycholic acid also exhibited cytoprotection. It is possible that the cytotoxicity of hydrophobic bile acids is ameliorated by more hydrophilic bile acids under certain conditions. The understanding of the precise mechanism of this phenomenon remains to be determined. PMID:14534721

  17. Effects of bile acid administration on bile acid synthesis and its circadian rhythm in man

    SciTech Connect

    Pooler, P.A.; Duane, W.C.

    1988-09-01

    In man bile acid synthesis has a distinct circadian rhythm but the relationship of this rhythm to feedback inhibition by bile acid is unknown. We measured bile acid synthesis as release of 14CO2 from (26-14C)cholesterol every 2 hr in three normal volunteers during five separate 24-hr periods. Data were fitted by computer to a cosine curve to estimate amplitude and acrophase of the circadian rhythm. In an additional six volunteers, we measured synthesis every 2 hr from 8:00 a.m. to 4:00 p.m. only. During the control period, amplitude (expressed as percentage of mean synthesis) averaged 52% and acrophase averaged 6:49 a.m. During administration of ursodeoxycholic acid (15 mg per kg per day), synthesis averaged 126% of baseline (p less than 0.1), amplitude averaged 43% and acrophase averaged 6:20 a.m. During administration of chenodeoxycholic acid (15 mg per kg per day), synthesis averaged 43% of baseline (p less than 0.001), amplitude averaged 53% and acrophase averaged 9:04 a.m. Addition of prednisone to this regimen of chenodeoxycholic acid to eliminate release of 14CO2 from corticosteroid hormone synthesis resulted in a mean amplitude of 62% and a mean acrophase of 6:50 a.m., values very similar to those in the baseline period. Administration of prednisone alone also did not significantly alter the baseline amplitude (40%) or acrophase (6:28 a.m.). We conclude that neither chenodeoxycholic acid nor ursodeoxycholic acid significantly alters the circadian rhythm of bile acid synthesis in man.

  18. Effects of bile and bile salts on growth and membrane lipid uptake by Giardia lamblia. Possible implications for pathogenesis of intestinal disease.

    PubMed Central

    Farthing, M J; Keusch, G T; Carey, M C

    1985-01-01

    We have shown previously that ox and pig bile accelerate in vitro growth of Giardia lamblia. We have now investigated the possible mechanisms by which mammalian biles promote parasite growth. Growth effects of (a) ox, pig, guinea pig, and human biles, (b) pure bile salts, and (c) egg and soybean lecithins were studied in the presence of a lecithin-containing growth medium. Individually, dilute native bile and pure sodium taurocholate (TC), glycocholate (GC), and taurodeoxycholate (TDC) promoted parasite growth; growth was most marked with biles of high phospholipid content, with biles enriched in more hydrophobic bile salts (ox approximately equal to human greater than pig greater than guinea pig) and with micellar concentrations of GC and submicellar concentrations of TC and TDC. By measuring uptake of radiolabeled biliary lipids from bile and bile salt-supplemented growth medium, we showed that the parasite consumed bile lipids, with the rank order lecithin greater than bile salts. Apparent net uptake of cholesterol was considered to be due to exchange, since net loss of cholesterol from the growth medium was not detected. Although bile and bile salt-stimulated parasite growth was associated with enhanced lecithin uptake, reduction in generation time was observed at low bile and bile salt concentrations when lecithin uptake was similar to bile free controls. Thus, bile salts may stimulate Giardia growth initially by a mechanism independent of enhanced membrane phospholipid uptake. However, since Giardia has no capacity to synthesize membrane lipid, biliary lecithin may be a major source of phospholipid for growth of this parasite. PMID:4056050

  19. [Morphological study of bile in the diagnosis of biliary diseases].

    PubMed

    Potekhina, Iu P

    2003-01-01

    The purpose of this work was to study principles of bile structurization in healthy people and patients with various biliary diseases. 160 patients with different biliary diseases and other diseases of the hepatopancreaticoduodenal zone were examined. Samples of gallbladder bile were taken from corpses of young men, who did not have any diseases of the hepatopancreaticoduodenal zone. Their diagnoses were confirmed by an ultrasound morphological study. Bile was studied by the cuneate dehydration and viscosimetric methods. The structure of facies of gallbladder bile under conditions of absence of diseases of the hepatopancreaticoduodenal zone was shown. The facies have a wide convex peripheral zone (a cushion) without any well-defined border. The central part of the facies is amorphous or fine-grained, sometimes with occasional inclusions of larger crystals. Markers of exacerbation of chronic cholecystitis (dendrites in the central zone of bile facies) as well as signs of the presence of a malignant neoplasm touching the bile (large diamond-shaped crystals in the central zone of bile facies where dendrites begin) were discovered. PMID:14556555

  20. Intestinal bile acid physiology and pathophysiology

    PubMed Central

    Martínez-Augustin, Olga; de Medina, Fermín Sánchez

    2008-01-01

    Bile acids (BAs) have a long established role in fat digestion in the intestine by acting as tensioactives, due to their amphipathic characteristics. BAs are reabsorbed very efficiently by the intestinal epithelium and recycled back to the liver via transport mechanisms that have been largely elucidated. The transport and synthesis of BAs are tightly regulated in part by specific plasma membrane receptors and nuclear receptors. In addition to their primary effect, BAs have been claimed to play a role in gastrointestinal cancer, intestinal inflammation and intestinal ionic transport. BAs are not equivalent in any of these biological activities, and structural requirements have been generally identified. In particular, some BAs may be useful for cancer chemoprevention and perhaps in inflammatory bowel disease, although further research is necessary in this field. This review covers the most recent developments in these aspects of BA intestinal biology. PMID:18837078

  1. Hepatic transport of bile acid and effect of conjugation.

    PubMed

    Kitani, K

    1995-06-01

    Biliary transport of bile salts was investigated by measuring: 1) biliary transport maxima values (Tm) for different conjugated bile salts; and 2) biliary excretion of unconjugated bile salts relative to their conjugates under the continuous i.v. infusion of various unconjugated bile salts. The order of Tm values found in the rat of both sexes was tauro (and glyco) ursodeoxycholate (TUDC, GUDC), tauro alpha- and beta-muricholate (T alpha-MC, T beta-MC) > taurocholate(TC) > taurochenodeoxycholate (TCDC), while in female hamsters it was TC > TCDC > TUDC. The differences in the Tm order between rats and hamsters cast doubt on the currently proposed view that the apparent Tm values of bile salts are primarily determined by their physical-chemical properties (detergent property in particular). The biliary excretion of unconjugated bile salts was most efficient with ursocholate (UC) and alpha-MC followed by beta-MC, with UDC (and probably 7 ketolithocholate) being the least efficient for excretion. Thus, while for some bile salts such as cholate and UC, the amidation is not a prerequisite to their efficient excretion, for other bile salts such as UDC, the amidation is an excellent mechanism for facilitating the biliary excretion. In an attempt to explain the above order for the efficacy of the biliary excretion of unconjugated bile salts on the basis of their physical-chemical properties, we must remember that unlike rats, the biliary excretion of dehydrocholate and cholate in dogs is more limited than their respective taurine conjugates.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8541581

  2. Glucose and Insulin Induction of Bile Acid Synthesis

    PubMed Central

    Li, Tiangang; Francl, Jessica M.; Boehme, Shannon; Ochoa, Adrian; Zhang, Youcai; Klaassen, Curtis D.; Erickson, Sandra K.; Chiang, John Y. L.

    2012-01-01

    Bile acids facilitate postprandial absorption of nutrients. Bile acids also activate the farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5 and play a major role in regulating lipid, glucose, and energy metabolism. Transgenic expression of cholesterol 7α-hydroxylase (CYP7A1) prevented high fat diet-induced diabetes and obesity in mice. In this study, we investigated the nutrient effects on bile acid synthesis. Refeeding of a chow diet to fasted mice increased CYP7A1 expression, bile acid pool size, and serum bile acids in wild type and humanized CYP7A1-transgenic mice. Chromatin immunoprecipitation assays showed that glucose increased histone acetylation and decreased histone methylation on the CYP7A1 gene promoter. Refeeding also induced CYP7A1 in fxr-deficient mice, indicating that FXR signaling did not play a role in postprandial regulation of bile acid synthesis. In streptozocin-induced type I diabetic mice and genetically obese type II diabetic ob/ob mice, hyperglycemia increased histone acetylation status on the CYP7A1 gene promoter, leading to elevated basal Cyp7a1 expression and an enlarged bile acid pool with altered bile acid composition. However, refeeding did not further increase CYP7A1 expression in diabetic mice. In summary, this study demonstrates that glucose and insulin are major postprandial factors that induce CYP7A1 gene expression and bile acid synthesis. Glucose induces CYP7A1 gene expression mainly by epigenetic mechanisms. In diabetic mice, CYP7A1 chromatin is hyperacetylated, and fasting to refeeding response is impaired and may exacerbate metabolic disorders in diabetes. PMID:22144677

  3. The Effect of Oxygen on Bile Resistance in Listeria monocytogenes

    PubMed Central

    Wright, Morgan L; Pendarvis, Ken; Nanduri, Bindu; Edelmann, Mariola J; Jenkins, Haley N; Reddy, Joseph S; Wilson, Jessica G; Ding, Xuan; Broadway, Paul R; Ammari, Mais G; Paul, Oindrila; Roberts, Brandy; Donaldson, Janet R

    2016-01-01

    Listeria monocytogenes is a Gram-positive facultative anaerobe that is the causative agent of the disease listeriosis. The infectious ability of this bacterium is dependent upon resistance to stressors encountered within the gastrointestinal tract, including bile. Previous studies have indicated bile salt hydrolase activity increases under anaerobic conditions, suggesting anaerobic conditions influence stress responses. Therefore, the goal of this study was to determine if reduced oxygen availability increased bile resistance of L. monocytogenes. Four strains representing three serovars were evaluated for changes in viability and proteome expression following exposure to bile in aerobic or anaerobic conditions. Viability for F2365 (serovar 4b), EGD-e (serovar 1/2a), and 10403S (serovar 1/2a) increased following exposure to 10% porcine bile under anaerobic conditions (P < 0.05). However, HCC23 (serovar 4a) exhibited no difference (P > 0.05) in bile resistance between aerobic and anaerobic conditions, indicating that oxygen availability does not influence resistance in this strain. The proteomic analysis indicated F2365 and EGD-e had an increased expression of proteins associated with cell envelope and membrane bioenergetics under anaerobic conditions, including thioredoxin-disulfide reductase and cell division proteins. Interestingly, HCC23 had an increase in several dehydrogenases following exposure to bile under aerobic conditions, suggesting that the NADH:NAD+ is altered and may impact bile resistance. Variations were observed in the expression of the cell shape proteins between strains, which corresponded to morphological differences observed by scanning electron microscopy. These data indicate that oxygen availability influences bile resistance. Further research is needed to decipher how these changes in metabolism impact pathogenicity in vivo and also the impact that this has on susceptibility of a host to listeriosis. PMID:27274623

  4. Bile salts of vertebrates: structural variation and possible evolutionary significance[S

    PubMed Central

    Hofmann, Alan F.; Hagey, Lee R.; Krasowski, Matthew D.

    2010-01-01

    Biliary bile salt composition of 677 vertebrate species (103 fish, 130 reptiles, 271 birds, 173 mammals) was determined. Bile salts were of three types: C27 bile alcohols, C27 bile acids, or C24 bile acids, with default hydroxylation at C-3 and C-7. C27 bile alcohols dominated in early evolving fish and amphibians; C27 bile acids, in reptiles and early evolving birds. C24 bile acids were present in all vertebrate classes, often with C27 alcohols or with C27 acids, indicating two evolutionary pathways from C27 bile alcohols to C24 bile acids: a) a ‘direct’ pathway and b) an ‘indirect’ pathway with C27 bile acids as intermediates. Hydroxylation at C-12 occurred in all orders and at C-16 in snakes and birds. Minor hydroxylation sites were C-1, C-2, C-5, C-6, and C-15. Side chain hydroxylation in C27 bile salts occurred at C-22, C-24, C-25, and C-26, and in C24 bile acids, at C-23 (snakes, birds, and pinnipeds). Unexpected was the presence of C27 bile alcohols in four early evolving mammals. Bile salt composition showed significant variation between orders but not between families, genera, or species. Bile salt composition is a biochemical trait providing clues to evolutionary relationships, complementing anatomical and genetic analyses. PMID:19638645

  5. Release of soluble intercellular adhesion molecule 1 into bile and serum in murine endotoxin shock.

    PubMed

    Jaeschke, H; Essani, N A; Fisher, M A; Vonderfecht, S L; Farhood, A; Smith, C W

    1996-03-01

    Neutrophil-induced liver injury during endotoxemia is dependent on the adhesion molecules Mac-1 (CD11b/CD18) on neutrophils and its counterreceptor on endothelial cells and hepatocytes, intercellular adhesion molecule 1 (ICAM-1). To investigate a potential release of a soluble form of ICAM-1 (sICAM-1), animals received 100 micrograms/kg Salmonella abortus equi endotoxin alone or in combination with 700 mg/kg galactosamine. In endotoxin-sensitive mice (C3Heb/FeJ), injection of endotoxin did not cause liver injury but induced a time-dependent increase of sICAM-1 in serum (300%) and in bile (615%) without affecting bile flow. In galactosamine/endotoxin-treated animals, which developed liver injury, the increase in both compartments was only 97% and 104%, respectively. In either case, the increase in sICAM-1 concentrations paralleled the enhanced ICAM-1 expression in the liver. The endotoxin-resistant strain (C3H/HeJ) did not show elevated sICAM-1 levels in serum or bile after endotoxin administration. In contrast, the intravenous injection of murine tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) or IL-1 beta (13-23 micrograms/kg) into endotoxin-resistant mice induced a 225% to 364% increase in serum sICAM-1 and a 370% elevation of the biliary efflux of sICAM-1, again independent of changes in bile flow. These data indicate that cytokines are major inducers of sICAM-1 formation during endotoxemia in vivo. The described experimental model can be used to investigate the role of sICAM-1 in the pathophysiology of inflammatory liver disease. PMID:8617433

  6. Clostridium perfringens and other anaerobes isolated from bile.

    PubMed Central

    Sakaguchi, Y; Murata, K; Kimura, M

    1983-01-01

    Clostridium perfringens was isolated from bile in 13 cases of 150 patients examined. The serotypes of C perfringens strains isolated from bile and faeces were investigated using antisera to Hobbs' type 1-17. Two or more serological types were often found in a single specimen, but in the same patient the serotypes of C perfringens strains isolated from the bile were identical with those from the faeces. Beta-glucuronidase production in these C perfringens serotypes was tested with the API-Strep system. Strains agglutinated with Hobbs' antisera produced beta-glucuronidase, but non-agglutinated strains did not. PMID:6298284

  7. Duplicated extrahepatic bile duct identified following cholecystectomy injury

    PubMed Central

    Hoepfner, Lauren; Sweeney, Mary Katherine; White, Jared A.

    2016-01-01

    Though variations of intrahepatic biliary anatomy are quite common, duplication of the extrahepatic biliary system is extremely rare and reported infrequently in the literature. Laparoscopic cholecystectomy is one of the most common general surgery procedures performed. Unfortunately, iatrogenic bile duct injuries can contribute to significant morbidity including hospital readmissions, infectious complications and death. Anomalous extrahepatic biliary anatomy may be one of the factors, which increases the likelihood of bile duct injury during laparoscopic cholecystectomy. We present a case of an iatrogenic bile duct injury that occurred during a laparoscopic cholecystectomy, in which a duplicated extrahepatic biliary system was identified intraoperatively during the definitive operative repair. PMID:27141049

  8. Binding of bile salts to fibre-enriched wheat fibre.

    PubMed

    Florén, C H; Nilsson, A

    1987-01-01

    A commercial product of fibre-enriched wheat fibre (Fiberform R) was tested for its binding of bile salts in vitro. The wheat fibre preparation was standardized and through enzymatic digestion of protein and starch contained 78 per cent fibre (w/w). Fibre-enriched wheat fibre bound with high capacity both conjugated and unconjugated bile salts. Binding was saturable, reversible and showed no specificity towards tauro- or glycine-conjugated bile salts. Binding was rapid, dependent on pH, was enhanced by the presence of high salt concentrations and partially inhibited by 6 M urea. This indicated that binding was a combination of hydrophobic and hydrophilic interactions. PMID:2820035

  9. Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer

    PubMed Central

    Tsuei, Jessica; Chau, Thinh; Mills, David; Wan, Yu-Jui Yvonne

    2015-01-01

    Because of increasingly widespread sedentary lifestyles and diets high in fat and sugar, the global diabetes and obesity epidemic continues to grow unabated. A substantial body of evidence has been accumulated which associates diabetes and obesity to dramatically higher risk of cancer development, particularly in the liver and gastrointestinal tract. Additionally, diabetic and obese individuals have been shown to suffer from dysregulation of bile acid (BA) homeostasis and dysbiosis of the intestinal microbiome. Abnormally elevated levels of cytotoxic secondary BAs and a pro-inflammatory shift in gut microbial profile have individually been linked to numerous enterohepatic diseases including cancer. However, recent findings have implicated a detrimental interplay between BA dysregulation and intestinal dysbiosis that promotes carcinogenesis along the gut–liver axis. This review seeks to examine the currently investigated interactions between the regulation of BA metabolism and activity of the intestinal microbiota and how these interactions can drive cancer formation in the context of diabesity. The precarcinogenic effects of BA dysregulation and gut dysbiosis including excessive inflammation, heightened oxidative DNA damage, and increased cell proliferation are discussed. Furthermore, by focusing on the mediatory roles of BA nuclear receptor farnesoid x receptor, ileal transporter apical sodium dependent BA transporter, and G-coupled protein receptor TGR5, this review attempts to connect BA dysregulation, gut dysbiosis, and enterohepatic carcinogenesis at a mechanistic level. A better understanding of the intricate interplay between BA homeostasis and gut microbiome can yield novel avenues to combat the impending rise in diabesity-related cancers. PMID:24951470

  10. A comparative study of the sulfation of bile acids and a bile alcohol by the Zebra danio (Danio rerio) and human cytosolic sulfotransferases (SULTs).

    PubMed

    Kurogi, Katsuhisa; Krasowski, Matthew D; Injeti, Elisha; Liu, Ming-Yih; Williams, Frederick E; Sakakibara, Yoichi; Suiko, Masahito; Liu, Ming-Cheh

    2011-11-01

    The current study was designed to examine the sulfation of bile acids and bile alcohols by the Zebra danio (Danio rerio) SULTs in comparison with human SULTs. A systematic analysis using the fifteen Zebra danio SULTs revealed that SULT3 ST2 and SULT3 ST3 were the major bile acid/alcohol-sulfating SULTs. Among the eleven human SULTs, only SULT2A1 was found to be capable of sulfating bile acids and bile alcohols. To further investigate the sulfation of bile acids and bile alcohols by the two Zebra danio SULT3 STs and the human SULT2A1, pH-dependence and kinetics of the sulfation of bile acids/alcohols were analyzed. pH-dependence experiments showed that the mechanisms underlying substrate recognition for the sulfation of lithocholic acid (a bile acid) and 5α-petromyzonol (a bile alcohol) differed between the human SULT2A1 and the Zebra danio SULT3 ST2 and ST3. Kinetic analysis indicated that both the two Zebra danio SULT3 STs preferred petromyzonol as substrate compared to bile acids. In contrast, the human SULT2A1 was more catalytically efficient toward lithocholic acid than petromyzonol. Collectively, the results imply that the Zebra danio and human SULTs have evolved to serve for the sulfation of, respectively, bile alcohols and bile acids, matching the cholanoid profile in these two vertebrate species. PMID:21839837

  11. A comparative study of the sulfation of bile acids and a bile alcohol by the Zebra danio (Danio rerio) and human cytosolic sulfotransferases (SULTs)

    PubMed Central

    Kurogi, Katsuhisa; Krasowski, Matthew D.; Injeti, Elisha; Liu, Ming-Yih; Williams, Frederick E.; Sakakibara, Yoichi; Suiko, Masahito; Liu, Ming-Cheh

    2012-01-01

    The current study was designed to examine the sulfation of bile acids and bile alcohols by the Zebra danio (Danio rerio) SULTs in comparison with human SULTs. A systematic analysis using the fifteen Zebra danio SULTs revealed that SULT3 ST2 and SULT3 ST3 were the major bile acid/alcohol-sulfating SULTs. Among the eleven human SULTs, only SULT2A1 was found to be capable of sulfating bile acids and bile alcohols. To further investigate the sulfation of bile acids and bile alcohols by the two Zebra danio SULT3 STs and the human SULT2A1, pH-dependence and kinetics of the sulfation of bile acids/alcohols were analyzed. pH-dependence experiments showed that the mechanisms underlying substrate recognition for the sulfation of lithocholic acid (a bile acid) and 5α-petromyzonol (a bile alcohol) differed between the human SULT2A1 and the Zebra danio SULT3 ST2 and ST3. Kinetic analysis indicated that both the two Zebra danio SULT3 STs preferred petromyzonol as substrate compared to bile acids. In contrast, the human SULT2A1 was more catalytically efficient toward lithocholic acid than petromyzonol. Collectively, the results imply that the Zebra danio and human SULTs have evolved to serve for the sulfation of, respectively, bile alcohols and bile acids, matching the cholanoid profile in these two vertebrate species. PMID:21839837

  12. Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity

    PubMed Central

    Verhaag, Esther M.; Buist-Homan, Manon; Koehorst, Martijn; Groen, Albert K.; Moshage, Han; Faber, Klaas Nico

    2016-01-01

    Introduction Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis. Aim To investigate the mechanisms that underlie the hormetic response that protect hepatocytes against experimental cholestatic conditions. Methods HepG2.rNtcp cells were preconditioned (24 h) with sub-apoptotic concentrations (0.1–50 μM) of various bile acids, the superoxide donor menadione, TNF-α or the Farsenoid X Receptor agonist GW4064, followed by a challenge with the apoptosis-inducing bile acid glycochenodeoxycholic acid (GCDCA; 200 μM for 4 h), menadione (50 μM, 6 h) or cytokine mixture (CM; 6 h). Levels of apoptotic and necrotic cell death, mRNA expression of the bile salt export pump (ABCB11) and bile acid sensors, as well as intracellular GCDCA levels were analyzed. Results Preconditioning with the pro-apoptotic bile acids GCDCA, taurocholic acid, or the protective bile acids (tauro)ursodeoxycholic acid reduced GCDCA-induced caspase-3/7 activity in HepG2.rNtcp cells. Bile acid preconditioning did not induce significant levels of necrosis in GCDCA-challenged HepG2.rNtcp cells. In contrast, preconditioning with cholic acid, menadione or TNF-α potentiated GCDCA-induced apoptosis. GCDCA preconditioning specifically reduced GCDCA-induced cell death and not CM- or menadione-induced apoptosis. The hormetic effect of GCDCA preconditioning was concentration- and time-dependent. GCDCA-, CDCA- and GW4064- preconditioning enhanced ABCB11 mRNA levels, but in contrast to the bile acids, GW4064 did not significantly reduce GCDCA-induced caspase-3/7 activity. The GCDCA challenge strongly increased intracellular levels of this bile acid, which was not lowered by GCDCA

  13. Synthesis of nucleoside and nucleotide conjugates of bile acids, and polymerase construction of bile acid-functionalized DNA.

    PubMed

    Ikonen, Satu; Macícková-Cahová, Hana; Pohl, Radek; Sanda, Miloslav; Hocek, Michal

    2010-03-01

    Aqueous Sonogashira cross-coupling reactions of 5-iodopyrimidine or 7-iodo-7-deazaadenine nucleosides with bile acid-derived terminal acetylenes linked via an ester or amide tether gave the corresponding bile acid-nucleoside conjugates. Analogous reactions of halogenated nucleoside triphosphates gave directly bile acid-modified dNTPs. Enzymatic incorporation of these modified nucleotides to DNA was successfully performed using Phusion polymerase for primer extension. One of the dNTPs (dCTP bearing cholic acid) was also efficient for PCR amplification. PMID:20165813

  14. HPLC-fluorescence determination of bile acids in pharmaceuticals and bile after derivatization with 2-bromoacetyl-6-methoxynaphthalene.

    PubMed

    Cavrini, V; Gatti, R; Roda, A; Cerrè, C; Roveri, P

    1993-08-01

    2-Bromoacetyl-6-methoxynaphthalene was used as a pre-chromatographic fluorescent labelling reagent for the high-performance liquid chromatographic (HPLC) analysis of bile acids. The derivatization reaction was performed in an aqueous medium in the presence of tetrahexylammonium bromide by ultrasonication at 40 degrees C to give fluorescent esters which were separated by reversed-phase HPLC and detected fluorimetrically (lambda ex = 300 nm, lambda em = 460 nm). Applications to the determination of ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) in their pharmaceutical formulations are described. The method was also applied to the determination of free and conjugated bile acids in human bile samples. PMID:8257742

  15. Effect of the structure of bile salt aggregates on the binding of aromatic guests and the accessibility of anions.

    PubMed

    Li, Rui; Carpentier, Eric; Newell, Edward D; Olague, Lana M; Heafey, Eve; Yihwa, Chang; Bohne, Cornelia

    2009-12-15

    The binding of naphthalene (Np), 1-ethylnaphthalene (EtNp), acenaphthene (AcN), and 1-naphthyl-1-ethanol (NpOH) as guests to the aggregates of sodium cholate (NaCh), taurocholate (NaTC), deoxycholate (NaDC), and deoxytaurocholate (NaTDC) was studied with the objective of determining how the structure of the bile salts affects the binding dynamics of guests and quenchers with the bile salt aggregates. Time-resolved and steady-state fluorescence experiments were used to determine the binding efficiency of the guests with the aggregates and were also employed to investigate the quenching of the singlet excited state of the guests by iodide anions. Quenching studies of the triplet excited states using laser flash photolysis were employed to determine the accessibility to the aggregate of nitrite anions, used as quenchers, and the dissociation rate constants of the guests from the bile salt aggregates. The binding efficiency of the guests to NaDC and NaTDC is higher than for NaCh and NaTC, and the protection efficiency is also higher for NaDC and NaTDC, in line with the larger aggregates formed for the latter bile salts. The formation of aggregates is in part driven by the structure of the guest, where an increased protection efficiency and residence time can be achieved by the introduction of short alkyl substituents (AcN or EtNp vs Np). NpOH was shown to be located in a very different environment in all four bile salts when compared to AcN, EtNp, and Np, suggesting that hydrogen bonding plays an important role in the formation of the aggregate around NpOH. PMID:19606836

  16. Maternal bile acid transporter deficiency promotes neonatal demise

    PubMed Central

    Zhang, Yuanyuan; Li, Fei; Wang, Yao; Pitre, Aaron; Fang, Zhong-ze; Frank, Matthew W.; Calabrese, Christopher; Krausz, Kristopher W.; Neale, Geoffrey; Frase, Sharon; Vogel, Peter; Rock, Charles O.; Gonzalez, Frank J.; Schuetz, John D.

    2015-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse neonatal survival and is estimated to impact between 0.4 and 5% of pregnancies worldwide. Here we show that maternal cholestasis (due to Abcb11 deficiency) produces neonatal death among all offspring within 24 h of birth due to atelectasis-producing pulmonary hypoxia, which recapitulates the neonatal respiratory distress of human ICP. Neonates of Abcb11-deficient mothers have elevated pulmonary bile acids and altered pulmonary surfactant structure. Maternal absence of Nr1i2 superimposed on Abcb11 deficiency strongly reduces maternal serum bile acid concentrations and increases neonatal survival. We identify pulmonary bile acids as a key factor in the disruption of the structure of pulmonary surfactant in neonates of ICP. These findings have important implications for neonatal respiratory failure, especially when maternal bile acids are elevated during pregnancy, and highlight potential pathways and targets amenable to therapeutic intervention to ameliorate this condition. PMID:26416771

  17. Relationship between duodenal bile acids and colorectal neoplasia.

    PubMed Central

    Moorehead, R J; Campbell, G R; Donaldson, J D; McKelvey, S T

    1987-01-01

    To investigate a possible relationship between bile acids and colorectal neoplasia duodenal bile acids were analysed in 50 patients with colorectal adenomas and 14 with carcinoma. Using gas liquid and high performance liquid chromatography a small, but significant increase in the proportion of chenodeoxycholic acid was found in the bile of adenoma patients compared with controls (mean % +/- SD 31.0 +/- 10.8, 26.4 +/- 8.3, p = 0.01). The difference in the proportions of chenodeoxycholic acid correlated with increasing malignant potential of the adenomas as determined by increasing size, histological type, degree of dysplasia and number present. In carcinoma patients an increase in the proportion of chenodeoxycholic acid was also observed compared with controls (mean % +/- SD, 47.2 +/- 9.6, 28.0 +/- 4.5, p less than 0.01). The proportions of other bile acids in those with adenoma or carcinoma were normal. PMID:3428671

  18. Bile Duct Diseases - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Bile Duct Diseases URL of this page: https://medlineplus.gov/languages/bileductdiseases.html Other topics A-Z A B ...

  19. What Are the Risk Factors for Bile Duct Cancer?

    MedlinePlus

    ... the large intestine called ulcerative colitis. Bile duct stones , which are similar to, but much smaller than ... between ulcerative colitis and primary sclerosing cholangitis. Older age Older people are more likely than younger people ...

  20. Bile Duct Diseases - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Bile Duct Diseases URL of this page: https://www.nlm.nih.gov/medlineplus/languages/bileductdiseases.html Other topics A-Z A B ...

  1. Vitamin E and omega-3 fatty acids independently attenuate plasma concentrations of proinflammatory cytokines and prostaglandin E3 in Escherichia coli lipopolysaccharide-challenged growing-finishing pigs.

    PubMed

    Upadhaya, S D; Kim, J C; Mullan, B P; Pluske, J R; Kim, I H

    2015-06-01

    This study tested the hypothesis that vitamin E (Vit E) and omega-3 fatty acids will additively attenuate the production of proinflammatory cytokines and PGE2 in immune system–stimulated growing–finishing pigs. A total of 80 mixed sex pigs weighing 50.7 ± 0.76 kg (mean ± SE) were blocked and stratified based on sex and BW to a 2 × 2 factorial design with the respective factors being 1) without and with 300 IU Vit E and 2) without and with 25% replacement of tallow to linseed oil as a source of n-3 fatty acids. Each treatment consisted of 4 replicate pens with 5 pigs (3 barrows and 2 gilts) per pen. All pigs were challenged with an intramuscular injection of Escherichia coli lipopolysaccharide (LPS; O111:B4) twice weekly over the 6-wk experiment. After LPS challenge, pigs fed a diet supplemented with n-3 fatty acids had fewer (P < 0.05) white blood cells and tended to show both a reduced (P < 0.10) proportion of lymphocytes and IgG concentration compared with pigs fed a diet without any supplements. Supplementation of n-3 fatty acids reduced (P < 0.01 and P < 0.05) serum concentrations of cortisol and tumor necrosis factor α (TNF-α), respectively. The serum concentration of PGE2 was decreased (P < 0.05) with supplementation of both Vit E and n-3 fatty acids; however, the extent of the reduction was greater (P < 0.001) in pigs fed an n-3 fatty acid–supplemented diet. However, there were no additive effects of the combined supplementation of Vit E and n-3 fatty acids on serum concentrations of proinflammatory cytokines and PGE2. The results suggest that n-3 fatty acids independently attenuate production of TNF-α and PGE2 in immune system–stimulated growing–finishing pigs. PMID:26115279

  2. Human erythrocyte Band 3 functions as a receptor for the sialic acid-independent invasion of Plasmodium falciparum. Role of the RhopH3-MSP1 complex

    PubMed Central

    Baldwin, Michael; Yamodo, Innocent; Ranjan, Ravi; Li, Xuerong; Mines, Gregory; Marinkovic, Marina; Hanada, Toshihiko; Oh, Steven S.; Chishti, Athar H.

    2014-01-01

    Plasmodium falciparum takes advantage of two broadly defined alternate invasion pathways when infecting human erythrocytes: one that depends on and the other that is independent of host sialic acid residues on the erythrocyte surface. Within the sialic acid-dependent (SAD) and sialic acid-independent (SAID) invasion pathways, several alternate host receptors are used by Plasmodium falciparum based on its particular invasion phenotype. Earlier, we reported that two putative extracellular regions of human erythrocyte band 3 termed 5C and 6A function as host invasion receptor segments binding parasite proteins MSP1 and MSP9 via a SAID mechanism. In this study, we developed two mono-specific anti-peptide chicken IgY antibodies to demonstrate that the 5C and 6A regions of band 3 are exposed on the surface of human erythrocytes. These antibodies inhibited erythrocyte invasion by the Plasmodium falciparum 3D7 and 7G8 strains (SAID invasion phenotype), and the blocking effect was enhanced in sialic acid-depleted erythrocytes. In contrast, the IgY antibodies had only a marginal inhibitory effect on FCR3 and Dd2 strains (SAD invasion phenotype). A direct biochemical interaction between erythrocyte band 3 epitopes and parasite RhopH3, identified by the yeast two-hybrid screen, was established. RhopH3 formed a complex with MSP119 and 5ABC region of band 3, and a recombinant segment of RhopH3 inhibited parasite invasion in human erythrocytes. Together, these findings provide evidence that erythrocyte band 3 functions as a major host invasion receptor in the SAID invasion pathway by assembling a multi-protein complex composed of parasite ligands RhopH3 and MSP1. PMID:25157665

  3. Effects of feeding bile acids and a bile acid sequestrant on hepatic bile acid composition in mice.

    PubMed

    Zhang, Youcai; Klaassen, Curtis D

    2010-11-01

    An improved ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method was established for the simultaneous analysis of various bile acids (BA) and applied to investigate liver BA content in C57BL/6 mice fed 1% cholic acid (CA), 0.3% deoxycholic acid (DCA), 0.3% chenodeoxycholic acid (CDCA), 0.3% lithocholic acid (LCA), 3% ursodeoxycholic acid (UDCA), or 2% cholestyramine (resin). Results indicate that mice have a remarkable ability to maintain liver BA concentrations. The BA profiles in mouse livers were similar between CA and DCA feedings, as well as between CDCA and LCA feedings. The mRNA expression of Cytochrome P450 7a1 (Cyp7a1) was suppressed by all BA feedings, whereas Cyp7b1 was suppressed only by CA and UDCA feedings. Gender differences in liver BA composition were observed after feeding CA, DCA, CDCA, and LCA, but they were not prominent after feeding UDCA. Sulfation of CA and CDCA was found at the 7-OH position, and it was increased by feeding CA or CDCA more in male than female mice. In contrast, sulfation of LCA and taurolithocholic acid (TLCA) was female-predominant, and it was increased by feeding UDCA and LCA. In summary, the present systematic study on BA metabolism in mice will aid in interpreting BA-mediated gene regulation and hepatotoxicity. PMID:20671298

  4. Effects of feeding bile acids and a bile acid sequestrant on hepatic bile acid composition in mice[S

    PubMed Central

    Zhang, Youcai; Klaassen, Curtis D.

    2010-01-01

    An improved ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method was established for the simultaneous analysis of various bile acids (BA) and applied to investigate liver BA content in C57BL/6 mice fed 1% cholic acid (CA), 0.3% deoxycholic acid (DCA), 0.3% chenodeoxycholic acid (CDCA), 0.3% lithocholic acid (LCA), 3% ursodeoxycholic acid (UDCA), or 2% cholestyramine (resin). Results indicate that mice have a remarkable ability to maintain liver BA concentrations. The BA profiles in mouse livers were similar between CA and DCA feedings, as well as between CDCA and LCA feedings. The mRNA expression of Cytochrome P450 7a1 (Cyp7a1) was suppressed by all BA feedings, whereas Cyp7b1 was suppressed only by CA and UDCA feedings. Gender differences in liver BA composition were observed after feeding CA, DCA, CDCA, and LCA, but they were not prominent after feeding UDCA. Sulfation of CA and CDCA was found at the 7-OH position, and it was increased by feeding CA or CDCA more in male than female mice. In contrast, sulfation of LCA and taurolithocholic acid (TLCA) was female-predominant, and it was increased by feeding UDCA and LCA. In summary, the present systematic study on BA metabolism in mice will aid in interpreting BA-mediated gene regulation and hepatotoxicity. PMID:20671298

  5. Metagenomic sequencing of bile from gallstone patients to identify different microbial community patterns and novel biliary bacteria

    PubMed Central

    Shen, Hongzhang; Ye, Fuqiang; Xie, Lu; Yang, Jianfeng; Li, Zhen; Xu, Peisong; Meng, Fei; Li, Lei; Chen, Ying; Bo, Xiaochen; Ni, Ming; Zhang, Xiaofeng

    2015-01-01

    Despite the high worldwide prevalence of gallstone disease, the role of the biliary microbiota in gallstone pathogenesis remains obscure. Next-generation sequencing offers advantages for systematically understanding the human microbiota; however, there have been few such investigations of the biliary microbiome. Here, we performed whole-metagenome shotgun (WMS) sequencing and 16S rRNA sequencing on bile samples from 15 Chinese patients with gallstone disease. Microbial communities of most individuals were clustered into two types, according to the relative enrichment of different intestinal bacterial species. In the bile samples, oral cavity/respiratory tract inhabitants were more prevalent than intestinal inhabitants and existed in both community types. Unexpectedly, the two types were not associated with fever status or surgical history, and many bacteria were patient-specific. We identified 13 novel biliary bacteria based on WMS sequencing, as well as genes encoding putative proteins related to gallstone formation and bile resistance (e.g., β-glucuronidase and multidrug efflux pumps). Bile samples from gallstone patients had reduced microbial diversity compared to healthy faecal samples. Patient samples were enriched in pathways related to oxidative stress and flagellar assembly, whereas carbohydrate metabolic pathways showed varying behaviours. As the first biliary WMS survey, our study reveals the complexity and specificity of biliary microecology. PMID:26625708

  6. Tubulopapillary adenoma of the common bile duct presenting with jaundice

    PubMed Central

    Yusif-zade, Kenan; Musayev, Jamal; Yeler, Maryam

    2016-01-01

    In this report, an adult patient with tubulopapillary adenoma of the common bile duct that manifested with jaundice is presented. Diagnostic challenges were analyzed. Although adenomas of the common bile duct are rare, they should be kept in mind in the differentiation of lesions of this region. It should be remembered that these lesions radiologically could mimic carcinoma and choledocholithiasis. Endoscopic resection should be considered as the primary method for treatment. Histopathology is the gold standard in diagnosis. PMID:27528819

  7. Mechanical properties of the porcine bile duct wall

    PubMed Central

    Duch, Birgitte U; Andersen, Helle; Gregersen, Hans

    2004-01-01

    Background and Aim The function of the common bile duct is to transport bile from the liver and the gall bladder to the duodenum. Since the bile duct is a distensible tube consisting mainly of connective tissue, it is important to obtain data on the passive mechanical wall properties. The aims of this study were to study morphometric and biomechanical wall properties during distension of the bile duct. Methods Ten normal porcine common bile ducts were examined in vitro. A computer-controlled volume ramp infusion system with concomitant pressure recordings was constructed. A video camera provided simultaneous measurement of outer dimensions of the common bile duct. Wall stresses and strains were computed. Results The common bile duct length increased by 25% from 24.4 ± 1.8 mm at zero pressure to 30.5 ± 2.0 mm at 5 kPa (p < 0.01). The diameter increased less than 10% in the same pressure range from 8.6 ± 0.4 mm to 9.3 ± 0.4 mm (p < 0.01). The stress-strain relations showed an exponential behavior with a good fit to the equation: σ = α . (exp(βε) - 1). The circumferential stress-strain curve was shifted to the left when compared to the longitudinal stress-strain curve, i.e. the linear constants (α values) were different (p < 0.01) whereas the exponential constants (β values) did not differ (p > 0.5). Conclusion The porcine bile duct exhibited nonlinear anisotropic mechanical properties. PMID:15260881

  8. [Combined effect of benzylpenicillin, furagin and bile acids on staphylococci].

    PubMed

    Sytnik, I A; Tkachuk, N I

    1982-11-01

    The results of the study of the effect of benzylpenicillin or furagin in combination with bile acids, such as cholic, glycocholic and desoxycholic on the collection cultures of staphylococci are presented. The study showed that the subbacteriostatic doses of the bile acids increased the bacteriostatic and bactericidal effects of benzylpenicillin and furagin by tens and hundreds times. The highest potentiation effect was attained with the use of the furagin combination and desoxycholic acid. PMID:7181465

  9. Quantitative microanalysis of bile acids in biological samples. Collaborative study.

    PubMed

    Nakayama, F

    1988-10-28

    The analysis of bile acids in biological samples has always presented a problem because of their complex nature and low concentration. Recently, newer analytical procedures for bile acids have become available, including enzymatic analysis, radioimmunoassay, thin-layer chromatography (TLC), gas chromatography, high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) with selected ion monitoring (SIM). However, they differ greatly with respect to specificity, sensitivity, accuracy and simplicity. On the other hand, the choice of analytical procedure differs according to the specific aims and the nature of biological samples to be analysed. These newer procedures have been compared in a double-blind fashion by distributing bile, plasma and urine samples to seven participating laboratories. GC-MS-SIM was found to be the most sensitive and reliable, but it requires other procedures for preliminary clean-up and fractionation steps. Enzymatic analysis is simple and gives small analytical errors but tends to over-estimate plasma bile acids. Radioimmunoassay gives variable results but is useful as a screening procedure for large numbers of plasma samples. TLC gives reliable results for biliary bile acids in experienced hands, except for differentiation between conjugated dihydroxycholanoic acids. HPLC, whether using derivatization or with fixed 3 alpha-hydroxy steroid dehydrogenase detection, is suitable for the analysis of major bile acids in normal human serum but not for the identification of unknown minor peaks. PMID:3243854

  10. Cotinine effects on bile flow and biliary NNK elimination.

    PubMed

    Meiser, H; Atawodi, S E; Richter, E

    2000-06-20

    Nicotine and its major metabolite cotinine inhibit alpha-hydroxylation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) suggesting that an alternative pathway of NNK metabolism and elimination, biliary excretion of the O-glucuronide of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL-Gluc) may be enhanced. To verify the possible role of cotinine on biliary elimination of NNK and its metabolites, bile duct cannulated rats were administered a single i.p. dose of 50 mg/kg [56sup;-3 H]-NNK with or without i.p. co-administration of 5 mg/kg cotinine or nicotine. Cotinine significantly reduced cumulative bile flow and biliary elimination of NNK-derived radioactivity within six hours to 42 and 27 percent, respectively. The pattern of NNK metabolites in bile was unchanged. Nicotine had a similar inhibitory effect on bile flow. This result constitutes the first experimental evidence that cotinine inhibits bile flow. In rats, biliary elimination of NNK is reduced accordingly which may lead to an increased carcinogen burden in the body. In humans, inhibition of bile flow by tobacco alkaloids may contribute to the appetite suppressing effect of tobacco products. PMID:10882639

  11. Indirect electrochemical detection for total bile acids in human serum.

    PubMed

    Zhang, Xiaoqing; Zhu, Mingsong; Xu, Biao; Cui, Yue; Tian, Gang; Shi, Zhenghu; Ding, Min

    2016-11-15

    Bile acids level in serum is a useful index for screening and diagnosis of hepatobiliary diseases. As bile acids concentration is closely related to the degree of hepatobiliary diseases, detecting it is a vital factor to understand the stage of the diseases. The prevalent determination for bile acids is the enzymatic cycling method which has low sensitivity while reagent-consuming. It is desirable to develop a new method with lower cost and higher sensitivity. An indirect electrochemical detection (IED) for bile acids in human serum was established using the screen printed carbon electrode (SPCE). Since bile acids do not show electrochemical signals, they were converted to 3-ketosteroids by 3-α-hydroxysteroid dehydrogenase (3α-HSD) in the presence of nicotinamide adenine dinucleotide (NAD(+)), which was reduced to NADH. NADH could then be oxidized on the surface of SPCE, generating a signal that was used to calculate the total bile acids (TBA) concentration. A good linear calibration for TBA was obtained at the concentration range from 5.00μM to 400μM in human serum. Both the precisions and recoveries were sufficient to be used in a clinical setting. The TBA concentrations in 35 human serum samples by our IED method didn't show significant difference with the result by enzymatic cycling method, using the paired t-test. Moreover, our IED method is reagent-saving, sensitive and cost-effective. PMID:27236139

  12. Bile acids induce hepatic differentiation of mesenchymal stem cells

    PubMed Central

    Sawitza, Iris; Kordes, Claus; Götze, Silke; Herebian, Diran; Häussinger, Dieter

    2015-01-01

    Mesenchymal stem cells (MSC) have the potential to differentiate into multiple cell lineages and their therapeutic potential has become obvious. In the liver, MSC are represented by stellate cells which have the potential to differentiate into hepatocytes after stimulation with growth factors. Since bile acids can promote liver regeneration, their influence on liver-resident and bone marrow-derived MSC was investigated. Physiological concentrations of bile acids such as tauroursodeoxycholic acid were able to initiate hepatic differentiation of MSC via the farnesoid X receptor and transmembrane G-protein-coupled bile acid receptor 5 as investigated with knockout mice. Notch, hedgehog, transforming growth factor-β/bone morphogenic protein family and non-canonical Wnt signalling were also essential for bile acid-mediated differentiation, whereas β-catenin-dependent Wnt signalling was able to attenuate this process. Our findings reveal bile acid-mediated signalling as an alternative way to induce hepatic differentiaion of stem cells and highlight bile acids as important signalling molecules during liver regeneration. PMID:26304833

  13. Bile salt-phospholipid aggregation at submicellar concentrations.

    PubMed

    Baskin, Rebekah; Frost, Laura D

    2008-04-01

    The aggregation behavior of the bile salts taurodeoxycholate (NaTDC) and sodium cholate (NaC), are followed at concentrations below critical micelle concentrations (CMCs) using the environment sensitive, fluorescent-labeled phospholipid, 2-(6-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoyl-1-hexadecanoyl-sn-glycero-3-phosphocholine (NBD-C(6)-HPC). A buffer solution containing NBD-C(6)-HPC is titrated with increasing NaC or NaTDC and the fluorescence changes followed. Both bile salts induced fluorescence changes below their critical micelle concentration indicating the presence of a bile salt-phospholipid aggregate. A critical control experiment using 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino) hexanoic acid (NBD-X) shows that the bile salts are interacting with the longer, C16 hydrocarbon tail, not the NBD probe. The fluorescence curves were fitted to the Hill equation as a model for cooperative aggregation. The cooperativity model provides a minimum estimate for the number of bile salts to give maximal fluorescence. This number was calculated for NaC and NaTDC to have a minimum value of approximately 2. A small aggregation number supports the existence of primary micellar aggregates at submicellar concentrations for bile salt-phospholipid aqueous solutions. PMID:18035524

  14. Olfactory sensitivity to bile acids in salmonid fishes.

    PubMed

    Døving, K B; Selset, R; Thommesen, G

    1980-02-01

    Monopolar DC-recordings were made simultaneously from two positions on the olfactory bulb of chars (Salmo alpinus L.) and graylings (Thymallus thymallu L.) using bile acids and amino acids as olfactory stimulants. The bile acids induced responses with characteristic spatial differences from those of the amino acids. The distribution of responses to bile acids indicated a neuronal activity in the medial part of the bulb. In contrast, amino acids elicit responses in the lateral part of the bulb. Taurine conjugated bile acids were up to 1 000 times more potent as olfactory stimuli than methionine. The results suggest that olfactory receptors are of two types, one responding to bile acids, the other to amino acids. 3 -alpha-hydroxysteroids are released from the fish into the water in quantities that suffice for detection by their olfactory system. The odorant potency of the bile acids, their evolutionary history and variability, together with their renowned adherent properties made them interesting candidates for specific signals in the acquatic environment. PMID:7376910

  15. Bile Acid Pool Dynamics in Progressive Familial Intrahepatic Cholestasis with Partial External Bile Diversion

    PubMed Central

    Jericho, Hilary Smith; Kaurs, Elizabeth; Boverhof, Renze; Knisely, Alex; Shneider, Benjamin L; Verkade, Henkjan J; Whitington, Peter F

    2015-01-01

    Objectives Partial external bile diversion (PEBD) is an established therapy for low-GGT Progressive Familial Intrahepatic Cholestasis (PFIC). This study sought to determine if the dynamics of the cholic acid (CA) and chenodeoxycholic acid (CDCA) pools in low-GGT-PFIC subjects with successful PEBD were equivalent to those achieved with successful liver transplantation (LTX). Methods The kinetics of CA and CDCA metabolism were measured by stable isotope dilution in plasma samples in 5 PEBD subjects all with intact canalicular BSEP expression and compared to low-GGT-PFIC subjects with successful LTX. Stomal loss of bile acids was measured in PEBD subjects. Results The fractional turnover rate for CA in the PEBD group ranged from 0.5 to 4.2 d−1 (LTX group, range 0.2 – 0.9 d−1, p = 0.076) and for CDCA from 0.7 to 4.5 d−1 (LTX group 0.3 – 0.4 d−1, p = 0.009). The CA and CDCA pool sizes were equivalent between groups; however pool composition in PEBD was somewhat more hydrophilic. The CA/CDCA ratio in PEBD ranged from 0.9 to 19.5, whereas in LTX it ranged from 0.5 to 2.6. Synthesis rates computed from isotope dilution correlated well with timed output for both CA: r2 = 0.760, p = 0.024 and CDCA: r2 = 0.690, p = 0.021. Conclusions PEBD results in bile acid fractional turnover rates greater than LTX, pool sizes equivalent to LTX and pool composition that is at least as hydrophilic as produced by LTX. PMID:25383786

  16. Individual bile acids have differential effects on bile acid signaling in mice

    SciTech Connect

    Song, Peizhen Rockwell, Cheryl E. Cui, Julia Yue Klaassen, Curtis D.

    2015-02-15

    Bile acids (BAs) are known to regulate BA synthesis and transport by the farnesoid X receptor in the liver (FXR-SHP) and intestine (FXR-Fgf15). However, the relative importance of individual BAs in regulating these processes is not known. Therefore, mice were fed various doses of five individual BAs, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxoycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) in their diets at various concentrations for one week to increase the concentration of one BA in the enterohepatic circulation. The mRNA of BA synthesis and transporting genes in liver and ileum were quantified. In the liver, the mRNA of SHP, which is the prototypical target gene of FXR, increased in mice fed all concentrations of BAs. In the ileum, the mRNA of the intestinal FXR target gene Fgf15 was increased at lower doses and to a higher extent by CA and DCA than by CDCA and LCA. Cyp7a1, the rate-limiting enzyme in BA synthesis, was decreased more by CA and DCA than CDCA and LCA. Cyp8b1, the enzyme that 12-hydroxylates BAs and is thus responsible for the synthesis of CA, was decreased much more by CA and DCA than CDCA and LCA. Surprisingly, neither a decrease in the conjugated BA uptake transporter (Ntcp) nor increase in BA efflux transporter (Bsep) was observed by FXR activation, but an increase in the cholesterol efflux transporter (Abcg5/Abcg8) was observed with FXR activation. Thus in conclusion, CA and DCA are more potent FXR activators than CDCA and LCA when fed to mice, and thus they are more effective in decreasing the expression of the rate limiting gene in BA synthesis Cyp7a1 and the 12-hydroxylation of BAs Cyp8b1, and are also more effective in increasing the expression of Abcg5/Abcg8, which is responsible for biliary cholesterol excretion. However, feeding BAs do not alter the mRNA or protein levels of Ntcp or Bsep, suggesting that the uptake or efflux of BAs is not regulated by FXR at physiological and

  17. Trastuzumab in Treating Patients With Locally Advanced or Metastatic Gallbladder Cancer or Bile Duct Cancer That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2014-05-15

    Adenocarcinoma of the Extrahepatic Bile Duct; Adenocarcinoma of the Gallbladder; Malignant Neoplasm; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  18. Benign disease of the common bile duct.

    PubMed

    Saxena, R; Pradeep, R; Chander, J; Kumar, P; Wig, J D; Yadav, R V; Kaushik, S P

    1988-08-01

    The incidence of common bile duct (CBD) pathology in a group of patients with benign biliary disease (n = 505) was found to be 23.2 per cent. The spectrum included 111 patients (90.2 per cent) with CBD stones, 37 of whom (33.3 per cent) had no symptoms or findings pre-operatively indicating CBD involvement. Five patients had papillary stenosis, three had postoperative CBD strictures, one had a choledochal cyst and one had an external biliary fistula. Of the 100 CBDs measuring more than 10 mm in diameter, 90 harboured calculi. In the remaining 23 CBDs measuring less than 10 mm, calculi were present in 21. The presence of CBD calculi was demonstrated by intra-operative cholangiography in 49 patients. In the remaining patients (n = 74), the diagnosis of CBD pathology was made either by percutaneous transhepatic cholangiography, endoscopic retrograde cholangio-pancreatography, T-tube cholangiography or peroperative palpation. The surgical procedures performed included choledochotomy and T-tube drainage (n = 74), transduodenal sphincteroplasty (n = 27) and choledochoduodenostomy (n = 18). The overall mortality and morbidity of CBD exploration was 3.3 per cent and 24.4 per cent respectively, which was significantly greater than that for cholecystectomy alone (0.3 per cent and 8.6 per cent respectively). Transduodenal sphincteroplasty carried a much higher mortality (11 per cent) and morbidity (52 per cent) when compared with other procedures. PMID:3167536

  19. Sarcoidosis of the liver and bile ducts.

    PubMed

    Ishak, K G

    1998-05-01

    In sarcoidosis, granulomas are frequently present in multiple organs, including the liver. Typically, epithelioid granulomas (noncaseating) are scattered throughout the liver, but confluent granulomas can be present in cases with severe hepatic involvement. The characteristic inclusions in giant cells (for example, Schaumann bodies and asteroid bodies) are not seen in all cases and are not pathognomonic. The granulomas of sarcoidosis may heal without a trace, but confluent granulomas can result in extensive, irregular scarring. Occlusion of intrahepatic portal vein branches by the granulomatous inflammation probably accounts for the development of portal hypertension in some cases. A granulomatous cholangitis leading to ductopenia seems to be the underlying pathogenetic mechanism of the chronic cholestatic syndrome of sarcoidosis. Recognition of this syndrome is important in the differential diagnosis of other chronic cholestatic diseases, such as primary biliary cirrhosis or primary sclerosing cholangitis. Other rare complications of sarcoidosis are the Budd-Chiari syndrome and obstructive jaundice attributable to hepatic hilar lymphadenopathy or strictures of the bile ducts. PMID:9581591

  20. Differentiation of various traditional Chinese medicines derived from animal bile and gallstone: simultaneous determination of bile acids by liquid chromatography coupled with triple quadrupole mass spectrometry.

    PubMed

    Qiao, Xue; Ye, Min; Pan, De-lin; Miao, Wen-juan; Xiang, Cheng; Han, Jian; Guo, De-an

    2011-01-01

    Animal biles and gallstones are popularly used in traditional Chinese medicines, and bile acids are their major bioactive constituents. Some of these medicines, like cow-bezoar, are very expensive, and may be adulterated or even replaced by less expensive but similar species. Due to poor ultraviolet absorbance and structural similarity of bile acids, effective technology for species differentiation and quality control of bile-based Chinese medicines is still lacking. In this study, a rapid and reliable method was established for the simultaneous qualitative and quantitative analysis of 18 bile acids, including 6 free steroids (cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid, hyodeoxycholic acid, and ursodeoxycholic acid) and their corresponding glycine conjugates and taurine conjugates, by using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). This method was used to analyze six bile-based Chinese medicines: bear bile, cattle bile, pig bile, snake bile, cow-bezoar, and artificial cow-bezoar. Samples were separated on an Atlantis dC₁₈ column and were eluted with methanol-acetonitrile-water containing ammonium acetate. The mass spectrometer was monitored in the negative electrospray ionization mode. Total ion currents of the samples were compared for species differentiation, and the contents of bile acids were determined by monitoring specific ion pairs in a selected reaction monitoring program. All 18 bile acids showed good linearity (r² > 0.993) in a wide dynamic range of up to 2000-fold, using dehydrocholic acid as the internal standard. Different animal biles could be explicitly distinguished by their major characteristic bile acids: tauroursodeoxycholic acid and taurochenodeoxycholic acid for bear bile, glycocholic acid, cholic acid and taurocholic acid for cattle bile, glycohyodeoxycholic acid and glycochenodeoxycholic acid for pig bile, and taurocholic acid for snake bile. Furthermore, cattle bile, cow

  1. How does bile salt penetration affect the self-assembled architecture of pluronic P123 micelles?--light scattering and spectroscopic investigations.

    PubMed

    Roy, Arpita; Kundu, Niloy; Banik, Debasis; Kuchlyan, Jagannath; Sarkar, Nilmoni

    2015-08-14

    The triblock copolymer of the type (PEO)20-(PPO)70-(PEO)20 (P123) forms a mixed supramolecular aggregate with different bile salts, sodium deoxycholate (NaDC) and sodium taurocholate (NaTC), having different hydrophobicity. These mixed micellar systems have been investigated through dynamic light scattering (DLS) and other various spectroscopic techniques. DLS measurements reveal that the bile salts penetrate into the core-corona region of the P123 micelle and further addition of bile salts causes formation of a new supramolecular aggregate. Further CONTIN analysis confirms existence of two types of complexes at higher molar ratios of bile salt-P123 (>1 : 3). Due to the bile salt penetration, the polarity of the core-corona region of bile salt-P123 mixed micelle increases which results in red shift in the absorption and emission spectra of coumarin 153 (C153) and coumarin 480 (C480). The rotational diffusion of the hydrophobic probe C153 and a hydrophilic probe C480 has been investigated in these bile salt-P123 mixed systems and for both the probes a decrease in the average reorientation time has been observed. The reason behind this decrease in the average reorientation time is the increase in both polarity and hydration of the core-corona region in these mixed micelles. Moreover, these bile salt-P123 mixed micelles are characterized by fluorescence correlation spectroscopy (FCS) techniques. As hydrophobic solute 4-(dicyanomethylene)-2-methyl-6-(p-dimethylamino-styryl)-4H-pyran (DCM) resides in the core region of the bile salt-P123 mixed micelles, the translational diffusion of DCM becomes faster in these mixed micelles compared to that in pure P123 micelle. However, for cationic probe rhodamine 6G perchlorate (R6G), a totally opposite trend in the translational diffusion coefficients has been observed. Both anisotropy and FCS measurements confirm that bile salts affect the core region of the P123 micelle more than the corona region. Besides, all these

  2. Structure and functional characterization of a bile acid 7α dehydratase BaiE in secondary bile acid synthesis.

    PubMed

    Bhowmik, Shiva; Chiu, Hsien-Po; Jones, David H; Chiu, Hsiu-Ju; Miller, Mitchell D; Xu, Qingping; Farr, Carol L; Ridlon, Jason M; Wells, James E; Elsliger, Marc-André; Wilson, Ian A; Hylemon, Phillip B; Lesley, Scott A

    2016-03-01

    Conversion of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) to the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) is performed by a few species of intestinal bacteria in the genus Clostridium through a multistep biochemical pathway that removes a 7α-hydroxyl group. The rate-determining enzyme in this pathway is bile acid 7α-dehydratase (baiE). In this study, crystal structures of apo-BaiE and its putative product-bound [3-oxo-Δ(4,6) -lithocholyl-Coenzyme A (CoA)] complex are reported. BaiE is a trimer with a twisted α + β barrel fold with similarity to the Nuclear Transport Factor 2 (NTF2) superfamily. Tyr30, Asp35, and His83 form a catalytic triad that is conserved across this family. Site-directed mutagenesis of BaiE from Clostridium scindens VPI 12708 confirm that these residues are essential for catalysis and also the importance of other conserved residues, Tyr54 and Arg146, which are involved in substrate binding and affect catalytic turnover. Steady-state kinetic studies reveal that the BaiE homologs are able to turn over 3-oxo-Δ(4) -bile acid and CoA-conjugated 3-oxo-Δ(4) -bile acid substrates with comparable efficiency questioning the role of CoA-conjugation in the bile acid metabolism pathway. PMID:26650892

  3. Bile Acids Improve the Antimicrobial Effect of Rifaximin▿ †

    PubMed Central

    Darkoh, Charles; Lichtenberger, Lenard M.; Ajami, Nadim; Dial, Elizabeth J.; Jiang, Zhi-Dong; DuPont, Herbert L.

    2010-01-01

    Diarrhea is one of the most common infirmities affecting international travelers, occurring in 20 to 50% of persons from industrialized countries visiting developing regions. Enterotoxigenic Escherichia coli (ETEC) is the most common causative agent and is isolated from approximately half of the cases of traveler's diarrhea. Rifaximin, a largely water-insoluble, nonabsorbable (<0.4%) antibiotic that inhibits bacterial RNA synthesis, is approved for use for the treatment of traveler's diarrhea caused by diarrheagenic E. coli. However, the drug has minimal effect on the bacterial flora or the infecting E. coli strain in the aqueous environment of the colon. The purpose of the present study was to evaluate the antimicrobial effect and bioavailability of rifaximin in aqueous solution in the presence and absence of physiologic concentrations of bile acids. The methods used included growth measurement of ETEC (strain H10407), rifaximin solubility measurements, total bacterial protein determination, and assessment of the functional activity of rifaximin by monitoring inhibition of bacterial β-galactosidase expression. Solubility studies showed rifaximin to be 70- to 120-fold more soluble in bile acids (approximately 30% in 4 mM bile acids) than in aqueous solution. Addition of both purified bile acids and human bile to rifaximin at subinhibitory and inhibitory concentrations significantly improved the drug's anti-ETEC effect by 71% and 73%, respectively, after 4 h. This observation was confirmed by showing a decrease in the overall amount of total bacterial protein expressed during incubation of rifaximin plus bile acids. Rifaximin-treated samples containing bile acids inhibited the expression of ETEC β-galactosidase at a higher magnitude than samples that did not contain bile acids. The study provides data showing that bile acids solubilize rifaximin on a dose-response basis, increasing the drug's bioavailability and antimicrobial effect. These observations suggest

  4. Bile acids in combination with low pH induce oxidative stress and oxidative DNA damage: relevance to the pathogenesis of Barrett's oesophagus

    PubMed Central

    Dvorak, Katerina; Payne, Claire M; Chavarria, Melissa; Ramsey, Lois; Dvorakova, Barbora; Bernstein, Harris; Holubec, Hana; Sampliner, Richard E; Guy, Naihsuan; Condon, Amanda; Bernstein, Carol; Green, Sylvan B; Prasad, Anil; Garewal, Harinder S

    2007-01-01

    Background Barrett's oesophagus is a premalignant condition associated with an increased risk for the development of oesophageal adenocarcinoma (ADCA). Previous studies indicated that oxidative damage contributes to the development of ADCA. Objective To test the hypothesis that bile acids and gastric acid, two components of refluxate, can induce oxidative stress and oxidative DNA damage. Methods Oxidative stress was evaluated by staining Barrett's oesophagus tissues with different degrees of dysplasia with 8‐hydroxy‐deoxyguanosine (8‐OH‐dG) antibody. The levels of 8‐OH‐dG were also evaluated ex vivo in Barrett's oesophagus tissues incubated for 10 min with control medium and medium acidified to pH 4 and supplemented with 0.5 mM bile acid cocktail. Furthermore, three oesophageal cell lines (Seg‐1 cells, Barrett's oesophagus cells and HET‐1A cells) were exposed to control media, media containing 0.1 mM bile acid cocktail, media acidified to pH 4, and media at pH 4 supplemented with 0.1 mM bile acid cocktail, and evaluated for induction of reactive oxygen species (ROS). Results Immunohistochemical analysis showed that 8‐OH‐dG is formed mainly in the epithelial cells in dysplastic Barrett's oesophagus. Importantly, incubation of Barrett's oesophagus tissues with the combination of bile acid cocktail and acid leads to increased formation of 8‐OH‐dG. An increase in ROS in oesophageal cells was detected after exposure to pH 4 and bile acid cocktail. Conclusions Oxidative stress and oxidative DNA damage can be induced in oesophageal tissues and cells by short exposures to bile acids and low pH. These alterations may underlie the development of Barrett's oesophagus and tumour progression. PMID:17145738

  5. Unconjugated Bilirubin and an Increased Proportion of Bilirubin Monoconjugates in the Bile of Patients with Gilbert's Syndrome and Crigler-Najjar Disease

    PubMed Central

    Fevery, Johan; Blanckaert, Norbert; Heirwegh, Karel P. M.; Préaux, Anne-Marie; Berthelot, Pierre

    1977-01-01

    Bilirubin pigments were studied in the bile of 20 normal adults, 25 patients with Gilbert's syndrome, 9 children with Crigler-Najjar disease, and 6 patients with hemolysis, to determine how a deficiency of hepatic bilirubin UDP-glucuronosyltransferase would affect the end products of bilirubin biotransformation. In the bile from patients with Gilbert's syndrome, a striking increase was found in the proportion of bilirubin monoconjugates (48.6±9.8% of total conjugates) relative to that in normal bile (27.2±7.8%). This increase was even more pronounced in children with Crigler-Najjar disease, in whom, even in the most severe cases, glucuronide could always be demonstrated in the bile. Furthermore, unconjugated bilirubin-IXα was unquestionably present in the bile of these children and amounted to 30-57% of their total bilirubin pigments (<1% in the controls). It was not possible to predict from the biliary bilirubin composition whether a child would respond to phenobarbital therapy or not. Bile composition was normal in patients with hemolysis, except when there was associated deficiency of hepatic glucuronosyltransferase. Therefore, the observed alterations were not a simple consequence of unconjugated hyperbilirubinemia. The present findings suggest that Crigler-Najjar disease represents a more pronounced expression than Gilbert's syndrome of a common biochemical defect. Hepatic bilirubin UDP-glucuronosyltransferase deficiency leads to decreased formation of diconjugates with an ensuing increase in the proportion of bilirubin monoconjugates in bile; in the most severe cases, an elevated content of biliary unconjugated bilirubin is also found. PMID:409736

  6. Urinary bile casts in bile cast nephropathy secondary to severe falciparum malaria

    PubMed Central

    Mohapatra, Manoj Kumar; Behera, Ashok Kumar; Karua, Purna Chandra; Bariha, Prafulla Kumar; Rath, Ashutosh; Aggrawal, Kailash Chandra; Nahak, Snigdha Rani; Gudaganatti, Santosh Shankar

    2016-01-01

    Background Severe cholestatic jaundice may complicate with bile cast nephropathy (BCN) causing severe acute kidney injury (AKI). In this study, we investigate BCN in severe falciparum malaria complicated with jaundice and AKI. Methods This prospective study was conducted in a tertiary health care institution with high prevalence of malaria. A cohort of 110 patients with falciparum malaria complicated with cerebral malaria, jaundice and AKI were enrolled. Species diagnosis was made from peripheral blood smear or rapid diagnostic test. Severe malaria was diagnosed from WHO criteria. BCN was diagnosed with the detection of bile casts in urine or in biopsy. The recovery pattern and outcome with and without BCN was assessed. Results Out of 110 patients, 20 (18.2%) patients had BCN and 15 (13.6%) patients had hepato-renal syndrome. Patients with BCN had high conjugated bilirubin (26.5 ± 4.1 mg/dL), urea (75.9 ± 10.3 mg/dL) and creatinine (7.2 ± 0.8 mg/dL), longer duration of illness (6.4 ± 1.1 days), higher mortality (25.0%) and prolonged recovery time of hepatic (9.6 ± 2.4 days) and renal dysfunction (15.1 ± 6.5 days) compared with patients without BCN. Conclusions Prolonged duration of illness and increased bilirubin cause BCN among patients with severe falciparum malaria with jaundice and AKI, which is associated with high mortality and morbidity. PMID:27478612

  7. Moulded calculus of common bile duct mimicking a stenosis

    PubMed Central

    Brocki, Marian; Śmigielski, Jacek

    2014-01-01

    Bile duct stenosis, in most cases, appears to be the consequence of pancreatic head, ampulla of Vater and bile duct tumours, cholangitis sclerosans, as well as iatrogenic damages, which may all be diagnosed during endoscopic retrograde cholangiopancreatography (ERCP). In very rare cases the restriction may result from an atypically shaped wedged stone. This situation creates many diagnostic problems, which in the majority of cases can be solved using imaging studies. However, in some patients even a significant extension of diagnostic procedures may not lead to a correct diagnosis. We present a diagnostically difficult case of a deposit imitating restriction. We present a 70-year-old woman with common bile duct restriction undiagnosed despite several ultrasound examinations (USG), computed tomography (CT), double magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP). Only after the third ERCP examination a fragmented, by formerly introduced prosthesis, deposit, imitating narrowing, was revealed. Identification of bile duct deposits depends on their composition, localisation and the imaging techniques used. Pigment calculi with atypical shape, bile density, air density or surrounding tissue density are very difficult to diagnose. Thus, the sensitivity of common bile duct stone detection in USG, CT, MRCP and endoscopic ultrasound (EUS) is 5–88%; 6–88%; 73–97%; and 84–98%, respectively. Moreover, ERCP may not diagnose the character of the restriction even in 5.2% up to 30% of the patients. Consequently, assessment of diagnosis in a number of patients is difficult. A deposit imitating common bile duct (CBD) restriction is a rare, difficult to diagnose phenomenon, which should be taken into account during differential diagnosis of CBD restrictions. PMID:25061493

  8. Colonic inflammation and secondary bile acids in alcoholic cirrhosis

    PubMed Central

    Kakiyama, Genta; Hylemon, Phillip B.; Zhou, Huiping; Pandak, William M.; Heuman, Douglas M.; Kang, Dae Joong; Takei, Hajime; Nittono, Hiroshi; Ridlon, Jason M.; Fuchs, Michael; Gurley, Emily C.; Wang, Yun; Liu, Runping; Sanyal, Arun J.; Gillevet, Patrick M.

    2014-01-01

    Alcohol abuse with/without cirrhosis is associated with an impaired gut barrier and inflammation. Gut microbiota can transform primary bile acids (BA) to secondary BAs, which can adversely impact the gut barrier. The purpose of this study was to define the effect of active alcohol intake on fecal BA levels and ileal and colonic inflammation in cirrhosis. Five age-matched groups {two noncirrhotic (control and drinkers) and three cirrhotic [nondrinkers/nonalcoholics (NAlc), abstinent alcoholic for >3 mo (AbsAlc), currently drinking (CurrAlc)]} were included. Fecal and serum BA analysis, serum endotoxin, and stool microbiota using pyrosequencing were performed. A subgroup of controls, NAlc, and CurrAlc underwent ileal and sigmoid colonic biopsies on which mRNA expression of TNF-α, IL-1β, IL-6, and cyclooxygenase-2 (Cox-2) were performed. One hundred three patients (19 healthy, 6 noncirrhotic drinkers, 10 CurrAlc, 38 AbsAlc, and 30 NAlc, age 56 yr, median MELD: 10.5) were included. Five each of healthy, CurrAlc, and NAlc underwent ileal/colonic biopsies. Endotoxin, serum-conjugated DCA and stool total BAs, and secondary-to-primary BA ratios were highest in current drinkers. On biopsies, a significantly higher mRNA expression of TNF-α, IL-1β, IL-6, and Cox-2 in colon but not ileum was seen in CurrAlc compared with NAlc and controls. Active alcohol use in cirrhosis is associated with a significant increase in the secondary BA formation compared with abstinent alcoholic cirrhotics and nonalcoholic cirrhotics. This increase in secondary BAs is associated with a significant increase in expression of inflammatory cytokines in colonic mucosa but not ileal mucosa, which may contribute to alcohol-induced gut barrier injury. PMID:24699327

  9. Bile salt recognition by human liver fatty acid binding protein.

    PubMed

    Favretto, Filippo; Santambrogio, Carlo; D'Onofrio, Mariapina; Molinari, Henriette; Grandori, Rita; Assfalg, Michael

    2015-04-01

    Fatty acid binding proteins (FABPs) act as intracellular carriers of lipid molecules, and play a role in global metabolism regulation. Liver FABP (L-FABP) is prominent among FABPs for its wide ligand repertoire, which includes long-chain fatty acids as well as bile acids (BAs). In this work, we performed a detailed molecular- and atomic-level analysis of the interactions established by human L-FABP with nine BAs to understand the binding specificity for this important class of cholesterol-derived metabolites. Protein-ligand complex formation was monitored using heteronuclear NMR, steady-state fluorescence spectroscopy, and mass spectrometry. BAs were found to interact with L-FABP with dissociation constants in the narrow range of 0.6-7 μm; however, the diverse substitution patterns of the sterol nucleus and the presence of side-chain conjugation resulted in complexes endowed with various degrees of conformational heterogeneity. Trihydroxylated BAs formed monomeric complexes in which single ligand molecules occupied similar internal binding sites, based on chemical-shift perturbation data. Analysis of NMR line shapes upon progressive addition of taurocholate indicated that the binding mechanism departed from a simple binary association equilibrium, and instead involved intermediates along the binding path. The co-linear chemical shift behavior observed for L-FABP complexes with cholate derivatives added insight into conformational dynamics in the presence of ligands. The observed spectroscopic features of L-FABP/BA complexes, discussed in relation to ligand chemistry, suggest possible molecular determinants of recognition, with implications regarding intracellular BA transport. Our findings suggest that human L-FABP is a poorly selective, universal BA binder. PMID:25639618

  10. Diagnosis and management of bile stone disease and its complications.

    PubMed

    Cremer, Anneline; Arvanitakis, Marianna

    2016-03-01

    Bile stone disease is one of the most prevalent gastroenterological diseases with a considerable geographical and ethnic variation. Bile stones can be classified according their origin, their localization and their biochemical structure. Development and clinical expression depend on a complex interaction between congenital and acquired risk factors. Indeed, bile stones can be either asymptomatic, or cause biliary colic or complications such as acute cholecystitis, jaundice, cholangitis and acute pancreatitis. Diagnosis is based on a combination of clinical features, laboratory findings and imaging techniques and correct identification of symptomatic gallstone patients is essential before cholecystectomy. Transabdominal ultrasonography is the gold standard for the diagnosis of gallstones. However, endoscopic ultrasonography, magnetic resonance cholangiopancreatography and intraoperative cholangiography may also play a role in the diagnosis of bile stones. Management includes prevention measures against modifiable risk factors. Biliary colic and acute cholecystitis are common indications of laparoscopic cholecystectomy, while endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy and stone extraction is the gold standard for the treatment of common bile duct (CBD) stones. Timing of ERCP and cholecystectomy are of critical importance in the management. Lithotripsy modalities are generally reserved for patients with technically difficult CBD stone removal. Percutaneous access combined with lithotripsy may be helpful for complicated intrahepatic stones. PMID:26771377

  11. 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

  12. Optimizing Human Bile Preparation for Two-Dimensional Gel Electrophoresis

    PubMed Central

    Cheng, Hao-Tsai; Sung, Chang-Mu; Pai, Betty Chien-Jung; Liu, Nai-Jen; Chen, Carl PC

    2016-01-01

    Aims. Bile is an important body fluid which assists in the digestion of fat and excretion of endogenous and exogenous compounds. In the present study, an improved sample preparation for human bile was established. Methods and Material. The method involved acetone precipitation followed by protein extraction using commercially available 2D Clean-Up kit. The effectiveness was evaluated by 2-dimensional electrophoresis (2DE) profiling quality, including number of protein spots and spot distribution. Results. The total protein of bile fluid in benign biliary disorders was 0.797 ± 0.465 μg/μL. The sample preparation method using acetone precipitation first followed by 2D Clean-Up kit protein extraction resulted in better quality of 2DE gel images in terms of resolution as compared with other sample preparation methods. Using this protocol, we obtained approximately 558 protein spots on the gel images and with better protein spots presentation of haptoglobin, serum albumin, serotransferrin, and transthyretin. Conclusions. Protein samples of bile prepared using acetone precipitation followed by 2D Clean-Up kit exhibited high protein resolution and significant protein profile. This optimized protein preparation protocol can effectively concentrate bile proteins, remove abundant proteins and debris, and yield clear presentation of nonabundant proteins and its isoforms on 2-dimensional electrophoresis gel images. PMID:26966686

  13. [A case of primary neuroendocrine carcinoma of the bile duct].

    PubMed

    Hamanaka, Michiko; Nakahira, Shin; Takeda, Yutaka; Kawashima, Hiroshi; Mukai, Yosuke; Kanemura, Takeshi; Uchiyama, Chieko; Okishiro, Masatsugu; Takeno, Atsushi; Suzuki, Rei; Taniguchi, Hirokazu; Egawa, Chiyomi; Nakata, Ken; Miki, Hirofumi; Kato, Takeshi; Nagano, Teruaki; Nakatsuka, Shinichi; Tamura, Shigeyuki

    2012-11-01

    A 74-year-old man presented to a physician with a chief complaint of jaundice. He was diagnosed with bile duct carcinoma and admitted to our hospital. Laboratory data revealed abnormally elevated levels of total bilirubin, serum hepatic transaminase, and CA19-9. Endoscopic retrograde cholangiopancreatography revealed neoplastic stenosis from the hilus hepatis to the common bile duct. Abdominal computed tomography (CT) revealed an enhancing tumor in the hilus hepatis bile duct, and positron emission tomography-CT (PET-CT) revealed abnormal fluorodeoxyglucose accumulation in the tumor. Under a diagnosis of hilar cholangiocarcinoma, the patient underwent an extended right hepatectomy and left hepatico -jejunostomy. Immunohistochemically, the tumor cells were positive for neuroendocrine markers such as chromogranin A, synaptophysin, and CD56. The tumor was diagnosed as primary neuroendocrine carcinoma of the bile duct. The patient exhibited multiple liver metastasis 6 months after the operation. Transcatheter arterial chemoembolization (TACE) was performed for the liver metastasis. Although TACE exerted a cytoreductive effect temporarily, multiple liver abscesses developed. The patient died of liver failure 16 months after the operation. We report this rare case of primary neuroendocrine carcinoma of the bile duct. PMID:23267998

  14. Quantitative profiling of bile acids in rat bile using ultrahigh-performance liquid chromatography-orbitrap mass spectrometry: Alteration of the bile acid composition with aging.

    PubMed

    Lee, Gakyung; Lee, Hyunbeom; Hong, Jongki; Lee, Soo Hyun; Jung, Byung Hwa

    2016-09-15

    Bile acids (BAs) play important roles in physiological functions, including the homeostasis of cholesterol and lipids and as ligands for G protein-coupled receptors (GPCRs). With the increasing importance of BAs, analytical methods for their quantification and screening have been developed. However, due to the diverse range and variety of BAs with different activation potency, a simple, effective, and sensitive method is required to screen BAs for accurate quantification and identification. This paper presents an application of ultrahigh-performance liquid chromatography-orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MS) for profiling BAs in bile. Using this method, along with the accurate quantification of 19 targeted BAs, 22 unknown BAs were detected and characterized by their fragmentation patterns. The method is beneficial for screening most of the BAs (quantitatively and qualitatively) in rat bile with simple preparation in a single run. The sample dilution ranges of each BA were optimized depending on the concentration of BAs in the bile to obtain good peak separation and accurate data. The method validation was performed successfully using charcoal-treated bile and the intra and inter-day coefficients of variation were less than 20% for all BAs while the recovery were above 88.5% except for the lithocholic acid. The method was applied to profile the age-dependent changes in the contents of rat BAs. Through statistical analysis, we found that as the rats aged, unconjugated BAs and glycine-conjugated BAs decreased or were unaffected, while taurine-conjugated BAs were increased in general. Among the unknown BAs, 5 of the taurine-conjugated BAs increased, while a glycine-conjugated BA decreased, in agreement with the trends of the targeted BAs. PMID:27450898

  15. Posttraumatic bile leaks: role of diagnostic imaging and impact on patient outcome.

    PubMed

    Fleming, Keith W; Lucey, Brian C; Soto, Jorge A; Oates, M Elizabeth

    2006-03-01

    The aim of this study was to evaluate the impact of bile leaks on patient morbidity and hospital course following blunt and penetrating liver trauma. Forty patients who underwent hepatobiliary scintigraphy after trauma were included. Scintigraphic results were classified as follows: free intraperitoneal bile leak, contained bile leak, and no bile leak. Outcomes measured were length of hospital stay, number of procedures required, and number of subsequent imaging studies. Bile leaks were identified in 25% of patients. Eight percent had free intraperitoneal leaks, 18% contained bile leaks, and 73% had no bile leak. One study was nondiagnostic due to poor hepatic function. Mean hospitalization was as follows: free bile leak group, 53 days; contained bile leak group, 10 days; no bile leak group, 14 days. Patients with free intraperitoneal bile leak had more imaging studies and procedures than patients without free bile leak. Patients with liver injury and free intraperitoneal bile leak have longer hospitalizations and undergo more therapeutic procedures than those without, who respond to conservative management. PMID:16369810

  16. Fluorescence properties and sequestration of peripheral anionic site specific ligands in bile acid hosts: Effect on acetylcholinesterase inhibition activity.

    PubMed

    Islam, Mullah Muhaiminul; Aguan, Kripamoy; Mitra, Sivaprasad

    2016-05-01

    The increase in fluorescence intensity of model acetyl cholinesterase (AChE) inhibitors like propidium iodide (PI) and ethidium bromide (EB) is due to sequestration of the probes in primary micellar aggregates of bile acid (BA) host medium with moderate binding affinity of ca. 10(2)-10(3)M(-1). Multiple regression analysis of solvent dependent fluorescence behavior of PI indicates the decrease in total nonradiative decay rate due to partial shielding of the probe from hydrogen bond donation ability of the aqueous medium in bile acid bound fraction. Both PI and EB affects AChE activity through mixed inhibition and consistent with one site binding model; however, PI (IC50=20±1μM) shows greater inhibition in comparison with EB (IC50=40±3μM) possibly due to stronger interaction with enzyme active site. The potency of AChE inhibition for both the compounds is drastically reduced in the presence of bile acid due to the formation of BA-inhibitor complex and subsequent reduction of active inhibitor fraction in the medium. Although the inhibition mechanism still remains the same, the course of catalytic reaction critically depends on equilibrium binding among several species present in the solution; particularly at low inhibitor concentration. All the kinetic parameters for enzyme inhibition reaction are nicely correlated with the association constant for BA-inhibitor complex formation. PMID:26974580

  17. Morphologic changes in livers of hamsters treated with high doses of ursodeoxycholic acid: correlation with bile acids in bile.

    PubMed

    Mamianetti, A; Konopka, H F; Lago, N; Vescina, C; Scarlato, E; Carducci, C N

    1994-01-01

    The effects of high doses of ursodeoxycholic acid on bile acid composition and the liver morphology was examined in 60 male Syrian golden hamsters. The animals were allocated to five groups: I, control; II and IV received 0.5 g and 1 g of ursodeoxycholic acid per 100 g of standard diet respectively over 30 days and III and V received 0.5 g and 1 g of ursodeoxycholic acid per 100 g of standard diet respectively over 60 days. Bile acids were determined by high performance liquid chromatography. In all treated groups there was a significant increase in chenodeoxycholic and lithocholic acid in the bile. The mean glyco/tauro ratio was significantly higher than in the control group, reaching values > 1 for individual bile acids, except for lithocholic acid values which remained < 1. Under light microscopy, the livers of the hamsters showed damage which was dose/time related, namely portal inflammatory infiltrate, bile duct proliferation, cholestasis, fat infiltration and necrosis. Electron microscopy revealed pronounced changes starting with microvilli edema and extending to canalicular membrane destruction and necrosis. The changes observed in the relation glyco/tauro lithocholic acids, may be due to defence mechanisms to avoid hepatotoxicity. The hepatotoxicity resulting from ursodeoxycholic acid administration is presumed to be due primarily to lithocholic acid or some lithocholic acid metabolite. PMID:8058592

  18. Fecal bile acids of black-footed ferrets

    USGS Publications Warehouse

    Richardson, Louise; Johnson, M.K.; Clark, T.W.; Schroder, M.H.

    1986-01-01

    Fecal bile acid characteristics have been used to identify scats to species of origin. Fecal bile acids in scats from 20 known black-footed ferrets ( Mustela nigripes ), 7 other known small carnivores, and 72 of unknown origin were analyzed to determine if this procedure could be used as a tool to verify ferret presence in an area. Seventeen ferret scats were suitable for analysis and had a mean fecal bile acid index of 156 ± 9. This was significantly different from mean indices for the other carnivores; however, substantial overlap among confidence intervals occurred for badgers, kit foxes, and especially long-tailed weasels. We conclude this method is not useful for making positive identifications if individual ferret scats and suggest that we may be able to definitively identify individual scats with reasonable confidence by using gas-liquid chromatography.

  19. Bactobilin: blue bile pigment isolated from Clostridium tetanomorphum.

    PubMed Central

    Brumm, P J; Fried, J; Friedmann, H C

    1983-01-01

    A blue bile pigment, possessing four acetic and four propionic acid side chains has been isolated from extracts of the anaerobic microorganism Clostridium tetanomorphum and in smaller amounts from Propionibacterium shermanii. The compound could be prepared in larger amounts by incubation of C. tetanomorphum enzyme extracts with added delta-aminolevulinic acid. The ultraviolet-visible, infrared, and proton magnetic resonance spectra of the pigment indicate a chromophore of the biliverdin type. Field-desorption mass spectrometry of the purified methyl ester showed a strong molecular ion at m/e = 962. This corresponds to the molecular weight expected for the octamethyl ester of a bilatriene type of bile pigment structurally derived from uroporphyrin III or I. Of the five possible structures, two could be eliminated by proton magnetic resonance spectroscopy. The name bactobilin is proposed for this previously unreported bile pigment. PMID:6575387

  20. Bile acid nuclear receptor FXR and digestive system diseases

    PubMed Central

    Ding, Lili; Yang, Li; Wang, Zhengtao; Huang, Wendong

    2015-01-01

    Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases. PMID:26579439

  1. Autofluorescent polarimetry of bile films in the liver pathology differentiation

    NASA Astrophysics Data System (ADS)

    Prysyazhnyuk, V. P.; Ushenko, Yu. O.; Dubolazov, O. V.; Ushenko, A. G.; Savich, V. O.; Karachevtsev, A. O.

    2015-09-01

    A new information optical technique of diagnostics of the structure of the polycrystalline bile films is proposed. The model of Mueller-matrix description of mechanisms of optical anisotropy of such objects as optical activity, birefringence, as well as linear and circular dichroism is suggested. The ensemble of informationally topical azimuthally stable Mueller-matrix invariants is determined. Within the statistical analysis of such parameters distributions the objective criteria of differentiation of the polycrystalline bile films taken from patients with fatty degeneration (group 1) chronic hepatitis (group 2) of the liver were determined. From the point of view of probative medicine the operational characteristics (sensitivity, specificity and accuracy) of the information-optical method of Mueller-matrix mapping of polycrystalline films of bile were found and its efficiency in diagnostics of pathological changes was demonstrated.

  2. Early diagnosis of common bile duct obstruction using cholescintigraphy

    SciTech Connect

    Kaplun, L.; Weissmann, H.S.; Rosenblatt, R.R.; Freeman, L.M.

    1985-11-01

    The technetium Tc 99m-labeled iminodiacetic acid cholescintigram is an extremely accurate examination for detecting early obstruction of the common bile duct in acutely ill patients suspected of having acute cholecystitis or possible obstruction days to years after cholecystectomy. The examination accurately detected common bile duct obstruction in 63 of 65 patients in these two diagnostic categories. Sonographic evaluations in 43 of these patients failed to reveal ductal dilatation or other abnormality in 26 cases, and was nondiagnostic because of overlying bowel gas in two cases. The success of the radionuclide examination is attributed to its ability to detect functional impedance to bile flow hours to days before anatomic ductal dilatation occurs, and occasionally even before the alkaline phosphatase level and other liver chemistry values suggest the presence of an obstruction.

  3. Endoscopic management of difficult common bile duct stones

    PubMed Central

    Trikudanathan, Guru; Navaneethan, Udayakumar; Parsi, Mansour A

    2013-01-01

    Endoscopy is widely accepted as the first treatment option in the management of bile duct stones. In this review we focus on the alternative endoscopic modalities for the management of difficult common bile duct stones. Most biliary stones can be removed with an extraction balloon, extraction basket or mechanical lithotripsy after endoscopic sphincterotomy. Endoscopic papillary balloon dilation with or without endoscopic sphincterotomy or mechanical lithotripsy has been shown to be effective for management of difficult to remove bile duct stones in selected patients. Ductal clearance can be safely achieved with peroral cholangioscopy guided laser or electrohydraulic lithotripsy in most cases where other endoscopic treatment modalities have failed. Biliary stenting may be an alternative treatment option for frail and elderly patients or those with serious co morbidities. PMID:23345939

  4. Flagging Drugs That Inhibit the Bile Salt Export Pump.

    PubMed

    Montanari, Floriane; Pinto, Marta; Khunweeraphong, Narakorn; Wlcek, Katrin; Sohail, M Imran; Noeske, Tobias; Boyer, Scott; Chiba, Peter; Stieger, Bruno; Kuchler, Karl; Ecker, Gerhard F

    2016-01-01

    The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis. Predictive computational models of BSEP inhibition may allow for fast identification of potentially harmful compounds in large databases. This article presents a predictive in silico model based on physicochemical descriptors that is able to flag compounds as potential BSEP inhibitors. This model was built using a training set of 670 compounds with available BSEP inhibition potencies. It successfully predicted BSEP inhibition for two independent test sets and was in a further step used for a virtual screening experiment. After in vitro testing of selected candidates, a marketed drug, bromocriptin, was identified for the first time as BSEP inhibitor. This demonstrates the usefulness of the model to identify new BSEP inhibitors and therefore potential cholestasis perpetrators. PMID:26642869

  5. Bile acid nuclear receptor FXR and digestive system diseases.

    PubMed

    Ding, Lili; Yang, Li; Wang, Zhengtao; Huang, Wendong

    2015-03-01

    Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases. PMID:26579439

  6. Nasogastric tube placement into the hepaticojejunostomy anastomosis in pancreaticoduodenectomy: a simple surgical technique for prevention of bile leak.

    PubMed

    Kaya, Bulent; Ozcabi, Yetkin; Tasdelen, Iksan; Onur, Ender; Memisoglu, Kemal

    2016-05-01

    Hepaticojejunostomy is an important part of many surgical procedures including pancreaticoduodenectomy. Biliary leakage from hepaticojejunostomy may be associated with intraabdominal abscess formation, biliary peritonitis, and even mortality. A 72-year-old female patient was admitted to our hospital with obstructive jaundice. After initial evaluation, she was diagnosed with distal common bile duct obstruction without accurate diagnosis. Before planned pancreaticoduodenectomy, biliary drainage with a T-tube was performed due to the presence of cholangitis. After the first operation, pancreaticoduodenectomy was performed. Postinflammatory changes around the hilar region made the hepaticojejunostomy risky. A bilio-digestive anastomosis was performed using a new technique. A nasogastric tube was placed into the common bile duct proximal to the anastomosis. The postoperative course of the patient was uneventful. The use of a nasogastric tube as a stent in risky hepaticojejunostomies is a simple technique that can be beneficial. PMID:27212998

  7. Nasogastric tube placement into the hepaticojejunostomy anastomosis in pancreaticoduodenectomy: a simple surgical technique for prevention of bile leak

    PubMed Central

    Ozcabi, Yetkin; Tasdelen, Iksan; Onur, Ender; Memisoglu, Kemal

    2016-01-01

    Hepaticojejunostomy is an important part of many surgical procedures including pancreaticoduodenectomy. Biliary leakage from hepaticojejunostomy may be associated with intraabdominal abscess formation, biliary peritonitis, and even mortality. A 72-year-old female patient was admitted to our hospital with obstructive jaundice. After initial evaluation, she was diagnosed with distal common bile duct obstruction without accurate diagnosis. Before planned pancreaticoduodenectomy, biliary drainage with a T-tube was performed due to the presence of cholangitis. After the first operation, pancreaticoduodenectomy was performed. Postinflammatory changes around the hilar region made the hepaticojejunostomy risky. A bilio-digestive anastomosis was performed using a new technique. A nasogastric tube was placed into the common bile duct proximal to the anastomosis. The postoperative course of the patient was uneventful. The use of a nasogastric tube as a stent in risky hepaticojejunostomies is a simple technique that can be beneficial. PMID:27212998

  8. Bile loss in the acute intestinal radiation syndrome in rats

    SciTech Connect

    Geraci, J.P.; Dunston, S.G.; Jackson, K.L.; Mariano, M.S.; Holeski, C.; Eaton, D.L.

    1987-01-01

    The effects of bile duct ligation (BDL), choledochostomy, bile acid sequestering within the intestinal lumen by cholestyramine, and fluid and electrolyte replacement on survival time and development of diarrhea after whole-body exposure to doses of ionizing radiation that result in death from acute intestinal injury were studied. BDL significantly prolonged survival and delayed the onset of diarrhea after exposure to /sup 137/Cs gamma rays, fission neutrons, or cyclotron-produced neutrons in the range of doses that produce intestinal death or death from a combination of intestinal and hematopoietic injuries. Cannulation of the bile duct with exteriorized bile flow (choledochostomy) to protect the irradiated intestine from the mucolytic action of bile salts did not duplicate the effect of BDL in increasing survival time. Choledochostomy without fluid replacement eliminated the occurrence of diarrhea in 15.4 Gy irradiated rats. Diarrhea did occur in irradiated animals with choledochostomy if they received duodenal injections of fluid and electrolytes to replace the fluid lost as a result of bile drainage. Duodenal injection of fluid and electrolytes had no significant effect on survival time in irradiated rats. Injection of fluid and electrolytes into the peritoneal cavity of irradiated rats resulted in an increase in survival time that was comparable to that observed after BDL. Addition of antibiotics to the peritoneally injected fluid and electrolytes further increased survival time (up to 9 days). This survival time approached that seen in animals receiving the same radiation dose but which had the intestine exteriorized and shielded to minimize radiation injury to the intestine. Postmortem histological examinations of the irradiated small intestine showed mucosal regeneration in these long-term survivors receiving fluid and antibiotic therapy.

  9. Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors.

    PubMed

    Brighton, Cheryl A; Rievaj, Juraj; Kuhre, Rune E; Glass, Leslie L; Schoonjans, Kristina; Holst, Jens J; Gribble, Fiona M; Reimann, Frank

    2015-11-01

    Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein-coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1-secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L-cells, we observed that taurodeoxycholate (TDCA) and taurolithocholate (TLCA) increased intracellular cAMP and Ca(2+). In primary intestinal cultures, TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca(2+) response to TDCA. Using small-volume Ussing chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT inhibition had no significant effect in nonpolarized primary cultures. Studies in the perfused rat gut confirmed that vascularly administered TDCA was more effective than luminal TDCA. Intestinal primary cultures and Ussing chamber-mounted tissues from GPBAR1-knockout mice did not secrete GLP-1 in response to either TLCA or TDCA. We conclude that the action of bile acids on GLP-1 secretion is predominantly mediated by GPBAR1 located on the basolateral L-cell membrane, suggesting that stimulation of gut hormone secretion may include postabsorptive mechanisms. PMID:26280129

  10. Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein–Coupled Bile Acid Receptors

    PubMed Central

    Brighton, Cheryl A.; Rievaj, Juraj; Kuhre, Rune E.; Glass, Leslie L.; Schoonjans, Kristina; Holst, Jens J.

    2015-01-01

    Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein–coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1–secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L-cells, we observed that taurodeoxycholate (TDCA) and taurolithocholate (TLCA) increased intracellular cAMP and Ca2+. In primary intestinal cultures, TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca2+ response to TDCA. Using small-volume Ussing chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT inhibition had no significant effect in nonpolarized primary cultures. Studies in the perfused rat gut confirmed that vascularly administered TDCA was more effective than luminal TDCA. Intestinal primary cultures and Ussing chamber–mounted tissues from GPBAR1-knockout mice did not secrete GLP-1 in response to either TLCA or TDCA. We conclude that the action of bile acids on GLP-1 secretion is predominantly mediated by GPBAR1 located on the basolateral L-cell membrane, suggesting that stimulation of gut hormone secretion may include postabsorptive mechanisms. PMID:26280129

  11. Extracorporeal abdominal massage may help prevent recurrent bile duct stones after endoscopic sphincterotomy

    PubMed Central

    Uchida, Naohito; Hamaya, Sae; Tatsuta, Miwa; Nakatsu, Toshiaki

    2016-01-01

    Background and study aims: Endoscopic sphincterotomy (EST) is effective, but recurrent bile duct stones are a common late complication. Because there are still no effective therapies for preventing this complication, some patients have experienced bile duct stone recurrence many times. We describe herein a method of abdominal massage to treat patients with prior cholecystectomy who have experienced recurrence of bile duct stones. PMID:27540575

  12. Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea

    SciTech Connect

    Schiller, L.R.; Bilhartz, L.E.; Santa Ana, C.A. )

    1990-04-01

    Fecal recovery of radioactivity after ingestion of a bolus of radiolabeled bile acid is abnormally high in most patients with idiopathic chronic diarrhea. To evaluate the significance of this malabsorption, concurrent fecal excretion of both exogenous radiolabeled bile acid and endogenous (unlabeled) bile acid were measured in patients with idiopathic chronic diarrhea. Subjects received a 2.5-microCi oral dose of taurocholic acid labeled with 14C in the 24th position of the steroid moiety. Endogenous bile acid excretion was measured by a hydroxysteroid dehydrogenase assay on a concurrent 72-h stool collection. Both radiolabeled and endogenous bile acid excretion were abnormally high in most patients with chronic diarrhea compared with normal subjects, even when equivoluminous diarrhea was induced in normal subjects by ingestion of osmotically active solutions. The correlation between radiolabeled and endogenous bile acid excretion was good. However, neither radiolabeled nor endogenous bile acid excretion was as abnormal as is typically seen in patients with ileal resection, and none of these diarrhea patients responded to treatment with cholestyramine with stool weights less than 200 g. These results suggest (a) that this radiolabeled bile acid excretion test accurately reflects excess endogenous bile acid excretion; (b) that excess endogenous bile acid excretion is not caused by diarrhea per se; (c) that spontaneously occurring idiopathic chronic diarrhea is often associated with increased endogenous bile acid excretion; and (d) that bile acid malabsorption is not likely to be the primary cause of diarrhea in most of these patients.

  13. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption

    PubMed Central

    Xie, Guoxiang; Zhong, Wei; Li, Houkai; Li, Qiong; Qiu, Yunping; Zheng, Xiaojiao; Chen, Huiyuan; Zhao, Xueqing; Zhang, Shucha; Zhou, Zhanxiang; Zeisel, Steven H.; Jia, Wei

    2013-01-01

    Our understanding of the bile acid metabolism is limited by the fact that previous analyses have primarily focused on a selected few circulating bile acids; the bile acid profiles of the liver and gastrointestinal tract pools are rarely investigated. Here, we determined how chronic ethanol consumption altered the bile acids in multiple body compartments (liver, gastrointestinal tract, and serum) of rats. Rats were fed a modified Lieber-DeCarli liquid diet with 38% of calories as ethanol (the amount equivalent of 4–5 drinks in humans). While conjugated bile acids predominated in the liver (98.3%), duodenum (97.8%), and ileum (89.7%), unconjugated bile acids comprised the largest proportion of measured bile acids in serum (81.2%), the cecum (97.7%), and the rectum (97.5%). In particular, taurine-conjugated bile acids were significantly decreased in the liver and gastrointestinal tract of ethanol-treated rats, while unconjugated and glycine-conjugated species increased. Ethanol consumption caused increased expression of genes involved in bile acid biosynthesis, efflux transport, and reduced expression of genes regulating bile acid influx transport in the liver. These results provide an improved understanding of the systemic modulations of bile acid metabolism in mammals through the gut-liver axis.—Xie, G., Zhong, W., Li, H., Li, Q., Qiu, Y., Zheng, X., Chen, H., Zhao, X., Zhang, S., Zhou, Z., Zeisel, S. H., Jia, W. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption. PMID:23709616

  14. Sertraline-Associated Cholestasis and Ductopenia Consistent with Vanishing Bile Duct Syndrome.

    PubMed

    Conrad, Máire A; Cui, Jiawei; Lin, Henry C

    2016-02-01

    An adolescent with depression treated with sertraline developed cholestasis and bile duct paucity, which resolved with medication discontinuation. Vanishing bile duct syndrome is an acquired destruction of interlobular bile ducts. This type of drug-induced liver injury has been associated with other medications and requires practitioners' awareness of potential hepatotoxicity. PMID:26597434

  15. Repair of extrahepatic bile duct defect using a collagen patch in a Swine model.

    PubMed

    Tao, Liang; Li, Qiang; Ren, Haozhen; Chen, Bing; Hou, Xianglin; Mou, Lingjun; Zhou, Siqiao; Zhou, Jianxin; Sun, Xitai; Dai, Jianwu; Ding, Yitao

    2015-04-01

    Extrahepatic bile duct (EBD) injury can happen during surgery. To repair a defect of the EBD and prevent postoperative biliary complications, a collagen membrane was designed. The collagen material was porous, biocompatible, and degradable and could maintain its shape in bile soaking for about 4 weeks. The goal was to induce rapid bile duct tissue regeneration. Twenty Chinese experimental hybrid pigs were used in this study and divided into a patch group and a control group. A spindle-shaped defect (20 mm × 6 mm) was made in the anterior wall of the lower EBD in the swine model, and then the defect was reconstructed using a collagen patch with a drainage tube and wrapped with greater omentum. Ultrasound was performed at 2, 4, 8, and 12 weeks postoperatively. Liver function tests and white blood cell count (WBC) were measured. Hematoxylin-eosin staining, cytokeratin 7 immunohistochemical staining, and Van Gieson's staining of EBD were used. The diameter and thickness of the EBD at the graft site were measured. There was no significant difference in liver function tests or WBC in the patch group compared with the control group. No evidence of leakage or stricture was observed, but some pigs developed biliary sludge or stone at 4 and 8 weeks. The drainage tube was lost within 12 weeks. The neo-EBD could withstand normal biliary pressure 2 weeks after surgery. Histological study showed the accessory glands and epithelial cells gradually regenerated at graft sites from 4 weeks, with increasing vessel infiltration and decreasing inflammation. The collagen fibers became regular with full coverage of epithelial cells. The statistical analysis of diameter and thickness showed no stricture formation at the graft site, but the EBD wall was slightly thicker than in the normal bile duct due to collagen fiber deposition. The structure of the neo-EBD was similar to that of the normal EBD. The collagen membrane patch associated with a drainage tube and wrapped with greater

  16. Effect of endoscopic sphincterotomy on gall bladder bile lithogenicity and motility

    PubMed Central

    Sharma, B; Agarwal, D; Baijal, S; Negi, T; Choudhuri, G; Saraswat, V

    1998-01-01

    Background—Endoscopic sphincterotomy has been shown to inhibit stone formation in the gall bladder of experimental animals. 
Aims—To investigate the alterations in bile composition and gall bladder motility after endoscopic sphincterotomy. 
Patients—A study was performed of gall bladder bile composition and gall bladder motility in patients with gallstone disease ((n = 20; age 40-60 years, median age 55 years: seven men), with gall bladder calculi (n = 12) and with diseased gall bladder (chronic inflammation) without gall bladder calculi (n = 8)), who had received endoscopic sphincterotomy for common bile duct stones. Age and sex matched disease controls comprised 20 patients with gallstone disease but without stones and an intact sphincter of Oddi (with gall bladder calculi (n = 10) and diseased gall bladder without gall bladder calculi (n =10)). 
Methods—Gall bladder motility was assessed by ultrasound. Duodenal bile collected by nasoduodenal tube after stimulation of gall bladder by intravenous ceruletid infusion was analysed for cholesterol, phospholipid, and bile acid concentrations, cholesterol saturation index, and nucleation time. 
Results—There was a significant reduction in mean (SEM) fasting volume (12.5 (1.7) ml v 26.4 (2.5) ml; p<0.001) and mean (SEM) residual volume (4.34 (0.9) ml v 14.7 (0.98) ml; p<0.001), and increase in mean (SEM) ejection fraction (65.7 (4.2)% v 43.6 (5.52)%; p<0.001) and mean (SEM) rate constant of gall bladder emptying (−0.031/min v −0.020/min; p<0.01) in patients who had been subjected to endoscopic sphincterotomy. Median nucleation time was significantly longer (17 days v 6 days; p<0.006) in treated patients. There was a reduction in total mean (SEM) lipid concentrations (6.73(0.32) g/dl v 7.72 (0.84) g/dl; p<0.05), cholesterol (5.6 (1.5) mmol/l v 10.3 (2.23) mmol/l; p<0.001) and CSI (0.72 (0.15) v 1.32(0.31); p<0.001). There was no significant change in mean (SEM) phospholipid (25.6 (3.5) mmol/l v 23

  17. 21 CFR 184.1560 - Ox bile extract.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Ox bile extract. 184.1560 Section 184.1560 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...

  18. 21 CFR 184.1560 - Ox bile extract.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... surfactant as defined in § 170.3 (o)(29) of this chapter. (d) The ingredient is used in food in accordance... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Ox bile extract. 184.1560 Section 184.1560 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR...

  19. Methotrexate in Liver and Bile after Intravenous Dosage in Man

    PubMed Central

    Creaven, P. J.; Hansen, H. H.; Alford, D. A.; Allen, L. M.

    1973-01-01

    Measurements of methotrexate have been made in the liver and plasma of 4 patients and in the bile and plasma of 1 patient receiving [3H]methotrexate. Projections from a theoretical model of concentration of methotrexate in liver are confirmed but projections of biliary excretion are not. PMID:4783160

  20. [Combined action of nitrofuran preparations and bile acids on staphylococci].

    PubMed

    Tkachuk, N I

    1984-03-01

    The effect of cholic, glycocholic and deoxycholic bile acids on the antimicrobial activity of furacin, furadonin, furagin and furoxone was studied with the use of collection strains and fresh isolates of staphylococci. The method of dilutions in liquid media was used. Cholic and glycocholic acids lowered the MIC of furacin, furadonin, furoxone and furagin with respect to the collection strains by 4-16, 5, 4-6 and 22-37 times, respectively. The potentiating effect of deoxycholic acid on the nitrofuran drugs was even more pronounced. Thus, when the nitrofurans were used in combination with deoxycholic acid, their MIC dropped by 16-114 times. A significant increase in the antimicrobial activity of the nitrofurans under the effect of the bile acids was also observed with respect to the fresh isolates of Staphylococcus, while it was somewhat lower. The subbacteriostatic doses of cholic, glycocholic and deoxycholic bile acids also increased the bactericidal effect of the nitrofuran drugs. The minimum bactericidal concentrations (MBC) of furacin, furoxone, furadonin and furagin decreased from 12.5, 2.08, 25.0 and 1.82 to 0.78, 0.26, 2.34 and 0.032 micrograms/ml, respectively. The most pronounced decrease in the MBC was observed under the effect of deoxycholic acid. Therefore, the bile acids potentiated the nitrofuran antistaphylococcal activity. The combinations of deoxycholic acid with furagin or furoxone were the most effective. PMID:6732204

  1. Chemical composition of blood and bile of the shovelnose sturgeon

    USGS Publications Warehouse

    Hunn, J.B.; Christenson, L.M.

    1977-01-01

    Samples of gallbladder bile and blood from shovelnose sturgeons (Scaphirhynchus platorynchus) collected from the Chippewa River, Wisconsin, contained concentrations of Na+, K+, Ca++, Mg++, Cl-, inorganic phosphate, and total cholesterol closely comparable with those reported for similar samples from other species of freshwater sturgeons.

  2. DOES LOSS OF BILE ACID HOMEOSTASIS MAKE MICE MELANCHOLY?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bile is at the center of the traditional medicines of many cultures. For the ancient Greeks and Romans, each of the four macrocosmic elements that comprised the natural world, fire, earth, air, and water, had a specific microcosmic reflection in the four humors from which the body was constructed: ...

  3. Role of transporter proteins in bile tolerance of Lactobacillus acidophilus.

    PubMed

    Pfeiler, Erika A; Klaenhammer, Todd R

    2009-09-01

    Lactobacillus acidophilus NCFM derivatives containing deletion mutations in the transporter genes LBA0552, LBA1429, LBA1446, and LBA1679 exhibited increased sensitivity to bile. These strains showed unique patterns of sensitivity to a variety of inhibitory compounds, as well as differential accumulations of ciprofloxacin and taurocholate. PMID:19633113

  4. Clear cell carcinoid tumor of the distal common bile duct

    PubMed Central

    Todoroki, Takeshi; Sano, Takaaki; Yamada, Shuji; Hirahara, Nobutsune; Toda, Naotaka; Tsukada, Katsuhiko; Motojima, Ryuji; Motojima, Teiji

    2007-01-01

    Background Carcinoid tumors rarely arise in the extrahepatic bile duct and can be difficult to distinguish from carcinoma. There are no reports of clear cell carcinoid (CCC) tumors in the distal bile duct (DBD) to the best of our knowledge. Herein, we report a CCC tumor in the DBD and review the literature concerning extrahepatic bile duct carcinoid tumors. Case presentation A 73-old man presented with fever and occult obstructive jaundice. Ultrasonography, computed tomography (CT) and magnetic resonance cholangiopancreaticography (MRCP) demonstrated a nodular tumor projection in the DBD without regional lymph node swelling. Under suspicion of carcinoma, we resected the head of the pancreas along with 2nd portion duodenectomy and a lymph node dissection. The surgical specimen showed a golden yellow polypoid tumor in the DBD (0.8 × 0.6 × 0.5 cm in size). The lesion was composed of clear polygonal cells arranged in nests and a trabecular pattern. The tumor invaded through the wall into the fibromuscular layer. Immunohistochemical stains showed that neoplastic cells were positive for neuron-specific enolase (NSE), chromogranin A, synaptophysin, and pancreatic polypeptide and negative for inhibin, keratin, CD56, serotonin, gastrin and somatostatin. The postoperative course was uneventful and he is living well without relapse 12 months after surgery. Conclusion Given the preoperative difficulty in differentiating carcinoid from carcinoma, the pancreaticoduodenectomy is an appropriate treatment choice for carcinoid tumors located within the intra-pancreatic bile duct. PMID:17227590

  5. Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis

    SciTech Connect

    Woolbright, Benjamin L.; Dorko, Kenneth; Antoine, Daniel J.; Clarke, Joanna I.; Gholami, Parviz; Li, Feng; Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson; Fan, Fang; Jenkins, Rosalind E.; Park, B. Kevin; Hagenbuch, Bruno; Olyaee, Mojtaba; Jaeschke, Hartmut

    2015-03-15

    Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. - Highlights: • Cholestatic liver injury is due to cytoplasmic bile acid accumulation in hepatocytes. • Primary human hepatocytes are resistant to BA-induced injury

  6. Ostα depletion protects liver from oral bile acid load

    PubMed Central

    Velazquez, Heino; Mennone, Albert; Ballatori, Nazzareno; Boyer, James L.

    2011-01-01

    Bile acid homeostasis is tightly maintained through interactions between the liver, intestine, and kidney. During cholestasis, the liver is incapable of properly clearing bile acids from the circulation, and alternative excretory pathways are utilized. In obstructive cholestasis, urinary elimination is often increased, and this pathway is further enhanced after bile duct ligation in mice that are genetically deficient in the heteromeric, basolateral organic solute transporter alpha-beta (Ostα-Ostβ). In this study, we examined renal and intestinal function in Ostα-deficient and wild-type mice in a model of bile acid overload. After 1% cholic acid feeding, Ostα-deficient mice had significantly lower serum ALT levels compared with wild-type controls, indicating partial protection from liver injury. Urinary clearance of bile acids, but not clearance of [3H]inulin, was significantly higher in cholic acid-fed Ostα-deficient mice compared with wild-type mice but was not sufficient to account for the protection. Fecal excretion of bile acids over the 5 days of cholic acid feeding was responsible for almost all of the bile acid loss in Ostα-deficient mice, suggesting that intestinal losses of bile acids accounted for the protection from liver injury. Thus fecal loss of bile acids after bile acid overload reduced the need for the kidney to filter and excrete the excess bile acids. In conclusion, Ostα-deficient mice efficiently eliminate excess bile acids via the feces. Inhibition of intestinal bile acid absorption might be an effective therapeutic target in early stages of cholestasis when bile acids are still excreted into bile. PMID:21719738

  7. Ostα depletion protects liver from oral bile acid load.

    PubMed

    Soroka, Carol J; Velazquez, Heino; Mennone, Albert; Ballatori, Nazzareno; Boyer, James L

    2011-09-01

    Bile acid homeostasis is tightly maintained through interactions between the liver, intestine, and kidney. During cholestasis, the liver is incapable of properly clearing bile acids from the circulation, and alternative excretory pathways are utilized. In obstructive cholestasis, urinary elimination is often increased, and this pathway is further enhanced after bile duct ligation in mice that are genetically deficient in the heteromeric, basolateral organic solute transporter alpha-beta (Ostα-Ostβ). In this study, we examined renal and intestinal function in Ostα-deficient and wild-type mice in a model of bile acid overload. After 1% cholic acid feeding, Ostα-deficient mice had significantly lower serum ALT levels compared with wild-type controls, indicating partial protection from liver injury. Urinary clearance of bile acids, but not clearance of [(3)H]inulin, was significantly higher in cholic acid-fed Ostα-deficient mice compared with wild-type mice but was not sufficient to account for the protection. Fecal excretion of bile acids over the 5 days of cholic acid feeding was responsible for almost all of the bile acid loss in Ostα-deficient mice, suggesting that intestinal losses of bile acids accounted for the protection from liver injury. Thus fecal loss of bile acids after bile acid overload reduced the need for the kidney to filter and excrete the excess bile acids. In conclusion, Ostα-deficient mice efficiently eliminate excess bile acids via the feces. Inhibition of intestinal bile acid absorption might be an effective therapeutic target in early stages of cholestasis when bile acids are still excreted into bile. PMID:21719738

  8. A prospective study of faecal bile acids and colorectal cancer.

    PubMed

    Haines, A; Hill, M J; Thompson, M H; Owen, R W; Williams, R E; Meade, T W; Wilkes, H; Griffin, M

    2000-10-01

    A prospective study of 7079 people aged 45-74 recruited through general practices in South Wales, Herefordshire and Edinburgh, Scotland was undertaken to test the hypothesis that faecal bile acids are implicated in the causation of large bowel cancer. The population was recruited between 1974 and 1980 and the response rate for stool collection was 67%. Bile acid analyses were performed on those cases that presented by 1990. It was decided in advance to examine the hypothesis separately for left- and right-sided bowel cancer because of known epidemiological differences between the two sites and to exclude the cases presenting within 2 years of the stool sample from the analyses because the cancer could have been present at recruitment and might have possibly affected faecal bile acid concentrations. Each case (n = 51 left-sided and 8 right-sided) was matched with three controls by age (within 5 years), sex, place of residence and time of providing the stool sample (within 3 months). Statistical analyses using conditional logistic regression showed no significant differences between the left-sided cases and controls for any of the concentrations of individual bile acids, total bile acid concentrations, faecal neutral steroids, percentage bacterial conversion and the ratio of lithocholic acid to deoxycholic acid concentrations. There was a statistically significant (P = 0.021) association of the presence of chenodeoxycholic acid (5/8 samples) in the right-sided cases compared with the controls (3/23), odds ratio 6.26 (95% confidence interval 1.19, 32.84). A high proportion of primary bile acids has also been found in other studies of patients with a genetic predisposition to proximal bowel cancer, however this pattern may also occur in low risk groups, such as Indian vegetarians, suggesting that they may predispose to right-sided bowel cancer only in the presence of other, as yet unknown factors. If bile acids are involved in the causation of large bowel cancer, they

  9. Enterobacteria modulate intestinal bile acid transport and homeostasis through apical sodium-dependent bile acid transporter (SLC10A2) expression.

    PubMed

    Miyata, Masaaki; Yamakawa, Hiroki; Hamatsu, Mayumi; Kuribayashi, Hideaki; Takamatsu, Yuki; Yamazoe, Yasushi

    2011-01-01

    In our study, ampicillin (AMP)-mediated decrease of enterobacteria caused increases in hepatic bile acid concentration through (at least in part) elevation of bile acid synthesis in C57BL/6N mice. We investigated the involvement of enterobacteria on intestinal bile acid absorption in AMP-treated mice in the present study. Fecal enterobacterial levels and fecal bile acid excretion rates were markedly decreased in mice treated with AMP (100 mg/kg) for 3 days, whereas bile acid concentrations in portal blood were significantly increased compared with those in mice treated with a vehicle. Ileal apical sodium-dependent bile acid transporter (SLC10A2) mRNA levels and ileal SLC10A2 protein levels in brush-border membranes were significantly increased compared with those in mice treated with the vehicle. In AMP-treated mice, total bile acid levels were increased, whereas levels of enterobacteria-biotransformed bile acid, taurodeoxycholic acid, and cholic acid were decreased in intestinal lumen. These phenomena were also observed in farnesoid X receptor-null mice treated with AMP for 3 days. Discontinuation of AMP administration after 3 days (vehicle administration for 4 days) increased levels of fecal enterobacteria, fecal bile acid excretion, and taurodeoxycholic acid and cholic acid in the intestinal lumen, whereas the discontinuation decreased ileal SLC10A2 expression and bile acid concentrations in the portal blood. Coadministration of taurodeoxycholic acid or cholic acid decreased ileal SLC10A2 expression in mice treated with AMP. These results suggest that enterobacteria-mediated bile acid biotransformation modulates intestinal bile acid transport and homeostasis through down-regulation of ileal SLC10A2 expression. PMID:20884752

  10. Effect of bile salts on the DNA and membrane integrity of enteric bacteria.

    PubMed

    Merritt, Megan E; Donaldson, Janet R

    2009-12-01

    Enteric bacteria are able to resist the high concentrations of bile encountered throughout the gastrointestinal tract. Here we review the current mechanisms identified in the enteric bacteria Salmonella, Escherichia coli, Bacillus cereus and Listeria monocytogenes to resist the dangerous effects of bile. We describe the role of membrane transport systems, and their connection with DNA repair pathways, in conferring bile resistance to these enterics. We discuss the findings from recent investigations that indicate bile tolerance is dependent upon being able to resist the detergent properties of bile at both the membrane and DNA level. PMID:19762477

  11. Expression of bile acid receptor TGR5 in gastric adenocarcinoma.

    PubMed

    Cao, Weibiao; Tian, Wei; Hong, Jie; Li, Dan; Tavares, Rosemarie; Noble, Lelia; Moss, Steven F; Resnick, Murray B

    2013-02-15

    Bile reflux is a risk factor in the development of intestinal metaplasia in the stomach and is believed to function as an initiator of gastric carcinogenesis. However, whether the G protein-coupled bile acid receptor TGR5 is expressed in this tumor is not known. In this study, we determined the expression of TGR5 in gastric adenocarcinoma and examined the role of TGR5 in cell proliferation. Strong TGR5 staining was present in 12% of cases of intestinal metaplasia but in no cases of normal gastric epithelium (P < 0.01). Moderate to strong TGR5 membranous and cytoplasmic staining was present in 52% of the intestinal but in only 25% of the diffuse subtype of adenocarcinomas (P < 0.001). Kaplan-Meier univariate survival analysis revealed that moderate to strong TGR5 staining was associated with decreased patient survival (P < 0.05). Treatment with taurodeoxycholic acid (TDCA, a bile acid) significantly increased thymidine incorporation in the AGS gastric adenocarcinoma cell line, suggesting that bile acids may increase cell proliferation. This increase was significantly decreased by knockdown of TGR5 with TGR5 small-interfering RNA (siRNA). In addition, overexpression of TGR5 significantly enhanced TDCA-induced increases in thymidine incorporation. TGR5 is coupled with G(q)α and Gα(i-3) proteins. TDCA-induced increase in thymidine incorporation was significantly decreased by knockdown of G(q)α and Gα(i-3) with their siRNAs. We conclude that TGR5 is overexpressed in most gastric intestinal-type adenocarcinomas, and moderate to strong TGR5 staining is associated with decreased patient survival in all gastric adenocarcinomas. Bile acids increase cell proliferation via activation of TGR5 receptors and G(q)α and Gα(i-3) proteins. PMID:23238937

  12. Increased acyclovir oral bioavailability via a bile acid conjugate.

    PubMed

    Tolle-Sander, Sanna; Lentz, Kimberley A; Maeda, Dean Y; Coop, Andrew; Polli, James E

    2004-01-12

    The objective of this work was to design an acyclovir prodrug that would utilize the human apical sodium-dependent bile acid transporter (hASBT) and enhance acyclovir oral bioavailability. Using each chenodeoxycholate, deoxycholate, cholate, and ursodeoxycholate, four bile acid prodrugs of acyclovir were synthesized, where acyclovir was conjugated to a bile acid via a valine linker. The affinity of the prodrug for hASBT was determined through inhibition of taurocholate uptake by COS-7 cells transfected with hASBT (hASBT-COS). The prodrug with the highest inhibitory affinity was further evaluated in vitro and in vivo. The prodrug acyclovir valylchenodeoxycholate yielded the highest affinity for hASBT (Ki = 35 microM), showing that chenodeoxycholate is the free bile acid with the greatest affinity for hASBT. Acyclovir valylchenodeoxycholate's affinity was similar to that of cholic acid (Ki = 25 microM). Further characterization showed that acyclovir was catalytically liberated from acyclovir valylchenode-oxycholate by esterase. Relative to cellular uptake studies of acyclovir alone, the cellular uptake from the prodrug resulted in a 16-fold greater acyclovir accumulation within hASBT-COS cells, indicating enhanced permeation properties of the prodrug. Enhanced permeability was due to hASBT-mediated uptake and increased passive permeability. The extent of acyclovir uptake in the presence of sodium was 1.4-fold greater than the extent of passive prodrug uptake in the absence of sodium (p = 0.02), indicating translocation of the prodrug by hASBT. The prodrug also exhibited an almost 12-fold enhanced passive permeability, relative to acyclovir's passive permeability. Oral administration of acyclovir valylchenodeoxycholate to rats resulted in a 2-fold increase in the bioavailability of acyclovir, compared to the bioavailability after administration of acyclovir alone. Results indicate that a bile acid prodrug strategy may be useful in improving the oral bioavailability of

  13. Aspirin Prevention of Cholesterol Gallstone Formation in Prairie Dogs

    NASA Astrophysics Data System (ADS)

    Lee, Sum P.; Carey, Martin C.; Lamont, J. Thomas

    1981-03-01

    When prairie dogs (Cynomys ludovicianus) are fed a diet containing cholesterol, a marked increase in gallbladder mucin secretion parallels the evolution of cholesterol supersaturated bile. Gelation of mucin precedes the precipitation of cholesterol liquid and solid crystals and the development of gallstones. Aspirin given to prairie dogs inhibited mucin hypersecretion and gel accumulation and prevented gallstone formation without influencing the cholesterol content of supersaturated bile. This suggests that gallbladder mucin is a nucleation matrix for cholesterol gallstones.

  14. Identification of the major endogenous leukotriene metabolite in the bile of rats as N-acetyl leukotriene E4

    SciTech Connect

    Hagmann, W.; Denzlinger, C.; Rapp, S.; Weckbecker, G.; Keppler, D.

    1986-02-01

    Mercapturic acid formation, an established pathway in the detoxication of xenobiotics, is demonstrated for cysteinyl leukotrienes generated in rats in vivo after endotoxin treatment. The mercapturate N-acetyl-leukotriene E4 (N-acetyl-LTE4) represented a major metabolite eliminated into bile after injection of (/sup 3/H)LTC4 as shown by cochromatography with synthetic N-acetyl-LTE4 in four different HPLC solvent systems. The identity of endogenous N-acetyl-LTE4 elicited by endotoxin in vivo was additionally verified by enzymatic deacetylation followed by chemical N-acetylation. The deacetylation was catalyzed by penicillin amidase. Endogenous cysteinyl leukotrienes were quantified by radioimmunoassay after HPLC separation. A N-acetyl-LTE4 concentration of 80 nmol/l was determined in bile collected between 30 and 60 min after endotoxin injection. Under this condition, other cysteinyl leukotrienes detected in bile by radioimmunoassay amounted to less than 5% of N-acetyl-LTE4. The mercapturic acid pathway, leading from the glutathione conjugate LTC4 to N-acetyl-LTE4, thus plays an important role in the deactivation and elimination of these potent endogenous mediators.

  15. Impact of Dry Solids and Bile Acid Concentrations on Bile Acid Binding Capacity of Extruded Oat Cereals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Extruded breakfast cereals (EBC), processed from two oat lines, N979-5-2-4 (N979) and ‘Jim’, with beta-glucan concentrations of 8.7 and 4.9%, respectively, were used to determine the impact of dry solids (DS) and bile acid (BA) concentrations on in vitro BA binding efficiency. A full fractional fact...

  16. Bile acid derivatives as ligands of the farnesoid x receptor: molecular determinants for bile acid binding and receptor modulation.

    PubMed

    Gioiello, Antimo; Cerra, Bruno; Mostarda, Serena; Guercini, Chiara; Pellicciari, Roberto; Macchiarulo, Antonio

    2014-01-01

    Bile acids are a peculiar class of steroidal compounds that never cease to amaze. From being simple detergents with a primary role in aiding the absorption of fats and fat-soluble vitamins, bile acids are now widely considered as crucial hormones endowed with genomic and non-genomic functions that are mediated by their interaction with several proteins including the nuclear receptor Farnesoid X Receptor (FXR). Taking advantages of the peculiar properties of bile acids in interacting with the FXR receptor, several biliary derivatives have been synthesized and tested as FXR ligands. The availability of these compounds has contributed to characterize the receptor from a structural, patho-physiological and therapeutic standpoint. Among these, obeticholic acid is a first-in-class FXR agonist that is demonstrating hepatoprotective effects upon FXR activation in patients with liver diseases such as primary biliary cirrhosis and nonalcoholic steatohepatitis. This review provides an historical overview of the rationale behind the discovery of obeticholic acid and chemical tools generated to depict the molecular features and bio-pharmacological relevance of the FXR receptor, as well as to summarize structure-activity relationships of bile acid-based FXR ligands so far reported. PMID:25388535

  17. Simultaneous Extensive Intraductal Papillary Neoplasm of the Bile Duct and Pancreas: A Very Rare Entity

    PubMed Central

    Luvira, Vor; Pugkhem, Ake; Tipwaratorn, Theerawee; Chamgramol, Yaovalux; Pairojkul, Chawalit; Bhudhisawasdi, Vajarabhongsa

    2016-01-01

    Intraductal papillary neoplasm of the bile duct (IPNB) is a specific type of bile duct tumor. It has been proposed that it could be the biliary counterpart of the intraductal papillary neoplasm of the pancreas (IPMN-P). This hypothesis is supported by the presence of simultaneous intraductal tumors of both the bile duct and pancreas. There have been five reports of patients with simultaneous IPNB and IPMN-P. In all of these cases, biliary involvement was limited to the intrahepatic and perihilar bile duct, which had characteristics similar to IPMN-P and usually had slow progression in nature. Herein, we present the first case of extensive intraductal neoplasm involving the extrahepatic bile duct, intrahepatic bile duct, and entire length of the pancreas with a poor outcome, even after being treated aggressively with radical surgery and adjuvant chemotherapy. Additionally, we summarize previous case reports of simultaneous intraductal lesions of the bile duct and pancreas. PMID:26925284

  18. Differential effects of cyclosporin A on transport of bile acids by rat hepatocytes: relationship to individual serum bile acid levels.

    PubMed

    Azer, S A; Stacey, N H

    1994-02-01

    Cyclosporin A treatment has been reported to induce hepatotoxicity marked by a rise in total serum bile acid and total bilirubin. The mechanism of cyclosporin A-induced hepatotoxicity seems to be related to interference with hepatocellular transport of these substrates although this remains to be fully substantiated. The purpose of this study was to investigate whether the hepatocellular uptake of the different bile acids, in the presence of cyclosporin A, is consistent with the changes in their respective individual serum bile acid concentrations. High-performance liquid chromatography has been used to assay individual serum bile acids in cyclosporin A-treated rats at doses of 0.1, 1, and 10 mg/kg/day for 4 days. Control rats were treated with Cremophor (1 ml/kg/day). At the higher doses, cyclosporin A produced a significant increase in levels of cholic acid, taurocholic acid, chenodeoxycholic acid, and deoxycholic acid compared with controls. Serum glycocholate was unaffected even at the highest dose. Inhibition of initial rate of uptake and accumulation of [14C]cholic acid, [14C]chenodeoxycholic acid, and [14C]deoxycholic acid by isolated rat hepatocytes was consistent with the changes in their respective serum bile acids. Coincubation of rat hepatocytes with unlabeled cholic acid (100 microM), the major serum bile acid in cyclosporin A-treated rats, showed a further inhibitory effect on [14C]cholic acid and [14C]deoxycholic acid accumulation. The initial rate of uptake of [14C]glycocholate was also inhibited. However, accumulation of glycocholic acid did not show significant changes at the longer incubation times (2-30 min). In addition, coincubation of rat hepatocytes with unlabeled cholic acid (100 microM) plus cyclosporin A did not induce any inhibition of glycocholate accumulation. Together, these differences provide an explanation for the unchanged serum levels of glycocholate. In conclusion, the changes in individual serum bile acids in cyclosporin A

  19. Effect of Bile Salt Hydrolase Inhibitors on a Bile Salt Hydrolase from Lactobacillus acidophilus.

    PubMed

    Lin, Jun; Negga, Rekek; Zeng, Ximin; Smith, Katie

    2014-01-01

    Bile salt hydrolase (BSH), a widely distributed function of the gut microbiota, has a profound impact on host lipid metabolism and energy harvest. Recent studies suggest that BSH inhibitors are promising alternatives to antibiotic growth promoters (AGP) for enhanced animal growth performance and food safety. Using a high-purity BSH from Lactobacillus salivarius strain, we have identified a panel of BSH inhibitors. However, it is still unknown if these inhibitors also effectively inhibit the function of the BSH enzymes from other bacterial species with different sequence and substrate spectrum. In this study, we performed bioinformatics analysis and determined the inhibitory effect of identified BSH inhibitors on a BSH from L. acidophilus. Although the L. acidophilus BSH is phylogenetically distant from the L. salivarius BSH, sequence analysis and structure modeling indicated the two BSH enzymes contain conserved, catalytically important amino residues and domain. His-tagged recombinant BSH from L. acidophilus was further purified and used to determine inhibitory effect of specific compounds. Previously identified BSH inhibitors also exhibited potent inhibitory effects on the L. acidophilus BSH. In conclusion, this study demonstrated that the BSH from L. salivarius is an ideal candidate for screening BSH inhibitors, the promising alternatives to AGP for enhanced feed efficiency, growth performance and profitability of food animals. PMID:25526498

  20. CPI-613 in Treating Patients With Advanced or Metastatic Bile Duct Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2015-12-28

    Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Unresectable Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Unresectable Extrahepatic Bile Duct Cancer

  1. PhoP-PhoQ-Regulated Loci Are Required for Enhanced Bile Resistance in Salmonella spp.

    PubMed Central

    van Velkinburgh, Jennifer C.; Gunn, John S.

    1999-01-01

    As enteric pathogens, Salmonella spp. are resistant to the actions of bile. Salmonella typhimurium and Salmonella typhi strains were examined to better define the bile resistance phenotype. The MICs of bile for wild-type S. typhimurium and S. typhi were 18 and 12%, respectively, and pretreatment of log-phase S. typhimurium with 15% bile dramatically increased bile resistance. Mutant strains of S. typhimurium and S. typhi lacking the virulence regulator PhoP-PhoQ were killed at significantly lower bile concentrations than wild-type strains, while strains with constitutively active PhoP were able to survive prolonged incubation with bile at concentrations of >60%. PhoP-PhoQ was shown to mediate resistance specifically to the bile components deoxycholate and conjugated forms of chenodeoxycholate, and the protective effect was not generalized to other membrane-active agents. Growth of both S. typhimurium and S. typhi in bile and in deoxycholate resulted in the induction or repression of a number of proteins, many of which appeared identical to PhoP-PhoQ-activated or -repressed products. The PhoP-PhoQ regulon was not induced by bile, nor did any of the 21 PhoP-activated or -repressed genes tested play a role in bile resistance. However, of the PhoP-activated or -repressed genes tested, two (prgC and prgH) were transcriptionally repressed by bile in the medium independent of PhoP-PhoQ. These data suggest that salmonellae can sense and respond to bile to increase resistance and that this response likely includes proteins that are members of the PhoP regulon. These bile- and PhoP-PhoQ-regulated products may play an important role in the survival of Salmonella spp. in the intestine or gallbladder. PMID:10084994

  2. A study of the physicochemical interactions between biliary lipids and chlorpromazine hydrochloride. Bile-salt precipitation as a mechanism of phenothiazine-induced bile secretory failure.

    PubMed Central

    Carey, M C; Hirom, P C; Small, D M

    1976-01-01

    Since chlorpromazine hydrochloride [2-chloro-10-(3-dimethylaminopropyl)-phenothiazine hydrochloride] is commonly implicated in causing bile-secretory failure in man and is secreted into bile, we have studied the physicochemical interactions of the drug with the major components of bile in vitro. Chlorpromazine hydrochloride molecules are amphiphilic by virtue of possessing a polar tertiary amine group linked by a short paraffin chain to a tricyclic hydrophobic part. At pH values below the apparent pK (pK'a 7.4) the molecules are water-soluble cationic detergents. We show that bile salts in concentrations above their critical micellar concentrations are precipitated from solution by chlorpromazine hydrochloride as insoluble 1:1 salt complexes. In the case of mixed bile-salt/phosphatidylcholine micellar solutions, however, the degree of precipitation is inhibited by the phospholipid in proportion to its mole fraction. With increases in the concentration of chlorpromazine hydrochloride or bile salt, micellar solubilization of the precipitated complexes results. Sonicated dispersions of the negatively charged phospholipid phosphatidylserine were also precipitated, but dispersions of the zwitterionic phospholipid phosphatidylcholine were not. Chlorpromazine hydrochloride efficiently solubilized these membrane phospholipids as mixed micellar solutions when the drug:phospholipid molar ratio reached 4:1. Polarizing-microscopy and X-ray-diffraction studies revealed that the precipitated complexes were amorphous and potentiometric studies confirmed the presence of a salt bond. Some dissociation of the complex occurred in the case of the most polar bile salt (Ks 0.365). As canalicular bile-salt secretion determines much of bile-water flow, we propose that complexing and precipitation of bile salts by chlorpromazine hydrochloride and its metabolites may be physicochemically related to the reversible bile-secretory failure produced by this drug. Images PLATE 1 PLATE 2 PMID

  3. Development of hepatolithiasis due to a celery stalk retained within the bile ducts of the liver.

    PubMed

    Lv, G Y; Qiu, W; Yu, Y; Li, T

    2016-05-01

    Introduction Commonly encountered foreign bodies are remnants from surgical procedures and ingested materials. Rarely, the latter cause stone formation in the biliary tract. Case History We describe a 51-year-old female who underwent choledoduodenostomy and who presented with abdominal distension caused by multiple stones in the bile ducts within the liver (hepatolithiasis) and an intact celery stalk. Hepatolithiasis was demonstrated by ultrasonography and computed tomography of the abdomen. The celery stalk was not confirmed until exploration of the biliary duct. Conclusions Here, we describe, for the first time, an intact, undigested celery stalk in the biliary tract which induced hepatolithiasis. We believe that choledochojejunostomy favoured reflux of the celery stalk from the duodenum into the biliary tract. PMID:27087342

  4. Prolapse into the bile duct and expansive growth is characteristic behavior of mucinous cystic neoplasm of the liver: report of two cases and review of the literature.

    PubMed

    Takano, Yuichi; Nagahama, Masatsugu; Yamamura, Eiichi; Maruoka, Naotaka; Mizukami, Hiroki; Tanaka, Jun-ichi; Ohike, Nobuyuki; Takahashi, Hiroshi

    2015-06-01

    Mucinous cystic neoplasm of the liver (MCN-L) is a very rare tumor whose detailed behavior is still unknown. We describe two cases of MCN-L that exhibited extremely interesting growth patterns, and discuss the characteristics of MCN-Ls. Both cases exhibited MCN-L that originated from the left hepatic lobe (Segment 4) and then prolapsed into the left hepatic duct and common bile duct, resulting in obstructive jaundice due to expansive growth. Endoscopic retrograde cholangiopancreatographies showed the characteristic oval-shaped filling defects in the bile ducts. Endoscopic ultrasound and intraductal ultrasound were useful for differentiating the tumors from stones, since multiple septal formations were observed inside the tumors. A literature search revealed that, over the past 10 years, 15 cases of MCN-L (biliary cystadenomas with ovarian-like stroma) that showed expansive growth in the bile duct had been reported. Prolapse into the bile duct and expansive growth appear to be characteristic behavior of MCN-L. In the future, additional data on more cases needs to be collected to further elucidate MCN-L pathophysiology. PMID:25951998

  5. Analysis of duodenal bile acids by high performance liquid chromatography in infants with cholestasis.

    PubMed

    Hsu, H Y; Tang, S Y; Chang, M H

    1991-05-01

    Non-sulfated bile acid levels including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), five taurine conjugates, and five glycine conjugates in duodenal juice were measured in 50 Chinese infants with cholestasis to test their diagnostic value. All 17 with biliary atresia (BA) cases, 11 out of 26 neonatal hepatitis (NH) cases and one case with paucity of the interlobular bile duct were without detectable bile acids. In those NH patients with detectable bile acids, the major components were conjugated forms of CA and CDCA, which was similar to all 6 cases of the comparison group with other diseases. The minor bile acid components identified in them were glycine conjugated UDCA, free CDCA, free CA, and free and conjugated DCA. Only one patient with NH had taurine conjugated LCA. The mean total duodenal bile acid level in 15 patients with NH was significantly lower than that in the 6 patients of the comparison group. Most patients with NH had a CDCA/CA ratio of less than one, indicating that cholic acid is the predominant form in their bile. Glycine conjugated bile acids were the predominant bile acids present in 11 out of 15 patients with NH and 4 out of 6 of the comparison group patients. The results suggest that the detection of duodenal bile acids by a sensitive HPLC method is of limited value in making a differential diagnosis between BA and NH.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1680988

  6. Identification and differentiation of bear bile used in medicinal products in Taiwan.

    PubMed

    Lin, D L; Chang, H C; Chang, C P; Chen, C Y

    1997-09-01

    One hundred eighty-three suspect bear bile used in medicinal products, collected in Taiwan as gall bladders or dried powder forms, were analyzed using FTIR, HPTLC, and HPLC techniques to identify whether they are indeed bear bile. Those confirmed were further examined to determine whether the observed analytical parameters can be reliably used for source inference, i.e., differentiating products among North American black bear, farmed Asiatic black bear, polar bear, etc. Our data suggested that North American and polar bears contain a higher concentration of TC (relative to TUDC and TCDC), whereas the relative concentration of TC in Asiatic bears (wild or farmed) is much lower. Thus, the relative concentration of TC can potentially be used for differentiating Asiatic bear bile from North American and polar bear products, but it cannot be used for the differentiation of wild and farmed bear bile as suggested in an earlier report by Espinoza et al. The origin of the 183 samples analyzed were found to be as follows: 118 (64%), bile salts, or gall bladders were of domestic pig; 56 (31%), bile products of Asiatic bear; 4 (2.2%), Asiatic bear mixed with pig bile salts; 3 (1.6%) goat gall bladders; 1 (0.55%) water buffalo bile salts; and 1 (0.55%), pig bile salts mixed with water buffalo bile salts. PMID:9304828

  7. In Sickness and in Health: The Relationships Between Bacteria and Bile in the Human Gut.

    PubMed

    Hay, A J; Zhu, J

    2016-01-01

    Colonization of a human host with a commensal microbiota has a complex interaction in which bacterial communities provide numerous health benefits to the host. An equilibrium between host and microbiota is kept in check with the help of biliary secretions by the host. Bile, composed primarily of bile salts, promotes digestion. It also provides a barrier between host and bacteria. After bile salts are synthesized in the liver, they are stored in the gallbladder to be released after food intake. The set of host-secreted bile salts is modified by the resident bacteria. Because bile salts are toxic to bacteria, an equilibrium of modified bile salts is reached that allows commensal bacteria to survive, yet rebuffs invading pathogens. In addition to direct toxic effects on cells, bile salts maintain homeostasis as signaling molecules, tuning the immune system. To cause disease, gram-negative pathogenic bacteria have shared strategies to survive this harsh environment. Through exclusion of bile, efflux of bile, and repair of bile-induced damage, these pathogens can successfully disrupt and outcompete the microbiota to activate virulence factors. PMID:27565580

  8. Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids.

    PubMed

    Ferrebee, Courtney B; Dawson, Paul A

    2015-03-01

    The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size, and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor (FXR) and the G-protein-coupled bile acid receptor (TGR5). PMID:26579438

  9. Non-Newtonian flow of pathological bile in the biliary system: experimental investigation and CFD simulations

    NASA Astrophysics Data System (ADS)

    Kuchumov, Alex G.; Gilev, Valeriy; Popov, Vitaliy; Samartsev, Vladimir; Gavrilov, Vasiliy

    2014-02-01

    The paper presents an experimental study of pathological human bile taken from the gallbladder and bile ducts. The flow dependences were obtained for different types of bile from patients with the same pathology, but of different age and sex. The parameters of the Casson's and Carreau's equations were found for bile samples. Results on the hysteretic bile behavior at loading-unloading tests are also presented, which proved that the pathologic bile is a non-Newtonian thixotropic liquid. The viscosity of the gallbladder bile was shown to be higher compared to the duct bile. It was found that at higher shear stress the pathological bile behaves like Newtonian fluid, which is explained by reorientation of structural components. Moreover, some pathological bile flow in the biliary system CFD simulations were performed. The velocity and pressure distributions as well as flow rates in the biliary segments during the gallbladder refilling and emptying phases are obtained. The results of CFD simulations can be used for surgeons to assess the patient's condition and choose an adequate treatment.

  10. Eosinophilic cholecystitis with common bile duct stricture: a rare disease.

    PubMed

    Mehanna, Daniel; Naseem, Zainab; Mustaev, Muslim

    2016-01-01

    Although the most common cause of cholecystitis is gallstones, other conditions may present as acute cholecystitis. We describe a case of eosinophilic cholecystitis with common bile duct stricture. A 36-year-old woman initially had generalised abdominal pain and peripheral eosinophilia. Diagnostic laparoscopy showed eosinophilic ascites and necrotic nodules on the posterior abdominal wall. She was treated with anthelminthics on presumption of toxacara infection based on borderline positivity of serological tests. She later presented with acute cholecystitis and had a cholecystectomy and choledocotomy. Day 9 T-tube cholangiogram showed irregular narrowing of the distal common bile duct. The patient's symptoms were improved with steroids and the T-tube was subsequently removed. PMID:27222280

  11. Synthesis and antifungal activity of bile acid-derived oxazoles.

    PubMed

    Fernández, Lucía R; Svetaz, Laura; Butassi, Estefanía; Zacchino, Susana A; Palermo, Jorge A; Sánchez, Marianela

    2016-04-01

    Peracetylated bile acids (1a-g) were used as starting materials for the preparation of fourteen new derivatives bearing an oxazole moiety in their side chain (6a-g, 8a-g). The key step for the synthetic path was a Dakin-West reaction followed by a Robinson-Gabriel cyclodehydration. A simpler model oxazole (12) was also synthesized. The antifungal activity of the new compounds (6a-g) as well as their starting bile acids (1a-g) was tested against Candida albicans. Compounds 6e and 6g showed the highest percentages of inhibition (63.84% and 61.40% at 250 μg/mL respectively). Deacetylation of compounds 6a-g, led to compounds 8a-g which showed lower activities than the acetylated derivatives. PMID:26827629

  12. Bile Acid-Induced Necrosis in Primary Human Hepatocytes and in Patients with Obstructive Cholestasis

    PubMed Central

    Woolbright, Benjamin L.; Dorko, Kenneth; Antoine, Daniel J.; Clarke, Joanna I.; Gholami, Parviz; Li, Feng; Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson; Fan, Fang; Jenkins, Rosalind E.; Park, B. Kevin; Hagenbuch, Bruno; Olyaee, Mojtaba; Jaeschke, Hartmut

    2015-01-01

    Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. PMID:25636263

  13. Biliary proteins. Unique inhibitors of cholesterol crystal nucleation in human gallbladder bile.

    PubMed Central

    Holzbach, R T; Kibe, A; Thiel, E; Howell, J H; Marsh, M; Hermann, R E

    1984-01-01

    The onset time for cholesterol crystal nucleation of supersaturated normal human gallbladder biles is consistently prolonged when compared with biles from patients with cholesterol gallstone disease. Investigation of the factor(s) responsible for the suspended supersaturation (metastability) of normal human biles revealed that model bile solutions of cholesterol saturation index (CSI) and molar lipid composition identical to individual gallbladder bile specimens had much shorter crystal nucleation times, i.e., exhibited decreased metastability. Unsaturated normal biles, after supplementation with lecithin, cholesterol, and sodium taurocholate to a 'standard' supersaturated lipid composition, also demonstrated nucleation times three- to 15-fold longer than the comparable standard model bile. Total lipid extracts of normal biles, however, when similarly supplemented, did not differ in nucleation time from the control model solution. Gallbladder biles were fractionated by gel chromatography and the eluted fractions were pooled into two fractions. The fractions eluting in about the first 25% of the included volume when mixed with the supersaturated standard model bile induced a modest increase in nucleation time of approximately 1.5 times the control value. The fractions eluting in the second 25% of the included volume and which contained all of the bile lipids, were concentrated and supplemented with lipids to the standard composition. The nucleation times of these supplements were 3-10 times longer than the control nucleation times. Delipidated bile protein mixtures, purified by discontinuous sucrose gradient centrifugation, were recombined with purified lipids at the standard composition used previously. The nucleation times of these mixtures were significantly prolonged to the same extent as those associated with the second chromatographic fraction. These observations demonstrate that the delayed onset (inhibition) of cholesterol crystal nucleation observed in

  14. Surgical treatment for hepatocellular carcinoma with bile duct invasion

    PubMed Central

    Hu, Xu-guang; Mao, Wei; Hong, Sung Yeon; Kim, Bong-Wan; Xu, Wei-guang

    2016-01-01

    Purpose There is still some debate on surgical procedures for hepatocellular carcinoma (HCC) patients with bile duct tumor thrombi (BDTT, Ueda type 3 or 4). What is adequate extent of liver resection for curative treatment? Is extrahepatic bile duct resection mandatory for cure? The aim of this study is to answer these questions. Methods Between February 1994 and December 2012, 877 consecutive HCC patients underwent hepatic resection at Ajou University Hospital. Thirty HCC patients (3.4%) with BDTT (Ueda type 3 or 4) were retrospective reviewed in this study. Results In total, 20 patients enrolled in this study were divided into 2 groups: patients who underwent hemihepatectomy with extrahepatic bile duct resection (group 1, n = 10) and with only removal of BDTT (group 2, n = 10). The 1-, 3- and 5-year overall survival rates were 75.0%, 50.0%, and 27.8%, respectively. The 1-, 3-, and 5-year survival rates of group 1 were 100.0%, 80.0%, and 45.7%, and those of group 2 were 50.0%, 20.0%, and 10.0%, respectively (P = 0.014). The 1-, 3-, and 5-year recurrences free survival rates of group 1 were 90.0%, 70.0%, and 42.0%, and those of group 2 were 36.0%, 36.0%, and 0%, respectively (P = 0.014). Thrombectomy and infiltrative growth type (Ig) were found as independent prognostic factors for recurrence free survival by multivariate analysis. Thrombectomy, Ig, and high indocyanine green retention rate at 15 minutes were found as independent prognostic factors for overall survival by multivariate analysis. Conclusion We suggest that the appropriate surgical procedure for icteric HCC patients should be comprised of ipsilateral hemihepatectomy with caudate lobectomy and extrahepatic bile duct resection. PMID:26942157

  15. Enzymatic synthesis of phosphatidylserine using bile salt mixed micelles.

    PubMed

    Pinsolle, Alexandre; Roy, Philippe; Buré, Corinne; Thienpont, Anne; Cansell, Maud

    2013-06-01

    Phosphatidylserine (PS) rich in polyunsaturated fatty acids of the n-3 series was obtained by enzymatic synthesis with phospholipase D (PLD) and a marine lipid extract as substrate. Synthesis was performed using mixed micelles composed of either sodium deoxycholate (SDC) or sodium cholate (SC). To limit the use of surfactant and to monitor the performance of PLD, the mixed micelles were characterized both in terms of bile salt/lipid molar ratio in the aggregates and of mean diameter. A fractional factorial experiment was selected to study the effect of pH, temperature, enzyme, L-serine concentrations, bile salt/lipid molar ratio and Ca(2+) content (in the case of SC only) on PS synthesis. The amount of L-serine was the main factor governing the equilibrium between transphosphatidylation and hydrolysis reaction. Increasing the bile salt/lipid molar ratio decreased PS synthesis yield. In contrast, pH (6.5-8) and temperature (35-45°C) did not affect PLD activity in the tested conditions. This statistical approach allowed determining a combination of parameters (pH, temperature, bile salt/lipid molar ratio, enzyme and alcohol acceptor concentrations) for PS synthesis. After 24 h, the transphosphatidylation reaction led to 57±2% and 56±3% of PS in the phospholipid mixtures with SDC and SC, respectively. In both cases, about 10% of phosphatidic acid was present as a side-product. On the whole, this work provided fundamental basis for a possible development of enzymatic PLD technology using food-grade emulsifiers to produce PS complying with industrial constraints for nutritional applications. PMID:23434712

  16. Regulation of hepatic bile acid transporters Ntcp and Bsep expression.

    PubMed

    Cheng, Xingguo; Buckley, David; Klaassen, Curtis D

    2007-12-01

    Sodium-taurocholate cotransporting polypeptide (Ntcp) and bile salt export pump (Bsep) are two key transporters for hepatic bile acid uptake and excretion. Alterations in Ntcp and Bsep expression have been reported in pathophysiological conditions. In the present study, the effects of age, gender, and various chemicals on the regulation of these two transporters were characterized in mice. Ntcp and Bsep mRNA levels in mouse liver were low in the fetus, but increased to its highest expression at parturition. After birth, mouse Ntcp and Bsep mRNA decreased by more than 50%, and then gradually increased to adult levels by day 30. Expression of mouse Ntcp mRNA and protein exhibit higher levels in female than male livers. No gender difference exists in BSEP/Bsep expression in human and mouse livers. Hormone replacements conducted in gonadectomized, hypophysectomized, and lit/lit mice indicate that female-predominant Ntcp expression in mouse liver is due to the inhibitory effect of male-pattern GH secretion, but not sex hormones. Ntcp and Bsep expression are in general resistant to induction by a large battery of microsomal enzyme inducers. Administration of cholestyramine increased Ntcp, whereas chenodeoxycholic acid (CDCA) increased Bsep mRNA expression. In conclusion, mouse Ntcp and Bsep are regulated by age, gender, cholestyramine, and bile acid, but resistant to induction by most microsomal enzyme inducers. PMID:17897632

  17. Regulation of human class I alcohol dehydrogenases by bile acids

    PubMed Central

    Langhi, Cédric; Pedraz-Cuesta, Elena; Haro, Diego; Marrero, Pedro F.; Rodríguez, Joan C.

    2013-01-01

    Class I alcohol dehydrogenases (ADH1s) are the rate-limiting enzymes for ethanol and vitamin A (retinol) metabolism in the liver. Because previous studies have shown that human ADH1 enzymes may participate in bile acid metabolism, we investigated whether the bile acid-activated nuclear receptor farnesoid X receptor (FXR) regulates ADH1 genes. In human hepatocytes, both the endogenous FXR ligand chenodeoxycholic acid and synthetic FXR-specific agonist GW4064 increased ADH1 mRNA, protein, and activity. Moreover, overexpression of a constitutively active form of FXR induced ADH1A and ADH1B expression, whereas silencing of FXR abolished the effects of FXR agonists on ADH1 expression and activity. Transient transfection studies and electrophoretic mobility shift assays revealed functional FXR response elements in the ADH1A and ADH1B proximal promoters, thus indicating that both genes are direct targets of FXR. These findings provide the first evidence for direct connection of bile acid signaling and alcohol metabolism. PMID:23772048

  18. Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures.

    PubMed

    Liu, Jie; Lu, Hong; Lu, Yuan-Fu; Lei, Xiaohong; Cui, Julia Yue; Ellis, Ewa; Strom, Stephen C; Klaassen, Curtis D

    2014-10-01

    Bile acids (BAs) are known to regulate their own homeostasis, but the potency of individual bile acids is not known. This study examined the effects of cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) on expression of BA synthesis and transport genes in human primary hepatocyte cultures. Hepatocytes were treated with the individual BAs at 10, 30, and 100μM for 48 h, and RNA was extracted for real-time PCR analysis. For the classic pathway of BA synthesis, BAs except for UDCA markedly suppressed CYP7A1 (70-95%), the rate-limiting enzyme of bile acid synthesis, but only moderately (35%) down-regulated CYP8B1 at a high concentration of 100μM. BAs had minimal effects on mRNA of two enzymes of the alternative pathway of BA synthesis, namely CYP27A1 and CYP7B1. BAs increased the two major target genes of the farnesoid X receptor (FXR), namely the small heterodimer partner (SHP) by fourfold, and markedly induced fibroblast growth factor 19 (FGF19) over 100-fold. The BA uptake transporter Na(+)-taurocholate co-transporting polypeptide was unaffected, whereas the efflux transporter bile salt export pump was increased 15-fold and OSTα/β were increased 10-100-fold by BAs. The expression of the organic anion transporting polypeptide 1B3 (OATP1B3; sixfold), ATP-binding cassette (ABC) transporter G5 (ABCG5; sixfold), multidrug associated protein-2 (MRP2; twofold), and MRP3 (threefold) were also increased, albeit to lesser degrees. In general, CDCA was the most potent and effective BA in regulating these genes important for BA homeostasis, whereas DCA and CA were intermediate, LCA the least, and UDCA ineffective. PMID:25055961

  19. A biosynthetic pathway for a prominent class of microbiota-derived bile acids

    PubMed Central

    Devlin, A. Sloan; Fischbach, Michael A.

    2015-01-01

    The gut bile acid pool is millimolar in concentration, varies widely in composition among individuals, and is linked to metabolic disease and cancer. Although these molecules derive almost exclusively from the microbiota, remarkably little is known about which bacterial species and genes are responsible for their biosynthesis. Here, we report a biosynthetic pathway for the second most abundant class in the gut, iso (3β-hydroxy) bile acids, whose levels exceed 300 µM in some humans and are absent in others. We show, for the first time, that iso bile acids are produced by Ruminococcus gnavus, a far more abundant commensal than previously known producers; and that the iso bile acid pathway detoxifies deoxycholic acid, favoring the growth of the keystone genus Bacteroides. By revealing the biosynthetic genes for an abundant class of bile acids, our work sets the stage for predicting and rationally altering the composition of the bile acid pool. PMID:26192599

  20. Solubilization and Interaction Studies of Bile Salts with Surfactants and Drugs: a Review.

    PubMed

    Malik, Nisar Ahmad

    2016-05-01

    In this review, bile salt, bile salt-surfactant, and bile salt-drug interactions and their solubilization studies are mainly focused. Usefulness of bile salts in digestion, absorption, and excretion of various compounds and their rare properties in ordering the shape and size of the micelles owing to the presence of hydrophobic and hydrophilic faces are taken into consideration while compiling this review. Bile salts as potential bio-surfactants to solubilize drugs of interest are also highlighted. This review will give an insight into the selection of drugs in different applications as their properties get modified by interaction with bile salts, thus influencing their solution behavior which, in turn, modifies the phase-forming behavior, microemulsion, and clouding phenomenon, besides solubilization. Finally, their future perspectives are taken into consideration to assess their possible uses as bio-surfactants without side effects to human beings. PMID:26781714

  1. High-performance liquid chromatographic determination for bile components in fish, chicken and duck.

    PubMed

    Yeh, Y H; Hwang, D F

    2001-02-10

    A HPLC procedure for the determination of 13 bile acids and cyprinol sulfate in animals was developed. The mobile system 0.3% ammonium carbonate solution-acetonitrile (73:27, v/v) 10 min-->(68:32) 10 min-->(50:50) 10 min was available for separating all 14 bile components, except for deoxycholic and glycodeoxycholic acids, which could be further separated with 0.3% ammonium carbonate solution-acetonitrile (73:27). After applying this method, grass carp and common carp bile was found to contain mainly cyprinol sulfate, while the other 12 fish species bile contained mainly taurocholic, taurochenodeoxycholic and cholic acids. Chicken bile was mainly composed of glycolithocholic and taurocholic acids, but duck bile was mainly composed of taurochenodeoxycholic, cholic and ursodeoxycholic acids. PMID:11232840

  2. Effect of ispaghula husk on the faecal output of bile acids in healthy volunteers.

    PubMed

    Chaplin, M F; Chaudhury, S; Dettmar, P W; Sykes, J; Shaw, A D; Davies, G J

    2000-04-01

    Faecal bile acids are associated with both colorectal cancer and serum cholesterol levels. We investigate whether dosing with ispaghula husk affects the faecal bile acid weights and concentrations in healthy adults. Sixteen healthy volunteers consumed 7.0 g/day ispaghula husk, containing 5.88 g/day Englyst-determinable dietary fibre, for the middle 8 weeks of a 12-week period. Stool samples were collected, analysed for faecal bile acids and their form and dry weight determined. Correlations between the faecal bile acids, the stool parameters and the dietary intake were tested. Ispaghula husk treatment significantly lowers faecal lithocholic and isolithocholic acids and the weighted ratio of lithocholic acids to deoxycholic acid. These effects revert towards their initial states at the end of the treatment period. These changes in the faecal bile acid profiles indicate a reduction in the hydrophobicity of the bile acids in the enterohepatic circulation. PMID:10822018

  3. AKR1B7 Is Induced by the Farnesoid X Receptor and Metabolizes Bile Acids*

    PubMed Central

    Schmidt, Daniel R.; Schmidt, Samuel; Holmstrom, Sam R.; Makishima, Makoto; Yu, Ruth T.; Cummins, Carolyn L.; Mangelsdorf, David J.; Kliewer, Steven A.

    2011-01-01

    Although bile acids are crucial for the absorption of lipophilic nutrients in the intestine, they are cytotoxic at high concentrations and can cause liver damage and promote colorectal carcinogenesis. The farnesoid X receptor (FXR), which is activated by bile acids and abundantly expressed in enterohepatic tissues, plays a crucial role in maintaining bile acids at safe concentrations. Here, we show that FXR induces expression of Akr1b7 (aldo-keto reductase 1b7) in murine small intestine, colon, and liver by binding directly to a response element in the Akr1b7 promoter. We further show that AKR1B7 metabolizes 3-keto bile acids to 3β-hydroxy bile acids that are less toxic to cultured cells than their 3α-hydroxy precursors. These findings reveal a feed-forward, protective pathway operative in murine enterohepatic tissues wherein FXR induces AKR1B7 to detoxify bile acids. PMID:21081494

  4. Bile acid nephropathy in a bodybuilder abusing an anabolic androgenic steroid.

    PubMed

    Luciano, Randy L; Castano, Ekaterina; Moeckel, Gilbert; Perazella, Mark A

    2014-09-01

    Bile acid nephropathy, also known as cholemic nephrosis or nephropathy, is an entity that can be seen in patients with severe cholestatic liver disease. It typically is associated with acute kidney injury (AKI) with various forms of hepatic disease. Most often, patients with severe obstructive jaundice develop this lesion, which is thought to occur due to direct bile acid injury to tubular cells, as well as obstructing bile acid casts. Patients with end-stage liver disease also can develop AKI, in which case a more heterogeneous lesion occurs that includes hepatorenal syndrome and acute tubular injury/necrosis. In this circumstance, acute tubular injury develops from a combination of hemodynamic changes with some contribution from direct bile acid-related tubular toxicity and obstructive bile casts. We present a case of AKI due to bile acid nephropathy in a bodybuilder who developed severe cholestatic liver disease in the setting of anabolic androgenic steroid use. PMID:24953892

  5. In vitro model systems to investigate bile salt export pump (BSEP) activity and drug interactions: A review.

    PubMed

    Cheng, Yaofeng; Woolf, Thomas F; Gan, Jinping; He, Kan

    2016-08-01

    The bile salt export pump protein (BSEP), expressed on the canalicular membranes of hepatocytes, is primarily responsible for the biliary excretion of bile salts. The inhibition of BSEP transport activity can lead to an increase in intracellular bile salt levels and liver injury. This review discusses the various in vitro assays currently available for assessing the effect of drugs or other chemical entities to modulate BSEP transport activity. BSEP transporter assays use one of the following platforms: Xenopus laevis oocytes; canalicular membrane vesicles (CMV); BSEP-expressed membrane vesicles; cell lines expressing BSEP; sandwich cultured hepatocytes (SCH); and hepatocytes in suspension. Two of these, BSEP-expressed insect membrane vesicles and sandwich cultured hepatocytes, are the most commonly used assays. BSEP membrane vesicles prepared from transfected insect cells are useful for assessing BSEP inhibition or substrate specificity and exploring mechanisms of BSEP-associated genetic diseases. This model can be applied in a high-throughput format for discovery-drug screening. However, experimental results from use of membrane vesicles may lack physiological relevance and the model does not allow for investigation of in situ metabolism in modulation of BSEP activity. Hepatocyte-based assays that use the SCH format provide results that are generally more physiologically relevant than membrane assays. The SCH model is useful in detailed studies of the biliary excretion of drugs and BSEP inhibition, but due to the complexity of SCH preparation, this model is used primarily for determining biliary clearance and BSEP inhibition in a limited number of compounds. The newly developed hepatocyte in suspension assay avoids many of the complexities of the SCH method. The use of pooled cryopreserved hepatocytes in suspension minimizes genetic variance and individual differences in BSEP activity and also provides the opportunity for higher throughput screening and cross

  6. Ceramide formation mediated by acid sphingomyelinase facilitates endosomal escape of caliciviruses.

    PubMed

    Shivanna, Vinay; Kim, Yunjeong; Chang, Kyeong-Ok

    2015-09-01

    Our recent results demonstrated that bile acids facilitate virus escape from the endosomes into the cytoplasm for successful replication of porcine enteric calicivirus (PEC). We report a novel finding that bile acids can be substituted by cold treatment for endosomal escape and virus replication. This endosomal escape by cold treatment or bile acids is associated with ceramide formation by acid sphingomyelinase (ASM). ASM catalyzes hydrolysis of sphingomyelin into ceramide, which is known to destabilize lipid bilayer. Treatment of LLC-PK cells with bile acids or cold led to ceramide formation, and small molecule antagonists or siRNA of ASM blocked ceramide formation in the endosomes and significantly reduced PEC replication. Inhibition of ASM resulted in the retention of PEC, feline calicivirus or murine norovirus in the endosomes in correlation with reduced viral replication. These results suggest the importance of viral escape from the endosomes for the replication of various caliciviruses. PMID:25985440

  7. Bile acid promotes liver regeneration via farnesoid X receptor signaling pathways in rats.

    PubMed

    Ding, Long; Yang, Yu; Qu, Yikun; Yang, Ting; Wang, Kaifeng; Liu, Weixin; Xia, Weibin

    2015-06-01

    Bile acids, which are synthesized from cholesterol in the hepatocytes of the liver, are amphipathic molecules with a steroid backbone. Studies have shown that bile acid exhibits important effects on liver regeneration. However, the mechanism underlying these effects remains unclear. The aim of the present study was to investigate the effect of bile acid and the farnesoid X receptor (FXR) on hepatic regeneration and lipid metabolism. Rats were fed with 0.2% bile acid or glucose for 7 days and then subjected to a 50 or 70% hepatectomy. Hepatic regeneration rate, serum and liver levels of bile acid, and expression of FXR and Caveolin‑1, were detected at 24, 48 or 72 h following hepatectomy. The expression of proliferating cell nuclear antigen (PCNA) in the liver was measured using immunohistochemistry at the end of the study. Hepatocytes isolated from rats were treated with bile acid, glucose, FXR agonist and FXR antagonist, separately or in combination. Lipid metabolism, the expression of members of the FXR signaling pathway and energy metabolism‑related factors were measured using ELISA kits or western blotting. Bile acid significantly increased the hepatic regeneration rate and the expression of FXR, Caveolin‑1 and PCNA. Levels of total cholesterol and high density lipoprotein were increased in bile acid‑ or FXR agonist‑treated hepatocytes in vitro. Levels of triglyceride, low density lipoprotein and free fatty acid were decreased. In addition, bile acid and FXR agonists increased the expression of bile salt export pump and small heterodimer partner, and downregulated the expression of apical sodium‑dependent bile acid transporter, Na+/taurocholate cotransporting polypeptide and cholesterol 7α‑hydroxylase. These results suggested that physiological concentrations of bile acid may promote liver regeneration via FXR signaling pathways, and may be associated with energy metabolism. PMID:25634785

  8. [Unusual evolution of a complex bile duct injury after a laparoscopic cholecystectomy].

    PubMed

    Mohamed, Hedfi; Hala, Bouhafa; Youssef, Elcadhi; Abdelhedi, Cherif; Karim, Sassi; Azza, Sridi; Adnen, Chouchene

    2016-01-01

    Since the advent of laparoscopic surgery of cholelithiasis the incidence rate of bile duct injuries has increased significantly in the literature in relation to the operators' learning curve. Unknown injuries can have dramatic, immediate consequences and progress to bile peritonitis. Moreover surgical repair of external biliary fistula at the stage of bile duct dilatation requires biliodigestive anastomosis or liver resections "réglées". PMID:27279975

  9. A Stated Preference Investigation into the Chinese Demand for Farmed vs. Wild Bear Bile

    PubMed Central

    Dutton, Adam J.; Hepburn, Cameron; Macdonald, David W.

    2011-01-01

    Farming of animals and plants has recently been considered not merely as a more efficient and plentiful supply of their products but also as a means of protecting wild populations from that trade. Amongst these nascent farming products might be listed bear bile. Bear bile has been exploited by traditional Chinese medicinalists for millennia. Since the 1980s consumers have had the options of: illegal wild gall bladders, bile extracted from caged live bears or the acid synthesised chemically. Despite these alternatives bears continue to be harvested from the wild. In this paper we use stated preference techniques using a random sample of the Chinese population to estimate demand functions for wild bear bile with and without competition from farmed bear bile. We find a willingness to pay considerably more for wild bear bile than farmed. Wild bear bile has low own price elasticity and cross price elasticity with farmed bear bile. The ability of farmed bear bile to reduce demand for wild bear bile is at best limited and, at prevailing prices, may be close to zero or have the opposite effect. The demand functions estimated suggest that the own price elasticity of wild bear bile is lower when competing with farmed bear bile than when it is the only option available. This means that the incumbent product may actually sell more items at a higher price when competing than when alone in the market. This finding may be of broader interest to behavioural economists as we argue that one explanation may be that as product choice increases price has less impact on decision making. For the wildlife farming debate this indicates that at some prices the introduction of farmed competition might increase the demand for the wild product. PMID:21799733

  10. A stated preference investigation into the Chinese demand for farmed vs. wild bear bile.

    PubMed

    Dutton, Adam J; Hepburn, Cameron; Macdonald, David W

    2011-01-01

    Farming of animals and plants has recently been considered not merely as a more efficient and plentiful supply of their products but also as a means of protecting wild populations from that trade. Amongst these nascent farming products might be listed bear bile. Bear bile has been exploited by traditional Chinese medicinalists for millennia. Since the 1980s consumers have had the options of: illegal wild gall bladders, bile extracted from caged live bears or the acid synthesised chemically. Despite these alternatives bears continue to be harvested from the wild. In this paper we use stated preference techniques using a random sample of the Chinese population to estimate demand functions for wild bear bile with and without competition from farmed bear bile. We find a willingness to pay considerably more for wild bear bile than farmed. Wild bear bile has low own price elasticity and cross price elasticity with farmed bear bile. The ability of farmed bear bile to reduce demand for wild bear bile is at best limited and, at prevailing prices, may be close to zero or have the opposite effect. The demand functions estimated suggest that the own price elasticity of wild bear bile is lower when competing with farmed bear bile than when it is the only option available. This means that the incumbent product may actually sell more items at a higher price when competing than when alone in the market. This finding may be of broader interest to behavioural economists as we argue that one explanation may be that as product choice increases price has less impact on decision making. For the wildlife farming debate this indicates that at some prices the introduction of farmed competition might increase the demand for the wild product. PMID:21799733

  11. Bile acid transformations by Alcaligenes recti.

    PubMed

    Mazumder, I; Mahato, S B

    1993-02-01

    Metabolism of cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and deoxycholic acid by the grown cells of the bacterium Alcaligenes recti suspended in water was studied. Each isolated metabolite was characterized by the application of various spectroscopic methods. Cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and deoxycholic acid yielded methylated derivatives 3 alpha-methoxy-7 alpha, 12 alpha-dihydroxy-5 beta-cholanoic acid, 3 alpha-methoxy-7 alpha-hydroxy-5 beta-cholanoic acid, 3 alpha-methoxy-7 beta-hydroxy-5 beta-cholanoic acid, and 3 alpha-methoxy-12 alpha-hydroxy-5 beta-cholanoic acid, respectively. In addition, cholic acid furnished 7 alpha, 12 alpha-dihydroxy-3-oxochol-4-en-24-oic acid; chenodeoxycholic acid gave 7 alpha-hydroxy-3-oxo-5 beta-cholanoic acid and 7 alpha-hydroxy-3-oxochol-4-en-24-oic acid while ursodeoxycholic acid yielded 7 beta-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochola-4,6-dien-24-oic acid. The formation of various metabolites showed that two competitive enzymic reactions, i.e., selective methylation of the 3 alpha-hydroxy group and dehydrogenation in the A/B rings, were operative. The methylation process was found to be enzymic involving an S-adenosyl-L-methionine (AdoMet)-dependent methyl transferase, and this reaction appeared to be inhibitory to the process of degradation of the ring system. In the other reaction sequence, degradation of the ring system was initiated by dehydrogenation of the 3 alpha-hydroxy group. A 7 beta-dehydratase activity producing the delta 6 double bond was also noticeable in the metabolism of ursodeoxycholic acid. PMID:8484188

  12. Association of diverse bacterial communities in human bile samples with biliary tract disorders: a survey using culture and polymerase chain reaction-denaturing gradient gel electrophoresis methods.

    PubMed

    Tajeddin, E; Sherafat, S J; Majidi, M R S; Alebouyeh, M; Alizadeh, A H M; Zali, M R

    2016-08-01

    Bacterial infection is considered a predisposing factor for disorders of the biliary tract. This study aimed to determine the diversity of bacterial communities in bile samples and their involvement in the occurrence of biliary tract diseases. A total of 102 bile samples were collected during endoscopic retrograde cholangiopancreatography (ERCP). Characterization of bacteria was done using culture and polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) methods. Antimicrobial susceptibility of the isolates was determined based on the Clinical and Laboratory Standards Institute (CLSI) guidelines and identity of the nucleotide sequences of differentiated bands from the DGGE gels was determined based on GenBank data. In total, 41.2 % (42/102) of the patients showed bacterial infection in their bile samples. This infection was detected in 21 % (4/19), 45.4 % (5/11), 53.5 % (15/28), and 54.5 % (24/44) of patients with common bile duct stone, microlithiasis, malignancy, and gallbladder stone, respectively. Escherichia coli showed a significant association with gallstones. Polymicrobial infection was detected in 48 % of the patients. While results of the culture method established coexistence of biofilm-forming bacteria (Pseudomonas aeruginosa, E. coli, Klebsiella pneumoniae, Enterococcus spp., and Acinetobacter spp.) in different combinations, the presence of Capnocytophaga spp., Lactococcus spp., Bacillus spp., Staphylococcus haemolyticus, Enterobacter or Citrobacter spp., Morganella spp., Salmonella spp., and Helicobacter pylori was also characterized in these samples by the PCR-DGGE method. Multidrug resistance phenotypes (87.5 %) and resistance to third- and fourth-generation cephalosporins and quinolones were common in these strains, which could evolve through their selection by bile components. Ability for biofilm formation seems to be a need for polymicrobial infection in this organ. PMID:27193890

  13. Effect of substituent pattern and molecular weight of cellulose ethers on interactions with different bile salts.

    PubMed

    Torcello-Gómez, Amelia; Fernández Fraguas, Cristina; Ridout, Mike J; Woodward, Nicola C; Wilde, Peter J; Foster, Timothy J

    2015-03-01

    Some known mechanisms proposed for the reduction of blood cholesterol by dietary fibre are: binding with bile salts in the duodenum and prevention of lipid absorption, which can be partially related with the bile salt binding. In order to gain new insights into the mechanisms of the binding of dietary fibre to bile salts, the goal of this work is to study the main interactions between cellulose derivatives and two types of bile salts. Commercial cellulose ethers: methyl (MC), hydroxypropyl (HPC) and hydroxypropylmethyl cellulose (HPMC), have been chosen as dietary fibre due to their highly functional properties important in manufactured food products. Two types of bile salts: sodium taurocholate (NaTC) and sodium taurodeoxycholate (NaTDC), have been chosen to understand the effect of the bile salt type. Interactions in the bulk have been investigated by means of differential scanning calorimetry (DSC) and linear mechanical spectroscopy. Results show that both bile salts have inhibitory effects on the thermal structuring of cellulose ethers and this depends on the number and type of substitution in the derivatised celluloses, and is not dependent upon molecular weight. Concerning the bile salt type, the more hydrophobic bile salt (NaTDC) has greater effect on these interactions, suggesting more efficient adsorption onto cellulose ethers. These findings may have implications in the digestion of cellulose-stabilised food matrices, providing a springboard to develop new healthy cellulose-based food products with improved functional properties. PMID:25679293

  14. Recent Progress on Bile Acid Receptor Modulators for Treatment of Metabolic Diseases.

    PubMed

    Xu, Yanping

    2016-07-28

    Bile acids are steroid-derived molecules synthesized in the liver, secreted from hepatocytes into the bile canaliculi, and subsequently stored in the gall bladder. During the feeding, bile flows into the duodenum, where it contributes to the solubilization and digestion of lipid-soluble nutrients. After a meal, bile-acid levels increase in the intestine, liver, and also in the systemic circulation. Therefore, serum bile-acid levels serve as an important sensing mechanism for nutrient and energy. Recent studies have described bile acids as versatile signaling molecules endowed with systemic endocrine functions. Bile acids are ligands for G-protein coupled receptors (GPCRs) such as TGR5 (also known as GPBAR1, M-BAR, and BG37) and nuclear hormone receptors including farnesoid X receptor (FXR; also known as NR1H4). Acting through these diverse signaling pathways, bile acids regulate triglyceride, cholesterol, glucose homeostasis, and energy expenditure. These bile-acid-controlled signaling pathways have become the source of promising novel drug targets to treat common metabolic and hepatic diseases. PMID:26878262

  15. Structural and Functional Implications of the Interaction between Macrolide Antibiotics and Bile Acids

    PubMed Central

    Glanzer, Simon; Pulido, Sergio A; Tutz, Sarah; Wagner, Gabriel E; Kriechbaum, Manfred; Gubensäk, Nina; Trifunovic, Jovana; Dorn, Markus; Fabian, Walter M F; Novak, Predrag; Reidl, Joachim; Zangger, Klaus

    2015-01-01

    Macrolide antibiotics, such as azithromycin and erythromycin, are in widespread use for the treatment of bacterial infections. Macrolides are taken up and excreted mainly by bile. Additionally, they have been implicated in biliary system diseases and to modify the excretion of other drugs through bile. Despite mounting evidence for the interplay between macrolide antibiotics and bile acids, the molecular details of this interaction remain unknown. Herein, we show by NMR measurements that macrolides directly bind to bile acid micelles. The topology of this interaction has been determined by solvent paramagnetic relaxation enhancements (solvent PREs). The macrolides were found to be bound close to the surface of the micelle. Increasing hydrophobicity of both the macrolide and the bile acid strengthen this interaction. Both bile acid and macrolide molecules show similar solvent PREs across their whole structures, indicating that there are no preferred orientations of them in the bile micelle aggregates. The binding to bile aggregates does not impede macrolide antibiotics from targeting bacteria. In fact, the toxicity of azithromycin towards enterotoxic E. coli (ETEC) is even slightly increased in the presence of bile, as was shown by effective concentration (EC50) values. PMID:25655041

  16. Characterization of a primary bile ductular cell culture from the livers of rats during extrahepatic cholestasis.

    PubMed Central

    Sirica, A. E.; Sattler, C. A.; Cihla, H. P.

    1985-01-01

    The establishment of novel bile ductular cell cultures was accomplished with the use of explants of a hyperplastic bile ductular tissue preparation obtained from rat livers at 10 to 15 weeks after bile duct ligation or a bile ductular cell fraction isolated from this tissue preparation by a procedure involving Percoll density gradient centrifugation. Observations made on these primary explant and monolayer bile ductular cell cultures were limited to the first 3 days of culture where the morphologic features of the bile ductular epithelium remained fairly well preserved, while fibroblast contamination was found to be very low. These cultured cells also retained over this period a high specific activity for the bile ductular cell marker enzyme gamma-glutamyl transpeptidase, as well as possessed measurable but decreasing specific activities for leucine aminopeptidase and alkaline phosphatase. Karyotypic analysis of the cultured monolayer cells further showed them to be diploid. In addition, preliminary transplantation studies demonstrated the presence of well-differentiated bile ductular-like structures following inoculation of the freshly isolated bile ductular cell fraction into the interscapular fat pads of recipient rats. Images Figure 2 Figure 1 Figure 3 Figure 4 Figure 5 Figure 6 PMID:2861743

  17. [Joint action of aminoglycoside antibiotics and nitrofurans with bile on bacteria of the genus Proteus].

    PubMed

    Sytnik, I A; Puzakova, E V

    1980-06-01

    The combined effect of monomycin, kanamycin, neomycin and nitrofurans, such as furacillin, furagin, nitrofurantoin and furazolidone with bovine bile was studied on 36 strains of Proteus mirabilis and 14 strains of Proteus vulgaris. It was found that sub-bacteriostatic doses of the bile significantly increased the antiproteus activity of the aminoglycoside antibiotics and nitrofurans. The combinations of the bile with monomycin and kanamycin and the bile with furazolidone and nitrofurantoin proved to be most effective. Clinical trials of the drugs in treatment of inflammatory diseases of the biliferous system of the Proteus etiology are recommended. PMID:7396441

  18. Comparison of endoscopic papillary balloon dilatation and endoscopic sphincterotomy for bile duct stones

    PubMed Central

    Sakai, Yuji; Tsuyuguchi, Toshio; Sugiyama, Harutoshi; Hayashi, Masahiro; Senoo, Jun-ichi; Kusakabe, Yuko; Yasui, Shin; Mikata, Rintaro; Yokosuka, Osamu

    2016-01-01

    Endoscopic treatment for bile duct stones is low-invasive and currently considered as the first choice of the treatment. For the treatment of bile duct stones, papillary treatment is necessary, and the treatments used at the time are broadly classified into two types; endoscopic papillary balloon dilatation where bile duct closing part is dilated with a balloon and endoscopic sphincterotomy (EST) where bile duct closing part is incised. Both procedures have advantages and disadvantages. Golden standard is EST, however, there are patients with difficulty for EST, thus we must select the procedure based on understanding of the characteristics of the procedure, and patient backgrounds. PMID:27247706

  19. Differential proteomic analysis of outer membrane enriched extracts of Bacteroides fragilis grown under bile salts stress.

    PubMed

    Boente, Renata F; Pauer, Heidi; Silva, Deborah N S; Filho, Joaquim Santos; Sandim, Vanessa; Antunes, Luis Caetano M; Ferreira, Rosana Barreto Rocha; Zingali, Russolina B; Domingues, Regina M C P; Lobo, Leandro A

    2016-06-01

    Bacteroides fragilis is the most commonly isolated anaerobic bacteria from infectious processes. Several virulence traits contribute to the pathogenic nature of this bacterium, including the ability to tolerate the high concentrations of bile found in the gastrointestinal tract (GIT). The activity of bile salts is similar to detergents and may lead to membrane permeabilization and cell death. Modulation of outer membrane proteins (OMPs) is considered a crucial event to bile salts resistance. The primary objective of the current work was to identify B. fragilis proteins associated with the stress induced by high concentration of bile salts. The outer membrane of B. fragilis strain 638R was isolated after growth either in the presence of 2% conjugated bile salts or without bile salts. The membrane fractions were separated on SDS-PAGE and analyzed by ESI-Q/TOF tandem mass spectrometry. A total of 37 proteins were identified; among them nine were found to be expressed exclusively in the absence of bile salts whereas eight proteins were expressed only in the presence of bile salts. These proteins are related to cellular functions such as transport through membrane, nutrient uptake, and protein-protein interactions. This study demonstrates the alteration of OMPs composition in B. fragilis during bile salts stress resistance and adaptation to environmental changes. Proteomics of OMPs was also shown to be a useful approach in the identification of new targets for functional analyses. PMID:26948242

  20. Bile duct invasion can be an independent prognostic factor in early stage hepatocellular carcinoma

    PubMed Central

    Jang, Ye-Rang; Kim, Hyeyoung; Lee, Jeong-Moo; Yi, Nam-Joon; Suh, Kyung-Suk

    2015-01-01

    Backgrounds/Aims In hepatocellular carcinoma (HCC), bile duct invasion occurs far more rarely than vascular invasion and is not well characterized. In addition, the pathologic finding of bile duct invasion is not considered an independent prognostic factor for HCC following surgery. In this study, we determined the characteristics of HCC with bile duct invasion, and assessed the clinical significance of bile duct invasion. Methods We retrospectively reviewed the medical records of 363 patients who underwent hepatic resection for HCC at Seoul National University Hospital (SNUH) from January 2009 to December 2011. Preoperative, operative, and pathological data were collected. The risk factors for recurrence and survival were analyzed. Subsequently, the patients were divided into 2 groups according to disease stage (American Joint Committee on Cancer/International Union Against Cancer 7th edition): early stage (T1 and 2) and advanced stage (T3 and 4) group; and risk factors in the sub-groups were analyzed. Results Among 363 patients, 13 showed bile duct invasion on pathology. Patients with bile duct invasion had higher preoperative total bilirubin levels, greater microvascular invasion, and a higher death rate than those without bile duct invasion. In multivariate analysis, bile duct invasion was not an independent prognostic factor for survival for the entire cohort, but, was an independent prognostic factor for early stage. Conclusions Bile duct invasion accompanied microvascular invasion in most cases, and could be used as an independent prognostic factor for survival especially in early stage HCC (T1 and T2). PMID:26693236

  1. Bile acids as possible human carcinogens: new tricks from an old dog.

    PubMed

    Costarelli, Vassiliki

    2009-01-01

    Bile first attracted man's interest long ago. The actual tumour-promoting effects of a bile acid were reported in 1939 for deoxycholic acid. Ever since, much evidence has accumulated that supports an important role for bile acids as cancer promoters in humans through DNA damage and selection for apoptosis-resistant cells, both of which can lead to increased mutation rates. The evidence reviewed here indicates that, in humans, bile acids are likely to be implicated in the aetiology of a number of different important cancers in terms of morbidity and mortality, such as cancer of the colon, oesophagus, stomach, pancreas, gall bladder and cancer of the breast. PMID:19499433

  2. Comparison of endoscopic papillary balloon dilatation and endoscopic sphincterotomy for bile duct stones.

    PubMed

    Sakai, Yuji; Tsuyuguchi, Toshio; Sugiyama, Harutoshi; Hayashi, Masahiro; Senoo, Jun-Ichi; Kusakabe, Yuko; Yasui, Shin; Mikata, Rintaro; Yokosuka, Osamu

    2016-05-25

    Endoscopic treatment for bile duct stones is low-invasive and currently considered as the first choice of the treatment. For the treatment of bile duct stones, papillary treatment is necessary, and the treatments used at the time are broadly classified into two types; endoscopic papillary balloon dilatation where bile duct closing part is dilated with a balloon and endoscopic sphincterotomy (EST) where bile duct closing part is incised. Both procedures have advantages and disadvantages. Golden standard is EST, however, there are patients with difficulty for EST, thus we must select the procedure based on understanding of the characteristics of the procedure, and patient backgrounds. PMID:27247706

  3. Comparative studies of bile salts. 5α-Chimaerol, a new bile alcohol from the white sucker Catostomus commersoni Lacépède

    PubMed Central

    Anderson, I. G.; Haslewood, G. A. D.

    1970-01-01

    1. G.l.c. examination of bile alcohols prepared from the sucker Catostomus commersoni Lacépède (family Catostomidae) showed that although 5α-cyprinol (5α-cholestane-3α,7α,12α,26,27-pentol) was a minor constituent, the principal bile alcohol was an undescribed substance, probably present in the bile as the C-26 sulphate ester, whose i.r., n.m.r. and mass spectra agreed with the structure 5α-cholestane-3α,7α,12α,24,26-pentol. 2. MD studies suggest that this 5α-chimaerol is the 24(+), 25S enantiomer and that 5β-chimaerol (chimaerol) from Chimaera monstrosa bile also has the 24(+), 25S configuration. These findings imply that bile alcohol biosynthesis in suckers and chimaeras includes stereospecific oxidation of cholesterol at C-26. 3. C. commersoni bile acids (present in minor amounts) probably consist largely of 3α,7α,12α-trihydroxy-5α-cholan-24-oic acid (allocholic acid). 4. 5α-Chimaerol sulphate and 5α-cyprinol sulphate are probably biochemically equivalent as bile salts, and can be considered as arising by parallel evolution. PMID:5435487

  4. Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice.

    PubMed

    Gujral, Jaspreet S; Farhood, Anwar; Bajt, Mary Lynn; Jaeschke, Hartmut

    2003-08-01

    Obstruction of the common bile duct in a variety of clinical settings leads to cholestatic liver injury. An important aspect of this injury is hepatic inflammation, with neutrophils as the prominent cell type involved. However, the pathophysiologic role of the infiltrating neutrophils during cholestatic liver injury remains unclear. Therefore, we tested the hypothesis that neutrophils contribute to the overall pathophysiology by using bile duct-ligated (BDL) wild-type animals and mice deficient in the beta(2) integrin CD18. In wild-type animals, neutrophils were activated systemically as indicated by the increased expression of Mac-1 (CD11b/CD18) and L-selectin shedding 3 days after BDL. Histologic evaluation (48 +/- 10% necrosis) and plasma transaminase levels showed severe liver injury. Compared with sham-operated controls (< 10 neutrophils per 20 high-power fields), large numbers of neutrophils were present in livers of BDL mice (425 +/- 64). About 60% of these neutrophils had extravasated into the parenchyma. In addition, a substantial number of extravasated neutrophils were found in the portal tract. In contrast, Mac-1 was not up-regulated and plasma transaminase activities and the area of necrosis (21 +/- 9%) were significantly reduced in CD18-deficient animals. These mice had overall 62% less neutrophils in the liver. In particular, extravasation from sinusoids and portal venules (PV) was reduced by 91% and 47%, respectively. Immunohistochemical staining for chlorotyrosine, a marker of neutrophil-derived oxidant stress, was observed in the parenchyma of BDL wild-type but not CD18-deficient mice. In conclusion, neutrophils aggravated acute cholestatic liver injury after BDL. This inflammatory injury involves CD18-dependent extravasation of neutrophils from sinusoids and reactive oxygen formation. PMID:12883479

  5. Segmental Bile Duct-Targeted Liver Resection for Right-Sided Intrahepatic Stones

    PubMed Central

    Li, Shao-Qiang; Hua, Yun-Peng; Shen, Shun-Li; Hu, Wen-Jie; Peng, Bao-Gang; Liang, Li-Jian

    2015-01-01

    Abstract Hepatectomy is a safe and effective treatment for intrahepatic stones (IHSs). However, the resection plane for right-sided stones distributed within 2 segments is obstacle because of atrophy-hypertrophy complex formation of the liver and difficult dissection of segmental pedicle within the Glissonean plate by conventional approach. Thus, we devised segmental bile duct-targeted liver resection (SBDLR) for IHS, which aimed at completely resection of diseased bile ducts. This study aimed to evaluate the outcomes of SBDLR for right-sided IHSs. From January 2009 to December 2013, 107 patients with IHS treated by SBDLR in our center were reviewed in a prospective database. Patients’ intermediate and long-term outcomes after SBDLR were analyzed. A total of 40 (37.4%) patients with localized right-sided stone and 67 (62.7%) patients with bilateral stones underwent SBDLR alone and SBDLR combined with left-sided hepatectomy, respectively. There was no hospital mortality of this cohort of patients. The postoperative morbidity was 35.5%. The mean intraoperative blood loss was 414 mL (range: 100–2500). Twenty-one (19.6%) patients needed red blood cells transfusion. The intermediate stone clearance rate was 94.4%; the final clearance rate reached 100% after subsequent postoperative cholangioscopic lithotomy. Only 2.8% patients developed stone recurrence in a median follow-up period of 38.3 months. SBDLR is a safe and effective treatment for right-sided IHS distributed within 2 segments. It is especially suitable for a subgroup of patients with bilateral stones whose right-sided stones are within 2 segments and bilateral liver resection is needed. PMID:26181559

  6. Segmental Bile Duct-Targeted Liver Resection for Right-Sided Intrahepatic Stones.

    PubMed

    Li, Shao-Qiang; Hua, Yun-Peng; Shen, Shun-Li; Hu, Wen-Jie; Peng, Bao-Gang; Liang, Li-Jian

    2015-07-01

    Hepatectomy is a safe and effective treatment for intrahepatic stones (IHSs). However, the resection plane for right-sided stones distributed within 2 segments is obstacle because of atrophy-hypertrophy complex formation of the liver and difficult dissection of segmental pedicle within the Glissonean plate by conventional approach. Thus, we devised segmental bile duct-targeted liver resection (SBDLR) for IHS, which aimed at completely resection of diseased bile ducts. This study aimed to evaluate the outcomes of SBDLR for right-sided IHSs. From January 2009 to December 2013, 107 patients with IHS treated by SBDLR in our center were reviewed in a prospective database. Patients' intermediate and long-term outcomes after SBDLR were analyzed. A total of 40 (37.4%) patients with localized right-sided stone and 67 (62.7%) patients with bilateral stones underwent SBDLR alone and SBDLR combined with left-sided hepatectomy, respectively. There was no hospital mortality of this cohort of patients. The postoperative morbidity was 35.5%. The mean intraoperative blood loss was 414  mL (range: 100-2500). Twenty-one (19.6%) patients needed red blood cells transfusion. The intermediate stone clearance rate was 94.4%; the final clearance rate reached 100% after subsequent postoperative cholangioscopic lithotomy. Only 2.8% patients developed stone recurrence in a median follow-up period of 38.3 months. SBDLR is a safe and effective treatment for right-sided IHS distributed within 2 segments. It is especially suitable for a subgroup of patients with bilateral stones whose right-sided stones are within 2 segments and bilateral liver resection is needed. PMID:26181559

  7. Interaction of Bile Salts with β-Cyclodextrins Reveals Nonclassical Hydrophobic Effect and Enthalpy-Entropy Compensation.

    PubMed

    Paul, Bijan K; Ghosh, Narayani; Mukherjee, Saptarshi

    2016-04-28

    Herein, we present an endeavor toward exploring the lacuna underlying the host:guest chemistry of inclusion complex formation between bile salt(s) and β-cyclodextrin(s) (βCDs). An extensive thermodynamic investigation based on isothermal titration calorimetry (ITC) demonstrates a dominant contribution from exothermic enthalpy change (ΔH < 0) accompanying the phenomenon of inclusion complex formation, along with a relatively smaller contribution to total free energy change from the entropic component. However, the negative heat capacity change (ΔCp < 0) displays the hallmark for a pivotal role of hydrophobic effect underlying the interaction. Contrary to the classical hydrophobic effect, such apparently paradoxical thermodynamic signature has been adequately described under the notion of "nonclassical hydrophobic effect". On the basis of our results, the displacement of disordered water from hydrophobic binding sites has been argued to mark the enthalpic signature and the key role of such interaction forces is further corroborated from enthalpy-entropy compensation behavior showing indication for almost complete compensation. To this end, we have quantified the interaction of two bile salt molecules (namely, sodium deoxycholate and sodium glycocholate) with a series of varying chemical substituents on the host counterpart, namely, βCD, (2-hydroxypropyl)-βCD, and methyl βCD. PMID:27054266

  8. Regulation of hepatic bile acid transporters Ntcp and Bsep expression

    PubMed Central

    Cheng, Xingguo; Buckley, David; Klaassen, Curtis D.

    2009-01-01

    Sodium-taurocholate cotransporting polypeptide (Ntcp) and bile salt export pump (Bsep) are two key transporters for hepatic bile acid uptake and excretion. Alterations in Ntcp and Bsep expression have been reported in pathophysiological conditions. In the present study, the effects of age, gender, and various chemicals on the regulation of these two transporters were characterized in mice. Ntcp and Bsep mRNA levels in mouse liver were low in the fetus, but increased to its highest expression at parturition. After birth, mouse Ntcp and Bsep mRNA decreased by more than 50%, and then gradually increased to adult levels by day 30. Expression of mouse Ntcp mRNA and protein exhibit higher levels in female than male livers, which is consistent with the trend of human NTCP mRNA expression between men and women. No gender difference exists in BSEP/Bsep expression in human and mouse livers. Hormone replacements conducted in gonadectomized, hypophysectomized, and lit/lit mice indicate that female-predominant Ntcp expression in mouse liver is due to the inhibitory effect of male-pattern GH secretion, but not sex hormones. Ntcp and Bsep expression are in general resistant to induction by a large battery of microsomal enzyme inducers. Administration of cholestyramine increased Ntcp, whereas chenodeoxycholic acid increased Bsep mRNA expression. In silico analysis indicates that female-predominant mouse and human Ntcp/NTCP expression may be due to GH. In conclusion, mouse Ntcp and Bsep are regulated by age, gender, cholestyramine, and bile acid, but resistant to induction by most microsomal enzyme inducers. PMID:17897632

  9. Bile acid conjugation in early stage cholestatic liver disease before and during treatment with ursodeoxycholic acid.

    PubMed

    Fracchia, M; Setchell, K D; Crosignani, A; Podda, M; O'Connell, N; Ferraris, R; Hofmann, A F; Galatola, G

    1996-04-30

    The efficiency of bile acid conjugation before and during therapy with 600 mg/day of ursodeoxycholic acid was measured in seven adult patients with early chronic cholestatic liver disease (6 with primary biliary cirrhosis; 1 with primary sclerosing cholangitis). Duodenal bile samples were obtained by aspiration and the proportion of unconjugated bile acids was determined using lipophilic anion exchange chromatography to separate bile acid classes, followed by analysis of individual bile acids by gas chromatography-mass spectrometry. The proportion of conjugated bile acids was determined by high-performance liquid chromatography. Use of a (99m)Tc-HIDA recovery marker permitted the absolute mass of unconjugated bile acids in the gallbladder to be calculated. Unconjugated bile acids comprised 0.4% of total biliary bile acids before and 0.2% during ursodeoxycholic acid therapy, indicating highly efficient conjugation of bile acids. During therapy, percentage unconjugated ursodeoxycholic acid significantly increased from (mean +/- S.D.) 13 +/- 13% to 54 +/- 12%; P < 0.002. When the unconjugated and conjugated fractions of bile acids were compared, there was an enrichment in unconjugated fraction for cholic acid and ursodeoxycholic acid and a depletion for chenodeoxycholic acid both in basal condition and during ursodeoxycholic acid therapy, suggesting that hydrophilic bile acids were conjugated less efficiently. During therapy, the conjugation efficiency significantly increased for cholic acid and ursodeoxycholic acid. The pretreatment mass of total unconjugated bile acids in the gallbladder was (mean +/- S.D.) 4.4 +/- 3.2 mumol, and was not significantly changed by ursodeoxycholic acid therapy (6.2 +/- 3.5 mumol). However, ursodeoxycholic acid therapy caused a significant increase in the mass of unconjugated ursodeoxycholic acid. It is concluded that endogenous bile acids and exogenous ursodeoxycholic acid when given at the usual dose are efficiently conjugated in

  10. In vitro evidence that phosphatidylcholine protects against indomethacin/bile acid-induced injury to cells

    PubMed Central

    Dial, Elizabeth J.; Dawson, Paul A.

    2014-01-01

    Indomethacin is a powerful analgesic nonsteroidal anti-inflammatory drug (NSAID), but is limited in use by its primary side effect to cause gastrointestinal bleeding and serious injury. One factor important for exacerbating NSAID injury is the presence of bile acids, which may interact with indomethacin to form toxic mixed micelles in the gut. The development of a safer gastrointestinal formulation of indomethacin that is chemically complexed with phosphatidylcholine (PC-indomethacin) may offer an improved therapeutic agent, particularly in the presence of bile acid, but its potential protective mechanism is incompletely understood. Intestinal epithelial cells (IEC-6) were tested for injury with indomethacin (alone and plus various bile acids) compared with PC-indomethacin (alone and plus bile acids). To explore a role for bile acid uptake into cells as a requirement for NSAID injury, studies were performed using Madin-Darby canine kidney cells transfected with the apical sodium-dependent bile acid transporter (ASBT). Indomethacin, but not PC-indomethacin, was directly and dose-dependently injurious to IEC-6 cells. Similarly, the combination of any bile acid plus indomethacin, but not PC-indomethacin, induced cell injury. The expression of ASBT had a modest effect on the acute cytotoxicity of indomethacin in the presence of some conjugated bile acids. Complexing PC with indomethacin protected against the acute intestinal epithelial injury caused by indomethacin regardless of the presence of bile acids. The presence of luminal bile acid, but not its carrier-mediated uptake into the enterocyte, is required for acute indomethacin-induced cell injury. It is likely that initial cell damage induced by indomethacin occurs at or near the cell membrane, an effect exacerbated by bile acids and attenuated by PC. PMID:25477376

  11. Gut microbiota, cirrhosis, and alcohol regulate bile acid metabolism in the gut.

    PubMed

    Ridlon, Jason M; Kang, Dae-Joong; Hylemon, Phillip B; Bajaj, Jasmohan S

    2015-01-01

    The understanding of the complex role of the bile acid-gut microbiome axis in health and disease processes is evolving rapidly. Our focus revolves around the interaction of the gut microbiota with liver diseases, especially cirrhosis. The bile acid pool size has recently been shown to be a function of microbial metabolism of bile acid, and regulation of the microbiota by bile acids is important in the development and progression of several liver diseases. Humans produce a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of farnesoid X receptor (FXR) in the intestine and liver. Microbes use bile acids, and via FXR signaling this results in a smaller, unconjugated hydrophobic bile acid pool. This equilibrium is critical to maintain health. The challenge is to examine the manifold functions of gut bile acids as modulators of antibiotic, probiotic, and disease progression in cirrhosis, metabolic syndrome, and alcohol use. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. With advancing liver disease and cirrhosis, there is dysbiosis in the fecal, ileal, and colonic mucosa, in addition to a decrease in bile acid concentration in the intestine due to the liver problems. This results in a dramatic shift toward the Firmicutes, particularly Clostridium cluster XIVa, and increasing production of deoxycholic acid. Alcohol intake speeds up these processes in the subjects with and without cirrhosis without significant FXR feedback. Taken together, these pathways can impact intestinal and systemic inflammation while worsening dysbiosis. The interaction between bile acids, alcohol, cirrhosis, and dysbiosis is an important relationship that influences intestinal and systemic inflammation, which in turn determines progression of the overall disease process. These interactions and the impact of commonly used therapies for liver disease can provide

  12. Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling.

    PubMed

    McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew; Divan, Ali; Grant, Stephanie; Patel, Nisha; Newell-Rogers, Karen; DeMorrow, Sharon

    2015-12-01

    Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease. PMID:26431088

  13. Gut microbiota, cirrhosis and alcohol regulate bile acid metabolism in the gut

    PubMed Central

    Ridlon, Jason M.; Kang, Dae-Joong; Hylemon, Phillip B.; Bajaj, Jasmohan S

    2015-01-01

    The understanding of the complex role of the bile acid-gut microbiome axis in health and disease processes is evolving rapidly. Our focus revolves around the interaction of the gut microbiota with liver diseases, especially cirrhosis. The bile acid pool size has recently been shown to be a function of microbial metabolism of bile acid and regulation of the microbiota by bile acids is important in the development and progression of several liver diseases. Humans produce a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of FXR in intestine and liver. Microbes use bile acids, and via FXR signaling this results in a smaller, unconjugated hydrophobic bile acid pool. This equilibrium is critical to maintain health. The challenge is to examine the manifold functions of gut bile acids as modulators of antibiotic, probiotic and disease progression in cirrhosis, metabolic syndrome and alcohol use. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. With advancing liver disease and cirrhosis, there is dysbiosis in the fecal, ileal and colonic mucosa, in addition to a decrease in bile acid concentration in the intestine due to the liver problems. This results in a dramatic shift toward the Firmicutes, particularly Clostridium cluster XIVa and increasing production of deoxycholic acid (DCA). Alcohol intake speeds up these processes in the subjects with and without cirrhosis without significant FXR feedback. Taken together, these pathways can impact intestinal and systemic inflammation while worsening dysbiosis. The interaction between bile acids, alcohol, cirrhosis and dysbiosis is an important relationship that influences intestinal and systemic inflammation, which in turn determines progression of the overall disease process. These interactions and the impact of commonly used therapies for liver disease can provide insight into the pathogenesis

  14. Synchronous double cancer of the common bile duct.

    PubMed

    Bedoui, Riadh; Ajmi, Mahmoud; Nouira, Ramzi; Dziri, Chadli

    2011-01-01

    Synchronous double cancer of the common bile duct is exceptional and only one reported case was found in the literature. We report a case in which the diagnosis of the double tumor was missed by computed tomography scan, magnetic resonance imaging, and endoscopic ultrasonography. The diagnosis of the distal tumor was made only during surgery. There was no communication in either the mucosal layer or the subepithelial layer between the 2 cancers without periductal lymphatic spread, thus suggesting that they are primary. PMID:21167357

  15. Probing the Binding Site of Bile Acids in TGR5.

    PubMed

    Macchiarulo, Antonio; Gioiello, Antimo; Thomas, Charles; Pols, Thijs W H; Nuti, Roberto; Ferrari, Cristina; Giacchè, Nicola; De Franco, Francesca; Pruzanski, Mark; Auwerx, Johan; Schoonjans, Kristina; Pellicciari, Roberto

    2013-12-12

    TGR5 is a G-protein-coupled receptor (GPCR) mediating cellular responses to bile acids (BAs). Although some efforts have been devoted to generate homology models of TGR5 and draw structure-activity relationships of BAs, none of these studies has hitherto described how BAs bind to TGR5. Here, we present an integrated computational, chemical, and biological approach that has been instrumental to determine the binding mode of BAs to TGR5. As a result, key residues have been identified that are involved in mediating the binding of BAs to the receptor. Collectively, these results provide new hints to design potent and selective TGR5 agonists. PMID:24900622

  16. Effects of controlled interruption of the enterohepatic circulation of bile salts by biliary diversion and by ileal resection on bile salt secretion, synthesis, and pool size in the rhesus monkey

    PubMed Central

    Dowling, R. Hermon; Mack, Eberhard; Small, Donald M.

    1970-01-01

    The effects of controlled interruption of the enterohepatic circulation (EHC) of bile salts by biliary diversion on bile volume, bile salt secretion and synthesis rates, bile salt pool size, and the relationship to fecal fat excretion were studied in 16 rhesus monkeys. Bile from a chronic bile fistula was returned to the intestine through an electronic stream-splitter which, by diverting different percentages of bile to a collecting system, provided graded and controlled interruption of the EHC. The increase in hepatic bile salt synthesis in response to interruption of the EHC was limited and reached a maximum rate at 20% interruption of the EHC. Up to this level of biliary diversion, the increased hepatic synthesis compensated for bile salt loss so that bile salt secretion and pool size were maintained at normal levels. With diversion of 33% or more, there was no further increase in hepatic bile salt synthesis to compensate for external loss, and as a result there was diminished bile salt secretion, a reduction in bile salt pool size, and steatorrhea was observed. The effects of interruption of the EHC by the streamsplitter were compared with those produced by resection of the distal one-third or two-thirds of small bowel. While ileal resection appreciably reduced bile salt secretion, the EHC was by no means abolished. Bile salt reabsorption from the residual intestine was greater after one-third than after two-thirds small bowel resection. These observations suggest that jejunal reabsorption of bile salts occurs and may well contribute to the normal EHC. PMID:4983661

  17. Disposition and metabolism of 2-fluoro-beta-alanine conjugates of bile acids following secretion into bile.

    PubMed

    Zhang, R W; Barnes, S; Diasio, R B

    1991-04-15

    Since 2-fluoro-beta-alanine (FBAL) conjugates of bile acids (BA), the primary biliary metabolites of fluoropyrimidine (FP) drugs, have been suggested to be related to the hepatotoxicity which develops in patients receiving FP chemotherapy by intrahepatic arterial infusion (Proc. Natl. Acad. Sci. USA 84, 5439-5443, 1987), it was important to determine whether they undergo enterohepatic circulation and hence accumulate in the liver and biliary system. In initial studies, sensitivity of FBAL-BA conjugates to hydrolysis by pancreatic enzymes was examined. In subsequent in vivo studies, a model FBAL-BA conjugate, FBAL-chenodeoxycholate (FBAL-CDC), was introduced into the lumen of the small intestine of anesthetized rats with biliary fistulas to quantitate the intestinal absorption, metabolism and tissue distribution of the conjugate. The results indicated that: (1) FBAL-BA conjugates were resistant to hydrolysis by pancreatic enzymes (carboxypeptidase A, carboxypeptidase B and trypsin) and by human pancreatic juice, but were completely hydrolyzed by cholyglycine hydrolase. (2) At least one-half of the administered FBAL-CDC was deconjugated during the process of intestinal absorption, as shown by HPLC analysis of the radioactivity in portal venous blood. (3) Deconjugated FBAL or CDC was reconjugated in liver with other bile acids or amino acids (glycine and taurine), respectively, as shown by radiochromatography of bile. (4) FBAL, formed as a result of hydrolysis of FBAL-CDC, had a wide tissue distribution. In conclusion, FBAL-CDC has a rapid turnover during its enterohepatic circulation due to deconjugation in the intestine and reconjugation in the liver. PMID:1902118

  18. Serum Bile Acids Are Associated with Pathological Progression of Hepatitis B-Induced Cirrhosis.

    PubMed

    Wang, Xiaoning; Xie, Guoxiang; Zhao, Aihua; Zheng, Xiaojiao; Huang, Fengjie; Wang, Yixing; Yao, Chun; Jia, Wei; Liu, Ping

    2016-04-01

    Recent metabonomic studies have identified an important role of bile acids in patients with liver cirrhosis. Serum bile acids, such as glycocholate (GCA), glycochenodeoxycholate (GCDCA), taurocholate (TCA), and taurochenodeoxycholate (TCDCA), increased significantly in liver cirrhosis patients. Our recently published urinary metabonomic study showed that glycocholate 3-glucuronide, taurohyocholate, TCA, glycolithocholate 3-sulfate, and glycoursodeoxycholate (GUDCA) were markedly increased in hepatitis B-induced cirrhotic patients (n = 63) compared with healthy controls (n = 31). The urinary levels of GUDCA were able to differentiate among three stages of cirrhotic patients with Child-Pugh (CP) score A, B, and C. In this study, we recruited two new cohorts of patients with hepatitis-B-induced cirrhosis and healthy control subjects and quantitatively profiled their serum bile acids using ultra-performance liquid chromatography triple quadrupole mass spectrometry. Serum bile acid profile and corresponding differential bile acids were characterized, in addition to the blood routine, liver, and renal function tests. The alterations of bile acids contributing to the intergroup variation between healthy controls and cirrhotic patients and among pathological stages of CP grade A, B and C were also investigated. Five bile acids, GCA, GCDCA, TCA, TCDCA, and GUDCA, were significantly altered among different stages of liver cirrhosis (n = 85), which was validated with an independent cohort of cirrhotic patients (n = 53). Our results show that dynamic alteration of serum bile acids is indicative of an exacerbated liver function, highlighting their potential as biomarkers for staging the liver cirrhosis and monitoring its progression. PMID:25964117

  19. Bile Acid Responses in Methane and Non-Methane Producers to Standard Breakfast Meals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bile acids and their conjugates are important regulators of glucose homeostasis. Previous research has revealed the ratio of cholic acid to deoxycholic acid to affect insulin resistance in humans. Bile acid de-conjugation and intestinal metabolism depend on gut microbes which may be affected by hos...

  20. Nod2 deficiency protects mice from cholestatic liver disease by increasing renal excretion of bile acids

    PubMed Central

    Wang, Lirui; Hartmann, Phillipp; Haimerl, Michael; Bathena, Sai P.; Sjöwall, Christopher; Almer, Sven; Alnouti, Yazen; Hofmann, Alan F.; Schnabl, Bernd

    2014-01-01

    Background & aims Chronic liver disease is characterized by fibrosis that may progress to cirrhosis. Nucleotide oligomerization domain 2 (Nod2), a member of the Nod-like receptor (NLR) family of intracellular immune receptors, plays an important role in the defense against bacterial infection through binding to the ligand muramyl dipeptide (MDP). Here, we investigated the role of Nod2 in the development of liver fibrosis. Methods We studied experimental cholestatic liver disease induced by bile duct ligation or toxic liver disease induced by carbon tetrachloride in wild type and Nod2−/− mice. Results Nod2 deficiency protected mice from cholestatic but not toxin-induced liver injury and fibrosis. Most notably, the hepatic bile acid concentration was lower in Nod2−/− mice than wild type mice following bile duct ligation for 3 weeks. In contrast to wild type mice, Nod2−/− mice had increased urinary excretion of bile acids, including sulfated bile acids, and an upregulation of the bile acid efflux transporters MRP2 and MRP4 in tubular epithelial cells of the kidney. MRP2 and MRP4 were downregulated by IL-1β in a Nod2 dependent fashion. Conclusions Our findings indicate that Nod2 deficiency protects mice from cholestatic liver injury and fibrosis through enhancing renal excretion of bile acids that in turn contributes to decreased concentration of bile acids in the hepatocyte. PMID:24560660

  1. Intestinal bile acid sensing is linked to key endocrine and metabolic signalng pathways

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bile acids have historically been considered to mainly function in cholesterol homeostasis and facilitate fat digestion in the gastrointestinal tract. Recent discoveries show that bile acids also function as signaling molecules that exert diverse endocrine and metabolic actions by activating G prote...

  2. Lithocholic acid feeding induces segmental bile duct obstruction and destructive cholangitis in mice.

    PubMed

    Fickert, Peter; Fuchsbichler, Andrea; Marschall, Hanns-Ulrich; Wagner, Martin; Zollner, Gernot; Krause, Robert; Zatloukal, Kurt; Jaeschke, Hartmut; Denk, Helmut; Trauner, Michael

    2006-02-01

    We determined the mechanisms of hepatobiliary injury in the lithocholic acid (LCA)-fed mouse, an increasingly used model of cholestatic liver injury. Swiss albino mice received control diet or 1% (w/w) LCA diet (for 1, 2, and 4 days), followed by assessment of liver morphology and ultrastructure, tight junctions, markers of fibrosis and key proteins of hepatobiliary function, and bile flow and composition. As expected LCA feeding led to bile infarcts, which were followed by a destructive cholangitis with activation and proliferation of periductal myofibroblasts. At the ultrastructural level, small bile ducts were frequently obstructed by crystals. Biliary-excreted fluorescence-labeled ursodeoxycholic acid accumulated in bile infarcts, whereas most infarcts did not stain with India ink injected into the common bile duct; both findings are indicative of partial biliary obstruction. Expression of the main basolateral bile acid uptake proteins (sodium-taurocholate cotransporter and organic anion-transporting polypeptide 1) was reduced, the canalicular transporters bile salt export pump and multidrug-related protein 2 were preserved, and the basolateral transporter multidrug-related protein 3 and the detoxifying enzyme sulfotransferase 2a1 were induced. Thus, we demonstrate that LCA feeding in mice leads to segmental bile duct obstruction, destructive cholangitis, periductal fibrosis, and an adaptive transporter and metabolic enzyme response. PMID:16436656

  3. Evaluation of Postmortem Drug Concentrations in Bile Compared with Blood and Urine in Forensic Autopsy Cases.

    PubMed

    Tominaga, Mariko; Michiue, Tomomi; Oritani, Shigeki; Ishikawa, Takaki; Maeda, Hitoshi

    2016-06-01

    For drug screening and pharmaco-/toxicokinetic analysis, bile as a major drug excretion route in addition to urine may be used in forensic autopsy cases; however, there are limited published data on correlations between bile and blood or urine drug concentrations. The present study retrospectively investigated drug concentrations in bile, compared with blood and urine concentrations, reviewing forensic autopsy cases during 6 years (January 2009-December 2014). Drugs were analyzed using automated gas chromatography-mass spectrometry following solid-liquid phase extraction. Compared with peripheral blood concentrations, bile concentrations were higher for most drugs; however, caffeine concentrations were similar. Bile concentrations were mostly lower than urine concentrations for amphetamines, caffeine and methylephedrine, but were usually similar to or higher for other drugs. Significant correlations were detected between bile and peripheral blood concentrations for amphetamines, several cold remedies, phenobarbital, phenothiazine derivatives and diazepam, as well as between bile and urine concentrations for amphetamines, caffeine, diphenhydramine, phenobarbital and promethazine derivatives. These findings suggest that bile can provide supplemental data useful in routine forensic toxicology, for the spectrum of drugs mentioned above, as well as for investigating pharmaco-/toxicokinetics and postmortem redistribution when analyzed in combination with drug concentrations at other sites. PMID:27185819

  4. [Kanamycin concentrations in liver tissue and bile in acute experimental cholecystocholangiohepatitis].

    PubMed

    Alekseenko, A V; Iftodiĭ, A G; Seniutovich, R V; Sidorchuk, I I; Palianina, S I

    1984-11-01

    The levels of kanamycin in the bile and liver tissue were studied on 10 healthy dogs and 10 dogs with experimental acute abacterial cholecystocholangiohepatitis. It was shown that bile excretion of kanamycin in the dogs increased 6-7 times with development of acute inflammation in the biliary system. PMID:6395793

  5. [Chemico-physical property and bile acid binding capacity of several antacids].

    PubMed

    Salvioli, G; Tambara, E; Gaetti, E; Lugli, R

    1989-01-01

    Liquid alginate (Gaviscon) binds small amount of bile acids. At pH 7 its viscosity (at low shear rate) is higher than that of other antiacids. High viscosity reduces the diffusion rate of bile salts and glucose and this property can play a role in the treatment of gastro-esophageal and duodeno-gastric refluxes. PMID:2548124

  6. Simple steatosis sensitizes cholestatic rats to liver injury and dysregulates bile salt synthesis and transport

    PubMed Central

    Lionarons, Daniël A.; Heger, Michal; van Golen, Rowan F.; Alles, Lindy K.; van der Mark, Vincent A.; Kloek, Jaap J.; de Waart, Dirk R.; Marsman, Hendrik A.; Rusch, Henny; Verheij, Joanne; Beuers, Ulrich; Paulusma, Coen C.; van Gulik, Thomas M.

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. It is uncertain if simple steatosis, the initial and prevailing form of NAFLD, sensitizes the liver to cholestasis. Here, we compared the effects of obstructive cholestasis in rats with a normal liver versus rats with simple steatosis induced by a methionine/choline-deficient diet. We found that plasma liver enzymes were higher and hepatic neutrophil influx, inflammation, and fibrosis were more pronounced in animals with combined steatosis and cholestasis compared to cholestasis alone. Circulating bile salt levels were markedly increased and hepatic bile salt composition shifted from hydrophilic tauro-β-muricholate to hydrophobic taurocholate. This shift was cytotoxic for HepG2 hepatoma cells. Gene expression analysis revealed induction of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1), and modulation of the hepatic bile salt transport system. In conclusion, simple steatosis sensitizes the liver to cholestatic injury, inflammation, and fibrosis in part due to a cytotoxic shift in bile salt composition. Plasma bile salt levels were elevated, linked to dysregulation of bile salt synthesis and enhanced trafficking of bile salts from the liver to the systemic circulation. PMID:27535001

  7. Protective effects of nonionic tri-block copolymers on bile acid-mediated epithelial barrier disruption.

    SciTech Connect

    Edelstein, A.; Fink, D.; Musch, M.; Valuckaite, V.; Zabornia, O.; Grubjesic, S.; Firestone, M. A.; Matthews, J. B.; Alverdy, J. C.

    2011-11-01

    Translocation of bacteria and other luminal factors from the intestine following surgical injury can be a major driver of critical illness. Bile acids have been shown to play a key role in the loss of intestinal epithelial barrier function during states of host stress. Experiments to study the ability of nonionic block copolymers to abrogate barrier failure in response to bile acid exposure are described. In vitro experiments were performed with the bile salt sodium deoxycholate on Caco-2 enterocyte monolayers using transepithelial electrical resistance to assay barrier function. A bisphenol A coupled triblock polyethylene glycol (PEG), PEG 15-20, was shown to prevent sodium deoxycholate-induced barrier failure. Enzyme-linked immunosorbent assay, lactate dehydrogenase, and caspase 3-based cell death detection assays demonstrated that bile acid-induced apoptosis and necrosis were prevented with PEG 15-20. Immunofluorescence microscopic visualization of the tight junctional protein zonula occludens 1 (ZO-1) demonstrated that PEG 15-20 prevented significant changes in tight junction organization induced by bile acid exposure. Preliminary transepithelial electrical resistance-based studies examining structure-function correlates of polymer protection against bile acid damage were performed with a small library of PEG-based copolymers. Polymer properties associated with optimal protection against bile acid-induced barrier disruption were PEG-based compounds with a molecular weight greater than 10 kd and amphiphilicity. The data demonstrate that PEG-based copolymer architecture is an important determinant that confers protection against bile acid injury of intestinal epithelia.

  8. Apoptosis mechanism of human cholangiocarcinoma cells induced by bile extract from crocodile.

    PubMed

    Kang, Jin-He; Zhang, Wen-Qing; Song, Wei; Shen, Dong-Yan; Li, Shan-Shan; Tian, Ling; Shi, Yan; Liang, Ge; Xiong, You-Xiong; Chen, Qing-Xi

    2012-02-01

    Animal bile is popularly used as a traditional medicine in China, and bile acids are their major bioactive constituents. In the present study, effects of bile extract from crocodile gallbladder on QBC939 cell growth, cell cycle, and apoptosis were investigated by MTT assay, inverted microscopy, fluorescence microscopy, transmission electron microscopy, scanning electron microscopy, PI single- and FITC/PI double-staining flow cytometry, and western blotting. Our data have revealed that bile extract inhibited cells growth significantly, and the cell cycle was arrested in G1 phase. Bile extract induced QBC939 cell apoptosis, which was associated with collapse of the mitochondrial membrane potential and increase of ROS. In bile extract-treated cells, it was observed that the expression of bcl-2 decreased and cytochrome c released to cytosol, but the expression of bax remained unchanged. The data indicated that mitochondrial pathway might play an important role in bile extract-induced apoptosis in QBC939 cells. These results provide significant insight into the anticarcinogenic action of bile extract on cholangiocarcinoma cells. PMID:22194052

  9. Percutaneous Transhepatic Biliary Drainage in the Management of Postsurgical Biliary Leaks in Patients with Nondilated Intrahepatic Bile Ducts

    SciTech Connect

    Cozzi, Guido Severini, Aldo; Civelli, Enrico; Milella, Marco; Pulvirenti, Andrea; Salvetti, Monica; Romito, Raffaele; Suman, Laura; Chiaraviglio, Francesca; Mazzaferro, Vincenzo

    2006-06-15

    Purpose. To assess the feasibility of percutaneous transhepatic biliary drainage (PTBD) for the treatment of postsurgical biliary leaks in patients with nondilated intrahepatic bile ducts, its efficacy in restoring the integrity of bile ducts, and technical procedures to reduce morbidity. Methods. Seventeen patients out of 936 undergoing PTBD over a 20-year period had a noncholestatic liver and were retrospectively reviewed. All patients underwent surgery for cancer and suffered a postsurgical biliary leak of 345 ml/day on average; 71% were in poor condition and required permanent nutritional support. An endoscopic approach failed or was excluded due to inaccessibility of the bile ducts. Results. Established biliary leaks and site of origin were diagnosed an average of 21 days (range 1-90 days) after surgery. In all cases percutaneous access to the biliary tree was achieved. An external (preleakage) drain was applied in 7 cases, 9 patients had an external-internal fistula bridging catheter, and 1 patient had a percutaneous hepatogastrostomy. Fistulas healed in an average of 31 days (range 3-118 days ) in 15 of 17 patients (88%) following PTBD. No major complications occurred after drainage. Post-PTBD cholangitis was observed in 6 of 17 patients (35%) and was related to biliary sludge formation occurring mostly when drainage lasted >30 days and was of the external-internal type. Median patient survival was 17.7 months and in all cases the repaired biliary leaks remained healed. Conclusions. PTBD is a feasible, effective, and safe procedure for the treatment of postsurgical biliary leaks. It is therefore a reliable alternative to surgical repair, which entails longer hospitalization and higher costs.

  10. Defense of mammalian body against heavy metal-induced toxicities: Sequestration by the choroid plexus and elimination via the bile

    SciTech Connect

    Zheng Wei.

    1991-01-01

    Tissue sequestration and biliary elimination are two of the important mechanisms by which mammalian body defends against heavy metal insults. In rats or rabbits that had received Pb, Cd, Hg, As and [sup 210]Po, these metal ions were sequestered in the choroid plexus at concentrations of Pb, Cd, Hg, As and Po that were 57, 33, 12, 13 and 5 times higher, respectively, than those found in the brain cortex. In addition, the concentrations of these heavy metal ions were many fold greater in the choroid plexus than in the CSF or blood. The accumulation of Pb in the choroid plexus was dose-dependent and time-related. When the choroid plexus was incubated, in vitro, with ouabain, the latter significantly inhibited the uptake of Cd from the CSF side of the choroid plexus. Cystine concentration was four times greater in the choroid plexus than in brain cortex. Results suggest that the choroid plexus sequesters toxic metal and metalloid ions. It appears to do this in order to protect the CSF and brain from toxic heavy metals in the blood. The effects of N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA), meso-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-1-propane sulfonic acid (DMPS) on biliary excretion of Cd was studied in rat chronic intoxication mode. DMPA (0.10 mmol/kg, iv), when given to rats three days after exposure to Cd, elicited within 30 min a 20-fold increase in biliary Cd excretion. GSH in rat bile was also increased three fold as compared to control. Neither DMSA nor DMPS increased biliary Cd or GSH. Upon iv administration, DMPA, not DMSA, appeared in bile. An altered, presumably disulfide, form of DMPS was also found in bile. Incubation of DMPA or DMSA with Cd-saturated MT resulted in the removal of Cd from MT. DMPS, however, promoted the formation of MT polymers. DMPA protected biliary GSH from autoxidation.

  11. Therapeutic uses of animal biles in traditional Chinese medicine: an ethnopharmacological, biophysical chemical and medicinal review.

    PubMed

    Wang, David Q-H; Carey, Martin C

    2014-08-01

    Forty-four different animal biles obtained from both invertebrates and vertebrates (including human bile) have been used for centuries for a host of maladies in traditional Chinese medicine (TCM) beginning with dog, ox and common carp biles approximately in the Zhou dynasty (c. 1046-256 BCE). Overall, different animal biles were prescribed principally for the treatment of liver, biliary, skin (including burns), gynecological and heart diseases, as well as diseases of the eyes, ears, nose, mouth and throat. We present an informed opinion of the clinical efficacy of the medicinal uses of the different animal biles based on their presently known principal chemical components which are mostly steroidal detergent-like molecules and the membrane lipids such as unesterified cholesterol and mixed phosphatidylcholines and sometimes sphingomyelin, as well as containing lipopigments derived from heme principally bilirubin glucuronides. All of the available information on the ethnopharmacological uses of biles in TCM were collated from the rich collection of ancient Chinese books on materia medica held in libraries in China and United States and the composition of various animal biles was based on rigorous separatory and advanced chemical identification techniques published since the mid-20(th) century collected via library (Harvard's Countway Library) and electronic searches (PubMed and Google Scholar). Our analysis of ethnomedical data and information on biliary chemistry shows that specific bile salts, as well as the common bile pigment bilirubin and its glucuronides plus the minor components of bile such as vitamins A, D, E, K, as well as melatonin (N-acetyl-5-methoxytryptamine) are salutary in improving liver function, dissolving gallstones, inhibiting bacterial and viral multiplication, promoting cardiac chronotropsim, as well as exhibiting anti-inflammatory, anti-pyretic, anti-oxidant, sedative, anti-convulsive, anti-allergic, anti-congestive, anti-diabetic and anti

  12. Therapeutic uses of animal biles in traditional Chinese medicine: An ethnopharmacological, biophysical chemical and medicinal review

    PubMed Central

    Wang, David Q-H; Carey, Martin C

    2014-01-01

    Forty-four different animal biles obtained from both invertebrates and vertebrates (including human bile) have been used for centuries for a host of maladies in traditional Chinese medicine (TCM) beginning with dog, ox and common carp biles approximately in the Zhou dynasty (c. 1046-256 BCE). Overall, different animal biles were prescribed principally for the treatment of liver, biliary, skin (including burns), gynecological and heart diseases, as well as diseases of the eyes, ears, nose, mouth and throat. We present an informed opinion of the clinical efficacy of the medicinal uses of the different animal biles based on their presently known principal chemical components which are mostly steroidal detergent-like molecules and the membrane lipids such as unesterified cholesterol and mixed phosphatidylcholines and sometimes sphingomyelin, as well as containing lipopigments derived from heme principally bilirubin glucuronides. All of the available information on the ethnopharmacological uses of biles in TCM were collated from the rich collection of ancient Chinese books on materia medica held in libraries in China and United States and the composition of various animal biles was based on rigorous separatory and advanced chemical identification techniques published since the mid-20th century collected via library (Harvard’s Countway Library) and electronic searches (PubMed and Google Scholar). Our analysis of ethnomedical data and information on biliary chemistry shows that specific bile salts, as well as the common bile pigment bilirubin and its glucuronides plus the minor components of bile such as vitamins A, D, E, K, as well as melatonin (N-acetyl-5-methoxytryptamine) are salutary in improving liver function, dissolving gallstones, inhibiting bacterial and viral multiplication, promoting cardiac chronotropsim, as well as exhibiting anti-inflammatory, anti-pyretic, anti-oxidant, sedative, anti-convulsive, anti-allergic, anti-congestive, anti-diabetic and anti

  13. Clinical application of transcriptional activators of bile salt transporters☆

    PubMed Central

    Baghdasaryan, Anna; Chiba, Peter; Trauner, Michael

    2014-01-01

    Hepatobiliary bile salt (BS) transporters are critical determinants of BS homeostasis controlling intracellular concentrations of BSs and their enterohepatic circulation. Genetic or acquired dysfunction of specific transport systems causes intrahepatic and systemic retention of potentially cytotoxic BSs, which, in high concentrations, may disturb integrity of cell membranes and subcellular organelles resulting in cell death, inflammation and fibrosis. Transcriptional regulation of canalicular BS efflux through bile salt export pump (BSEP), basolateral elimination through organic solute transporters alpha and beta (OSTα/OSTβ) as well as inhibition of hepatocellular BS uptake through basolateral Na+-taurocholate cotransporting polypeptide (NTCP) represent critical steps in protection from hepatocellular BS overload and can be targeted therapeutically. In this article, we review the potential clinical implications of the major BS transporters BSEP, OSTα/OSTβ and NTCP in the pathogenesis of hereditary and acquired cholestatic syndromes, provide an overview on transcriptional control of these transporters by the key regulatory nuclear receptors and discuss the potential therapeutic role of novel transcriptional activators of BS transporters in cholestasis. PMID:24333169

  14. Hyperspectral image segmentation of the common bile duct

    NASA Astrophysics Data System (ADS)

    Samarov, Daniel; Wehner, Eleanor; Schwarz, Roderich; Zuzak, Karel; Livingston, Edward

    2013-03-01

    Over the course of the last several years hyperspectral imaging (HSI) has seen increased usage in biomedicine. Within the medical field in particular HSI has been recognized as having the potential to make an immediate impact by reducing the risks and complications associated with laparotomies (surgical procedures involving large incisions into the abdominal wall) and related procedures. There are several ongoing studies focused on such applications. Hyperspectral images were acquired during pancreatoduodenectomies (commonly referred to as Whipple procedures), a surgical procedure done to remove cancerous tumors involving the pancreas and gallbladder. As a result of the complexity of the local anatomy, identifying where the common bile duct (CBD) is can be difficult, resulting in comparatively high incidents of injury to the CBD and associated complications. It is here that HSI has the potential to help reduce the risk of such events from happening. Because the bile contained within the CBD exhibits a unique spectral signature, we are able to utilize HSI segmentation algorithms to help in identifying where the CBD is. In the work presented here we discuss approaches to this segmentation problem and present the results.

  15. Suppression of Autophagic Flux by Bile Acids in Hepatocytes

    PubMed Central

    Kong, Bo; Guo, Grace; Ding, Wen-Xing

    2014-01-01

    Retention of bile acids (BAs) in the liver during cholestasis plays an important role in the development of cholestatic liver injury. Several studies have reported that high concentrations of certain BAs induce cell death and inflammatory response in the liver, and BAs may promote liver tumorigenesis. Macroautophagy (hereafter referred to as autophagy) is a lysosomal degradation process that regulates organelle and protein homeostasis and serves as a cell survival mechanism under a variety of stress conditions. However, it is not known if BAs modulate autophagy in hepatocytes. In the present study, we determined autophagic flux in livers of farnesoid X receptor (FXR) knockout (KO) mice that have increased concentrations of hepatic BAs and in primary cultured mouse hepatocytes treated with BAs. The results showed that autophagic flux was impaired in livers of FXR KO mice and in BA-treated primary mouse hepatocytes. Mechanistically, BAs did not affect the activities of cathepsin or the proteasome, but impaired autophagosomal-lysosomal fusion likely due to reduction of Rab7 protein expression and targeting to autophagosomes. In conclusion, BAs suppress autophagic flux in hepatocytes by impairing autophagosomal-lysosomal fusion, which may be implicated in bile acid-induced liver tumor promotion observed in FXR KO mice. PMID:24189133

  16. Liquid crystal based biosensors for bile acid detection

    NASA Astrophysics Data System (ADS)

    He, Sihui; Liang, Wenlang; Tanner, Colleen; Fang, Jiyu; Wu, Shin-Tson

    2013-03-01

    The concentration level of bile acids is a useful indicator for early diagnosis of liver diseases. The prevalent measurement method in detecting bile acids is the chromatography coupled with mass spectrometry, which is precise yet expensive. Here we present a biosensor platform based on liquid crystal (LC) films for the detection of cholic acid (CA). This platform has the advantage of low cost, label-free, solution phase detection and simple analysis. In this platform, LC film of 4-Cyano-4'-pentylbiphenyl (5CB) was hosted by a copper grid supported with a polyimide-coated glass substrate. By immersing into sodium dodecyl sulfate (SDS) solution, the LC film was coated with SDS which induced a homeotropic anchoring of 5CB. Addition of CA introduced competitive adsorption between CA and SDS at the interface, triggering a transition from homeotropic to homogeneous anchoring. The detection limit can be tuned by changing the pH value of the solution from 12uM to 170uM.

  17. Mechanisms of triglyceride metabolism in patients with bile acid diarrhea.

    PubMed

    Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

    2016-08-14

    Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment. PMID:27570415

  18. Mechanisms of triglyceride metabolism in patients with bile acid diarrhea

    PubMed Central

    Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

    2016-01-01

    Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment. PMID:27570415

  19. Bile Acid Alters Male Mouse Fertility in Metabolic Syndrome Context

    PubMed Central

    Baptissart, Marine; De Haze, Angélique; Vaz, Frederic; Kulik, Wim; Damon-Soubeyrand, Christelle; Baron, Silvère; Caira, Françoise; Volle, David H.

    2015-01-01

    Bile acids have recently been demonstrated as molecules with endocrine activities controlling several physiological functions such as immunity and glucose homeostases. They act mainly through two receptors, the nuclear receptor Farnesol-X-Receptor alpha (FXRα) and the G-protein coupled receptor (TGR5). These recent studies have led to the idea that molecules derived from bile acids (BAs) and targeting their receptors must be good targets for treatment of metabolic diseases such as obesity or diabetes. Thus it might be important to decipher the potential long term impact of such treatment on different physiological functions. Indeed, BAs have recently been demonstrated to alter male fertility. Here we demonstrate that in mice with overweight induced by high fat diet, BA exposure leads to increased rate of male infertility. This is associated with the altered germ cell proliferation, default of testicular endocrine function and abnormalities in cell-cell interaction within the seminiferous epithelium. Even if the identification of the exact molecular mechanisms will need more studies, the present results suggest that both FXRα and TGR5 might be involved. We believed that this work is of particular interest regarding the potential consequences on future approaches for the treatment of metabolic diseases. PMID:26439743

  20. Inflammatory bowel disease alters intestinal bile acid transporter expression.

    PubMed

    Jahnel, Jörg; Fickert, Peter; Hauer, Almuthe C; Högenauer, Christoph; Avian, Alexander; Trauner, Michael

    2014-09-01

    The enterohepatic circulation of bile acids (BAs) critically depends on absorption of BA in the terminal ileum and colon, which can be affected by inflammatory bowel disease (IBD). Diarrhea in IBD is believed to result in part from BA malabsorption (BAM). We explored whether IBD alters mRNA expression of key intestinal BA transporters, BA detoxifying systems, and nuclear receptors that regulate BA transport and detoxification. Using real-time polymerase chain reaction, mucosal biopsy specimens from the terminal ileum in Crohn's disease (CD) patients and from the descending colon in ulcerative colitis (UC) patients were assessed for mRNA expression. Levels were compared with healthy controls. The main ileal BA uptake transporter, the apical sodium dependent bile acid transporter, was downregulated in active CD and UC and in CD in remission. Other significant changes such as repression of breast cancer-related protein and sulphotransferase 2A1 were seen only during active disease. In UC, pancolitis (but not exclusively left-sided colitis) was associated with altered expression of major BA transporters [multidrug resistance-associated protein 3 (MRP3), MRP4, multidrug resistance gene 1, organic solute transporter α/β] and nuclear receptors (pregnane X receptor, vitamin D receptor) in the descending colon. UC pancolitis leads to broad changes and CD ileitis to selective changes in intestinal BA transporter expression. Early medical manipulation of intestinal BA transporters may help prevent BAM. PMID:24965812

  1. Microbial Biotransformations of Bile Acids as Detected by Electrospray Mass Spectrometry123

    PubMed Central

    Hagey, Lee R.; Krasowski, Matthew D.

    2013-01-01

    Many current experiments investigating the effects of diet, dietary supplements, and pre- and probiotics on the intestinal environments do not take into consideration the potential for using bile salts as markers of environmental change. Intestinal bacteria in vertebrates can metabolize bile acids into a number of different structures, with deamidation, hydroxyl group oxidation, and hydroxyl group elimination. Fecal bile acids are readily available to sample and contain a considerable structural complexity that directly relates to intestinal morphology, bile acid residence time in the intestine, and the species of microbial forms in the intestinal tract. Here we offer a classification scheme that can serve as an initial guide to interpret the different bile acid patterns expressed in vertebrate feces. PMID:23319120

  2. Faecal bile acids are natural ligands of the mouse accessory olfactory system.

    PubMed

    Doyle, Wayne I; Dinser, Jordan A; Cansler, Hillary L; Zhang, Xingjian; Dinh, Daniel D; Browder, Natasha S; Riddington, Ian M; Meeks, Julian P

    2016-01-01

    The accessory olfactory system (AOS) guides behaviours that are important for survival and reproduction, but understanding of AOS function is limited by a lack of identified natural ligands. Here we report that mouse faeces are a robust source of AOS chemosignals and identify bile acids as a class of natural AOS ligands. Single-unit electrophysiological recordings from accessory olfactory bulb neurons in ex vivo preparations show that AOS neurons are strongly and selectively activated by peripheral stimulation with mouse faecal extracts. Faecal extracts contain several unconjugated bile acids that cause concentration-dependent neuronal activity in the AOS. Many AOS neurons respond selectively to bile acids that are variably excreted in male and female mouse faeces, and others respond to bile acids absent in mouse faeces. These results identify faeces as a natural source of AOS information, and suggest that bile acids may be mammalian pheromones and kairomones. PMID:27324439

  3. Mechanism of bile acid-regulated glucose and lipid metabolism in duodenal-jejunal bypass

    PubMed Central

    Chai, Jie; Zou, Lei; Li, Xirui; Han, Dali; Wang, Shan; Hu, Sanyuan; Guan, Jie

    2015-01-01

    Bile acid plays an important role in regulating blood glucose, lipid and energy metabolism. The present study was implemented to determine the effect of duodenal-jejunal bypass (DJB) on FXR, TGR-5expression in terminal ileum and its bile acid-related mechanism on glucose and lipid metabolism. Immunohistochemistry was used to detect relative gene or protein expression in liver and intestine. Firstly, we found that expression of FXR in liver and terminal ileum of DJB group was significantly higher than that in S-DJB group (P<0.05). In addition, DJB dramatically increased the activation of TGR-5 in the liver of rats. Furthermore, PEPCK, G6Pase, FBPase 1 and GLP-1 were up-regulated by DJB. In conclusion, these results showed that bile acid ameliorated glucose and lipid metabolism through bile acid-FXR and bile acid- TGR-5 signaling pathway. PMID:26884847

  4. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism.

    PubMed

    Wahlström, Annika; Sayin, Sama I; Marschall, Hanns-Ulrich; Bäckhed, Fredrik

    2016-07-12

    The gut microbiota is considered a metabolic "organ" that not only facilitates harvesting of nutrients and energy from the ingested food but also produces numerous metabolites that signal through their cognate receptors to regulate host metabolism. One such class of metabolites, bile acids, is produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. These bioconversions modulate the signaling properties of bile acids via the nuclear farnesoid X receptor and the G protein-coupled membrane receptor 5, which regulate numerous metabolic pathways in the host. Conversely, bile acids can modulate gut microbial composition both directly and indirectly through activation of innate immune genes in the small intestine. Thus, host metabolism can be affected through microbial modifications of bile acids, which lead to altered signaling via bile acid receptors, but also by altered microbiota composition. PMID:27320064

  5. Bile cast nephropathy: A case report and review of the literature

    PubMed Central

    Patel, Jaymon; Walayat, Saqib; Kalva, Nikhil; Palmer-Hill, Sidney; Dhillon, Sonu

    2016-01-01

    Bile cast nephropathy is a condition of renal dysfunction in the setting of hyperbilirubinemia. There are very few cases of this condition reported in the last decade and a lack of established treatment guidelines. While the exact etiology remains unknown, bile cast nephropathy is presumed to be secondary to multiple concurrent insults to the kidney including direct toxicity from bile acids, obstructive physiology from bile casts, and systemic hypoperfusion from vasodilation. Therapy directed at bilirubin reduction may improve renal function, but will likely need dialysis or plasmapheresis as well. We report our case of bile cast nephropathy and the therapeutic measures undertaken in a middle-aged male with chronic renal insufficiency that developed hyperbilirubinemia and drug-induced liver injury secondary to antibiotic use. He developed acute renal injury in the setting of rising bilirubin. He subsequently had a progressive decline in renal and hepatic function, requiring dialysis and plasmapheresis with some improvement, ultimately requiring transplantation. PMID:27468221

  6. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.

    PubMed

    Huang, Wendong; Ma, Ke; Zhang, Jun; Qatanani, Mohammed; Cuvillier, James; Liu, Jun; Dong, Bingning; Huang, Xiongfei; Moore, David D

    2006-04-14

    Liver mass depends on one or more unidentified humoral signals that drive regeneration when liver functional capacity is diminished. Bile acids are important liver products, and their levels are tightly regulated. Here, we identify a role for nuclear receptor-dependent bile acid signaling in normal liver regeneration. Elevated bile acid levels accelerate regeneration, and decreased levels inhibit liver regrowth, as does the absence of the primary nuclear bile acid receptor FXR. We propose that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver. FXR, and possibly other nuclear receptors, may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth. PMID:16614213

  7. Ultrasonographic assessment of gallbladder bile exchanges in healthy subjects and in gallstone patients.

    PubMed

    Cicala, M; Guarino, M P; Vavassori, P; Alloni, R; Emerenziani, S; Arullani, A; Pallone, F

    2001-11-01

    Impaired gallbladder motility may contribute to gallstone pathogenesis by providing time for nucleation and aggregation of cholesterol crystals. Simultaneous scintigraphic-ultrasonographic techniques have been proposed to assess alternating phases of gallbladder emptying and filling. To evaluate patterns of gallbladder motility and of postprandial bile flow by means of a single ultrasonographic technique, 12 healthy volunteers and 20 gallstone patients underwent minute-by-minute gallbladder ultrasonography for 3 h postprandially. Mathematical analysis of volume measurements was used to estimate hepatic and cholecystic bile flux through the gallbladder. Compared to controls, gallstone patients showed greater amounts of unexchanged cholecystic-to-hepatic bile (11% vs. 1%, p <.001) and most of them showed impaired gallbladder washout efficacy. Utrasonographic values of bile exchanges were similar to those derived from scintigraphic-sonographic studies in comparable groups of subjects. This study provides new ultrasonographic variables, which better express gallbladder bile retention in gallstone patients and strongly discriminate gallstone patients from controls. PMID:11750742

  8. Bile cast nephropathy: A case report and review of the literature.

    PubMed

    Patel, Jaymon; Walayat, Saqib; Kalva, Nikhil; Palmer-Hill, Sidney; Dhillon, Sonu

    2016-07-21

    Bile cast nephropathy is a condition of renal dysfunction in the setting of hyperbilirubinemia. There are very few cases of this condition reported in the last decade and a lack of established treatment guidelines. While the exact etiology remains unknown, bile cast nephropathy is presumed to be secondary to multiple concurrent insults to the kidney including direct toxicity from bile acids, obstructive physiology from bile casts, and systemic hypoperfusion from vasodilation. Therapy directed at bilirubin reduction may improve renal function, but will likely need dialysis or plasmapheresis as well. We report our case of bile cast nephropathy and the therapeutic measures undertaken in a middle-aged male with chronic renal insufficiency that developed hyperbilirubinemia and drug-induced liver injury secondary to antibiotic use. He developed acute renal injury in the setting of rising bilirubin. He subsequently had a progressive decline in renal and hepatic function, requiring dialysis and plasmapheresis with some improvement, ultimately requiring transplantation. PMID:27468221

  9. Faecal bile acids are natural ligands of the mouse accessory olfactory system

    PubMed Central

    Doyle, Wayne I.; Dinser, Jordan A.; Cansler, Hillary L.; Zhang, Xingjian; Dinh, Daniel D.; Browder, Natasha S.; Riddington, Ian M.; Meeks, Julian P.

    2016-01-01

    The accessory olfactory system (AOS) guides behaviours that are important for survival and reproduction, but understanding of AOS function is limited by a lack of identified natural ligands. Here we report that mouse faeces are a robust source of AOS chemosignals and identify bile acids as a class of natural AOS ligands. Single-unit electrophysiological recordings from accessory olfactory bulb neurons in ex vivo preparations show that AOS neurons are strongly and selectively activated by peripheral stimulation with mouse faecal extracts. Faecal extracts contain several unconjugated bile acids that cause concentration-dependent neuronal activity in the AOS. Many AOS neurons respond selectively to bile acids that are variably excreted in male and female mouse faeces, and others respond to bile acids absent in mouse faeces. These results identify faeces as a natural source of AOS information, and suggest that bile acids may be mammalian pheromones and kairomones. PMID:27324439

  10. Excretion of 14C-edrophonium and its metabolites in bile

    PubMed Central

    Back, D. J.; Calvey, T. N.

    1972-01-01

    1. The metabolism and biliary excretion of 14C-edrophonium chloride was studied in Wistar rat. 2. Approximately 5% of the dose was recovered from bile in 6 hours. Most of the radioactivity was eliminated as 14C-edrophonium glucuronide. Small amounts of the unchanged drug were also detected in bile, particularly during the first hour after administration of the drug. 3. The concentration of 14C-edrophonium glucuronide in bile was approximately 15-20 times its concentration in plasma. 4. In contrast, the concentration of unchanged 14C-edrophonium was similar in bile and plasma. 5. Evidence is presented that unchanged 14C-edrophonium is transferred from plasma to bile via the peribiliary vascular plexus. PMID:5040663

  11. Bile Diversion in Roux-en-Y Gastric Bypass Modulates Sodium-Dependent Glucose Intestinal Uptake.

    PubMed

    Baud, Gregory; Daoudi, Mehdi; Hubert, Thomas; Raverdy, Violeta; Pigeyre, Marie; Hervieux, Erik; Devienne, Magalie; Ghunaim, Mohamed; Bonner, Caroline; Quenon, Audrey; Pigny, Pascal; Klein, André; Kerr-Conte, Julie; Gmyr, Valery; Caiazzo, Robert; Pattou, François

    2016-03-01

    Gastro-intestinal exclusion by Roux-en-Y gastric bypass (RYGB) improves glucose metabolism, independent of weight loss. Although changes in intestinal bile trafficking have been shown to play a role, the underlying mechanisms are unclear. We performed RYGB in minipigs and showed that the intestinal uptake of ingested glucose is blunted in the bile-deprived alimentary limb (AL). Glucose uptake in the AL was restored by the addition of bile, and this effect was abolished when active glucose intestinal transport was blocked with phlorizin. Sodium-glucose cotransporter 1 remained expressed in the AL, while intraluminal sodium content was markedly decreased. Adding sodium to the AL had the same effect as bile on glucose uptake. It also increased postprandial blood glucose response in conscious minipigs following RYGB. The decrease in intestinal uptake of glucose after RYGB was confirmed in humans. Our results demonstrate that bile diversion affects postprandial glucose metabolism by modulating sodium-glucose intestinal cotransport. PMID:26924216

  12. The Effects of Boron Derivatives on Lipid Absorption from the Intestine and on Bile Lipids and Bile Acids of Sprague Dawley Rats

    PubMed Central

    Hall, Iris H.; Reynolds, David J.; Wong, O. T.; Sood, A.; Spielvogel, B. F.

    1995-01-01

    N,N-dimethyl-n-octadecylamine borane 1 at 8 mg/kg/day, tetrakis-u-(trimethylamine boranecarboxylato)-bis(trimethyl-carboxyborane)-dicopper(II) 2 at 2.5 mg/kg/day and trimethylamine-carboxyborane 3 at 8 mg/kg/day were evaluated for their effects on bile lipids, bile acids, small intestinal absorption of cholesterol and cholic acid and liver and small intestinal enzyme activities involved in lipid metabolism. The agent administered orally elevated rat bile excretion of lipids, e.g. cholesterol and phospholipids, and compounds 2 and 3 increased the bile flow rate. These agents altered the composition of the bile acids, but there was no significant increase in lithocholic acid which is most lithogenic agent in rats. The three agents did decrease cholesterol absorption from isolated in situ intestinal duodenum loops in the presence of drug. Hepatic and small intestinal mucosa enzyme activities, e.g. ATP-dependent citrate lyase, acyl CoA cholesterol acyl transferase, cholsterol-7-α -hydroxylase, sn glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase, and lipoprotein lipase, were reduced. However, the boron derivatives 1 and 3 decreased hepatic HMG-CoA reductase activity, the regulatory enzyme for cholesterol synthesis, but the compounds had no effects on small intestinal mucosa HMG-CoA reductase activity. There was no evidence of hepatic cell damage afforded by the drugs based on clinical chemistry values which would induce alterations in bile acid concentrations after treatment of the rat. PMID:18472747

  13. Steam Cooking Significantly Improves in Vitro Bile Acid Binding of Beets, Eggplant, Asparagus, Carrots, Green Beans and Cauliflower

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The relative healthful potential of cooked beets, okra, eggplant, asparagus, carrots, green beans, cauliflower and turnips was evaluated by determining their in vitro bile acid binding using a mixture of bile acids secreted in human bile at a duodenal physiological pH of 6.3. Six treatments and two...

  14. Profiling of urinary bile acids in piglets by a combination of enzymatic deconjugation and targeted LC-MRM-MS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bile acids (BAs) have an important role in the control of fat, glucose and cholesterol metabolism. Synthesis of bile acids is the major pathway for the metabolism of cholesterol and for the excretion of excess cholesterol in mammals. Bile acid intermediates and/or their metabolites are excreted in...

  15. Health promoting potential of cereals, grain fractions and beans as determined by their in vitro bile acid binding

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Health promoting potential (Cholesterol lowering and cancer risk reduction) of foods have been determined by in-vitro bile acid binding under physiological conditions. Lowered bile acids result in reduced fat absorption, conversion of cholesterol to bile acids and reduced cancer causing secondary b...

  16. N-acetylglucosaminides. A new type of bile acid conjugate in man.

    PubMed

    Marschall, H U; Egestad, B; Matern, H; Matern, S; Sjövall, J

    1989-08-01

    Bile acids were extracted from human urine and were separated into groups of nonamidated and glycine- and taurine-conjugated compounds. Each group was subfractionated in a reversed-phase high performance liquid chromatography system, and the fractions were analyzed by negative ion fast atom bombardment mass spectrometry and also by gas chromatography-mass spectrometry after enzymatic removal of glycine and taurine moieties. The major glycosides of the non-amidated bile acids were more polar than reference bile acid glucosides and gave quasimolecular ions at m/z 592, 594, and 610 consistent with N-acetylglucosaminides of unsaturated dihydroxy and saturated di- and trihydroxy bile acids. Gas chromatography-mass spectrometry analyses of methyl ester trimethylsilyl ether derivatives showed fragments typical for N-acetylglucosaminides (m/z 173 and 186) in addition to those also given by glucosides (m/z 204 and 217). The N-acetylglucosaminides were inert toward alpha- and beta-glucosidase but were cleaved completely with N-acetylglucosaminidase. The released sugar moiety was identified as N-acetylglucosamine. One of the liberated bile acids was identified as ursodeoxycholic acid. The other acids were not identical to any known primary or secondary bile acid in humans. Fast atom bombardment mass spectrometry analyses of the glycine-and taurine-conjugated bile acid glycosides only showed ions consistent with the presence of glucosides (m/z 626 and 676). These compounds were sensitive only toward beta-glucosidase which liberated a trihydroxy bile acid as the major compound. Based on the recover of 13C- and 14C-labeled chenodeoxycholic acid glucoside added as internal standard, the daily excretion of nonamidated bile acid glycosides was estimated to be about 137 micrograms or 0.29 mumol, N-acetylglucosaminides constituting about 90%. The daily excretion of the glucosides of amidated bile acids was about 150 micrograms or 0.25 mumol, glycine conjugates constituting about 90

  17. Triketocholanoic (Dehydrocholic) Acid. HEPATIC METABOLISM AND EFFECT ON BILE FLOW AND BILIARY LIPID SECRETION IN MAN

    PubMed Central

    Soloway, Roger D.; Hofmann, Alan F.; Thomas, Paul J.; Schoenfield, Leslie J.; Klein, Peter D.

    1973-01-01

    [24-14C]Dehydrocholic acid (triketo-5-β-cholanoic acid) was synthesized from [24-14C]cholic acid, mixed with 200 mg of carrier, and administered intravenously to two patients with indwelling T tubes designed to permit bile sampling without interruption of the enterohepatic circulation. More than 80% of infused radioactivity was excreted rapidly in bile as glycine- and taurine-conjugated bile acids. Radioactive products were identified, after deconjugation, as partially or completely reduced derivatives of dehydrocholic acid. By mass spectrometry, as well as chromatography, the major metabolite (about 70%) was a dihydroxy monoketo bile acid (3α,7α-dihydroxy-12-keto-5β-cholanoic acid); a second metabolite (about 20%) was a monohydroxy diketo acid (3α-hydroxy-7,12-di-keto-5β-cholanoic acid); and about 10% of radioactivity was present as cholic acid. Reduction appeared to have been sequential (3 position, then 7 position, and then 12 position) and stereospecific (only α epimers were recovered). Bile flow, expressed as the ratio of bile flow to bile acid excretion, was increased after dehydrocholic acid administration. It was speculated that the hydroxy keto metabolites are hydrocholeretics. The proportion of cholesterol to lecithin and bile acids did not change significantly after dehydrocholic acid administration. In vitro studies showed that the hydroxy keto metabolites dispersed lecithin poorly compared to cholate; however, mixtures of cholate and either metabolite had dispersant properties similar to those of cholate alone, provided the ratio of metabolite to cholate remained below a value characteristic for each metabolite. These experiments disclose a new metabolic pathway in man, provide further insight into the hydrocholeresis induced by keto bile acids, and indicate the striking change in pharmacologic and physical properties caused by replacement of hydroxyl by a keto substituent in the bile acid molecule. Images PMID:4685091

  18. Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice

    PubMed Central

    Silvennoinen, Reija; Quesada, Helena; Kareinen, Ilona; Julve, Josep; Kaipiainen, Leena; Gylling, Helena; Blanco-Vaca, Francisco; Escola-Gil, Joan Carles; Kovanen, Petri T; Lee-Rueckert, Miriam

    2015-01-01

    Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids. C57Bl/6J mice exposed to intermittent stress for 5 days exhibited increased transit through the large intestine and enhanced fecal bile acid excretion. Of the transcription factors and transporters that regulate bile acid homeostasis, the mRNA expression levels of the hepatic farnesoid X receptor (FXR), the bile salt export pump (BSEP), and the intestinal fibroblast growth factor 15 (FGF15) were reduced, whereas those of the ileal apical sodium-dependent bile acid transporter (ASBT), responsible for active bile acid absorption, remained unchanged. Neither did the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme regulating bile acid synthesis, change in the stressed mice. Evaluation of the functionality of the m-RCT pathway revealed increased fecal excretion of bile acids that had been synthesized from macrophage-derived cholesterol. Overall, our study reveals that chronic intermittent stress in mice accelerates m-RCT specifically by increasing fecal excretion of bile acids. This novel mechanism of m-RCT induction could have antiatherogenic potential under conditions of chronic stress. PMID:25969465

  19. Ursodeoxycholic acid in the Ursidae: biliary bile acids of bears, pandas, and related carnivores.

    PubMed

    Hagey, L R; Crombie, D L; Espinosa, E; Carey, M C; Igimi, H; Hofmann, A F

    1993-11-01

    The biliary bile acid composition of gallbladder bile obtained from six species of bears (Ursidae), the Giant panda, the Red panda, and 11 related carnivores were determined by reversed phase liquid chromatography and gas chromatography-mass spectrometry. Bile acids were conjugated solely with taurine (in N-acyl linkage) in all species. Ursodeoxycholic acid (3 alpha, 7 beta-dihydroxy-5 beta-cholan-24-oic acid) was present in all Ursidae, averaging 1-39% of biliary bile acids depending on the species; it was not detected or present as a trace constituent (< 0.5%) in all other species, including the Giant panda. Ursodeoxycholic acid was present in 73 of 75 American Black bears, and its proportion averaged 34% (range 0-62%). Ursodeoxycholic acid averaged 17% of biliary bile acids in the Polar bear (n = 4) and 18% in the Brown bear (n = 6). Lower proportions (1-8%) were present in the Sun bear (n = 2), Ceylon Sloth bear (n = 1), and the Spectacled bear (n = 1). Bile of all species contained taurine-conjugated chenodeoxycholic acid and cholic acid. In some related carnivores, deoxycholic acid, the 7-dehydroxylation product of cholic acid, was also present. To determine whether the 7 beta hydroxy group of ursodeoxycholic acid was formed by hepatic or bacterial enzymes, bile acids were determined in hepatic bile obtained from bears with chronic biliary fistulae. Fistula bile samples contained ursodeoxycholic acid, chenodeoxycholic acid, and a trace amount of cholic acid, all as taurine conjugates, indicating that ursodeoxycholic acid is a primary bile acid formed in the liver in Ursidae.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8263415

  20. Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice.

    PubMed

    Silvennoinen, Reija; Quesada, Helena; Kareinen, Ilona; Julve, Josep; Kaipiainen, Leena; Gylling, Helena; Blanco-Vaca, Francisco; Escola-Gil, Joan Carles; Kovanen, Petri T; Lee-Rueckert, Miriam

    2015-05-11

    Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids. C57Bl/6J mice exposed to intermittent stress for 5 days exhibited increased transit through the large intestine and enhanced fecal bile acid excretion. Of the transcription factors and transporters that regulate bile acid homeostasis, the mRNA expression levels of the hepatic farnesoid X receptor (FXR), the bile salt export pump (BSEP), and the intestinal fibroblast growth factor 15 (FGF15) were reduced, whereas those of the ileal apical sodium-dependent bile acid transporter (ASBT), responsible for active bile acid absorption, remained unchanged. Neither did the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme regulating bile acid synthesis, change in the stressed mice. Evaluation of the functionality of the m-RCT pathway revealed increased fecal excretion of bile acids that had been synthesized from macrophage-derived cholesterol. Overall, our study reveals that chronic intermittent stress in mice accelerates m-RCT specifically by increasing fecal excretion of bile acids. This novel mechanism of m-RCT induction could have antiatherogenic potential under conditions of chronic stress. PMID:25969465

  1. Structural basis of the alternating-access mechanism in a bile acid transporter

    NASA Astrophysics Data System (ADS)

    Zhou, Xiaoming; Levin, Elena J.; Pan, Yaping; McCoy, Jason G.; Sharma, Ruchika; Kloss, Brian; Bruni, Renato; Quick, Matthias; Zhou, Ming

    2014-01-01

    Bile acids are synthesized from cholesterol in hepatocytes and secreted through the biliary tract into the small intestine, where they aid in absorption of lipids and fat-soluble vitamins. Through a process known as enterohepatic recirculation, more than 90% of secreted bile acids are then retrieved from the intestine and returned to the liver for resecretion. In humans, there are two Na+-dependent bile acid transporters involved in enterohepatic recirculation, the Na+-taurocholate co-transporting polypeptide (NTCP; also known as SLC10A1) expressed in hepatocytes, and the apical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in the terminal ileum. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hypercholesterolaemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption. However, a lack of three-dimensional structures of bile acid transporters hampers our ability to understand the molecular mechanisms of substrate selectivity and transport, and to interpret the wealth of existing functional data. The crystal structure of an ASBT homologue from Neisseria meningitidis (ASBTNM) in detergent was reported recently, showing the protein in an inward-open conformation bound to two Na+ and a taurocholic acid. However, the structural changes that bring bile acid and Na+ across the membrane are difficult to infer from a single structure. To understand the structural changes associated with the coupled transport of Na+ and bile acids, here we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBTYf) in a lipid environment, which reveal that a large rigid-body rotation of a substrate-binding domain gives the conserved `crossover' region, where two discontinuous helices cross each other, alternating accessibility from either side of the cell membrane. This result has implications

  2. Influence of dietary retrograded starch on the metabolism of neutral steroids and bile acids in rats.

    PubMed

    Verbeek, M J; De Deckere, E A; Tijburg, L B; Van Amelsvoort, J M; Beynen, A C

    1995-12-01

    Diets enriched in retrograded amylose (RS3) have been shown to lower serum cholesterol concentrations in rats. The possibility was tested that this hypocholesterolaemic effect of RS3 is caused by an increase in excretion of neutral steroids and/or bile acids. Six groups of ten rats were fed on purified diets containing either 12 or 140 g RS3/kg solid ingredients with and without added cholesterol (5g/kg). Low-RS3 diets, with and without added cholesterol, to which the bile-acid-binding resin cholestyramine (20 g/kg) was added, were used as reference. The high-RS3 diets v. the low-RS3 diets tended to reduce the increase in the total serum cholesterol concentration during the course of the experiment (P = 0.067), decreased serum triacylglycerol concentrations, raised total neutral steroids and total bile acids in caecal contents and faecal excretion of total bile acids, but lowered faecal excretion of neutral steroids. In addition, the serum concentration of total 3 alpha-bile acids was markedly raised by the high-RS3 diets. The high-RS3 diets raised the faecal excretion of lithocholic and muricholic acids, but lowered that of hyodeoxycholic acid, and increased the caecal amounts of lithocholic, ursodeoxycholic, beta-muricholic and omega-muricholic acids. Apart from the stimulation of faecal bile acids excretion, the effects of cholestyramine on bile acid metabolism differed at various points from those of RS3. Cholesterol feeding had predictable effects on cholesterol metabolism and led to greater elevating effects of RS3 on the faecal and caecal amounts of muricholic acids. The results suggest that the serum-cholesterol-lowering effect of high-RS3 diets may be explained by an increased influx of neutral steroids and bile acids into the caecum, and increased faecal excretion of bile acids, and/or by an altered intestinal bile acid profile. PMID:8562568

  3. Molecular Switch Controlling the Binding of Anionic Bile Acid Conjugates to Human Apical Sodium-dependent Bile Acid Transporter

    PubMed Central

    Rais, Rana; Acharya, Chayan; Tririya, Gasirat; MacKerell, Alexander D.; Polli, James E.

    2010-01-01

    The human apical sodium-dependent bile acid transporter (hASBT) may serve as a prodrug target for oral drug absorption. Synthetic, biological, NMR and computational approaches identified the structure-activity relationships of mono- and dianionic bile acid conjugates for hASBT binding. Experimental data combined with a conformationally-sampled pharmacophore/QSAR modeling approach (CSP-SAR) predicted that dianionic substituents with intramolecular hydrogen bonding between hydroxyls on the cholane skeleton and the acid group on the conjugate's aromatic ring increased conjugate hydrophobicity and improved binding affinity. Notably, the model predicted the presence of a conformational molecular switch, where shifting the carboxylate substituent on an aromatic ring by a single position controlled binding affinity. Model validation was performed by effectively shifting the spatial location of the carboxylate by inserting a methylene adjacent to the aromatic ring, resulting in the predicted alteration in binding affinity. This work illustrates conformation as a determinant of ligand binding affinity to a biological transporter. PMID:20504026

  4. Dansyl labeling to modulate the relative affinity of bile acids for the binding sites of human serum albumin.

    PubMed

    Rohacova, Jana; Sastre, German; Marin, M Luisa; Miranda, Miguel A

    2011-09-01

    Binding of natural bile acids to human serum albumin (HSA) is an important step in enterohepatic circulation and provides a measure of liver function. In this article, we report on the use of four dansyl (Dns) derivatives of cholic acid (ChA) to demonstrate a regiodifferentiation in their relative affinity for the two binding sites of HSA. Using both steady-state and time-resolved fluorescence, formation of Dns-ChA@HSA complexes was confirmed; the corresponding binding constants were determined, and their distribution between bulk solution and HSA microenvironment was estimated. By means of energy transfer from Trp to the Dns moiety, donor-acceptor distances were estimated (21-25 Å) and found to be compatible with both site 1 and site 2 occupancies. Nevertheless, titration using warfarin and ibuprofen as specific displacement probes clearly indicated that 3α- and 3β-Dns-ChA bind to HSA at site 2, whereas their C-7 regioisomers bind to HSA at site 1. Furthermore, the C-3-labeled compounds are displaced by lithocholic acid, whereas they are insensitive to ChA, confirming the assumption that the former binds to HSA at site 2. Thus, Dns labeling provides a useful tool to modulate the relative affinity of ChA to the major binding sites of HSA and, in combination with other fluorescent ChA analogs, to mimic the binding behavior of natural bile acids. PMID:21797258

  5. Bile Acid Metabolome after an Oral Lipid Tolerance Test by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)

    PubMed Central

    Schmid, Andreas; Neumann, Hannah; Karrasch, Thomas; Liebisch, Gerhard; Schäffler, Andreas

    2016-01-01

    Context Besides their role in intestinal resorption of lipids, bile acids are regarded as endocrine and metabolic signaling molecules. The detailed profile of bile acid species in peripheral blood after an oral lipid tolerance test (OLTT) is unknown. Objective We quantified the regulation of 18 bile acids after OLTT in healthy individuals. Material and methods 100 volunteers were characterized by anthropometric and laboratory parameters and underwent OLTT. Venous blood was drawn in the fasted state (0 h) and at 2h, 4h, and 6 h after OLTT. Serum concentrations of 18 bile acids were measured by LC-MS/MS. Results All of the 6 taurine-conjugated bile acids (TUDCA, THDCA, TCA, TCDCA, TDCA, TLCA) and all of the 6 glycine-conjugated bile acids (GUDCA, GHDCA, GCA, GCDCA, GDCA, GLCA) rose significantly at 2h and remained elevated during OLTT. Of the primary bile acids, CA remained unchanged, whereas CDCA significantly decreased at 4h. Of the secondary bile acids, DCA, UDCA and HDCA were not altered, whereas LCA decreased. There was a significant positive correlation between the intestinal feed-back regulator of bile acid synthesis FGF-19 and bile acids. This correlation seems to depend on all of the six taurine-conjugated bile acids and on GCA, GDCA, and GCDCA. Females and users of hormonal contraception displayed higher levels of taurine-conjugated bile acids. Conclusions The novelty of the study is based on the identification of single bile acids during OLTT. LC-MS/MS-based quantification of bile acids in serum provides a reliable tool for future investigation of endocrine and metabolic effects of bile acids. PMID:26863103

  6. Increased formation of ursodeoxycholic acid in patients treated with chenodeoxycholic acid.

    PubMed Central

    Salen, G; Tint, G S; Eliav, B; Deering, N; Mosbach, E H

    1974-01-01

    The formation of ursodeoxycholic acid, the 7 beta-hydroxy epimer of chenodeoxycholic acid, was investigated in three subjects with cerebrotendinous xanthomatosis and in four subjects with gallstones. Total biliary bile acid composition was analyzed by gas-liquid chromatography before and after 4 months of treatment with 0.75 g/day of chenodeoxycholic acid. Individual bile acids were identified by mass spectrometry. Before treatment, bile from cerebrotendinous xanthomatosis (CTX) subjects contained cholic acid, 85%; chenodeoxycholic acid, 7%; deoxycholic acid, 3%; allocholic acid, 3%; and unidentified steroids, 2%; while bile from gallstone subjects contained cholic acid, 45%; chenodeoxycholic acid, 43%; deoxycholic acid, 11%, and lithocholic acid, 1%. In all subjects, 4 months of chenodeoxycholic acid therapy increased the proportion of this bile acid to approximately 80% and decreased cholic acid to 3% of the total biliary bile acids, the remaining 17% of bile acids were identified as ursodeoxycholic acid. After the intravenous injection of [3H]chenodeoxycholic acid, the specific activity of biliary ursodeoxycholic acid exceeded the specific activity of chenodeoxycholic acid, and the resulting specific activity decay curves suggested precursor-product relationships. When [3H]7-ketolithocholic acid was administrated to another patient treated with chenodeoxycholic acid, radioactivity was detected in both the ursodeoxycholic acid and chenodeoxycholic acid fractions. These results indicate that substantial amounts of ursodeoxycholic acid are formed in patients treated with chenodeoxycholic acid. The ursodeoxycholic acid was synthesized from chenodeoxycholic acid presumably via 7-ketolithocholic acid. Images PMID:11344576

  7. Ileal apical sodium-dependent bile acid transporter protein levels are down-regulated through ubiquitin-dependent protein degradation induced by bile acids.

    PubMed

    Miyata, Masaaki; Yamakawa, Hiroki; Hayashi, Kenjiro; Kuribayashi, Hideaki; Yamazoe, Yasushi; Yoshinari, Kouichi

    2013-08-15

    The ileal apical sodium-dependent bile acid transporter (ASBT or SLC10A2) has a crucial role in intestinal bile acid absorption. We previously reported that enterobacteria-mediated bile acid conversion was involved in the alteration of ileal ASBT expression levels. In the present study, to investigate the hypothesis that ileal ASBT protein levels are post-translationally regulated by enterobacteria-associated bile acids, alteration of ileal ASBT protein levels was analysed in mice 12 h and 24 h after anti-bacterial drug ampicillin (ABPC) treatment (100 mg/kg, single shot) that altered bile acid composition in the intestinal lumen. In ABPC-treated mice, enterobacteria-biotransformed bile acid, taurodeoxycholic acid (TDCA) and cholic acid (CA) levels were decreased, whereas taurocholic acid (TCA) and tauro-β-muricholic acid levels were increased in the intestinal lumen. Ileal ASBT protein levels in brush-border membrane vesicles (BBMVs), but not ileal Asbt mRNA levels, were significantly increased in the ABPC-treated mice, and the extent of ubiquitination of the ileal ASBT protein was reduced in the ABPC-treated mice. Treatment of ABPC-pretreated mice with CA or TDCA, but not TCA, significantly decreased ileal ASBT protein levels and increased the extent of ubiquitination of ileal ASBT protein. Treatment of mice with the lysosome inhibitor, chloroquine, or the proteasome inhibitor, MG132, increased ileal ASBT protein levels in BBMVs. CA-mediated reduction of ASBT protein levels in the ABPC-pretreated mice was attenuated by co-treatment with chloroquine or MG132. These results suggest that ileal ASBT protein is degraded by a ubiquitin-dependent pathway in response to enterobacteria-associated bile acids. PMID:23872411

  8. Bile acid production in human subjects: rate of oxidation of (24,25-/sup 3/H)cholesterol compared to fecal bile acid excretion

    SciTech Connect

    Davidson, N.O.; Bradlow, H.L.; Ahrens, E.H. Jr.; Rosenfeld, R.S.; Schwartz, C.C.

    1986-02-01

    Bile acid production has been quantitated in seven subjects by methods that compare the results of two independent approaches, namely, quantitation of cholesterol side-chain oxidation and fecal bile acid excretion. Six hypertriglyceridemic (HT) subjects and one normolipidemic control were studied by both techniques. A further control subject was studied by the cholesterol side-chain oxidation method alone. Cholesterol side-chain oxidation was quantitated by measuring the appearance of /sup 3/H/sub 2/O after intravenous administration of (24,25-/sup 3/H)cholesterol, using multicompartmental analysis of plasma cholesterol and (/sup 3/H)water specific activity. Body water kinetics were independently defined by use of oral D/sub 2/O. Two HT subjects were restudied while they were taking cholestyramine, 16 g/day. In all ten studies, multicompartmental analysis closely simulated the observed appearance of /sup 3/H/sub 2/O. Values obtained for bile acid production suggest that cholesterol oxidation, or bile acid input, was significantly greater than fecal bile acid output in the HT subjects (P less than 0.05). Cholesterol side-chain oxidation rates in the two normal subjects were lower than those encountered in HT subjects, being similar to published values for normal subjects both for bile acid synthesis as determined by isotope dilution kinetics and fecal bile acid excretion. Studies conducted with two, synthetically different, preparations of (24,25-/sup 3/H)cholesterol indicated that, in one of the two preparations, approximately 20% of the tritium label was at positions proximal to C24. In the other preparation examined, all of the tritium was located at, or distal to, C24. Further studies revealed that 0.055-0.24% of the dose was present as labile tritium by virtue of its appearance as /sup 3/H/sub 2/O following in vitro incubation with human plasma. (Abstract Truncated)

  9. Fecal losses of sterols and bile acids induced by feeding rats guar gum are due to greater pool size and liver bile acid secretion.

    PubMed

    Moundras, C; Behr, S R; Rémésy, C; Demigné, C

    1997-06-01

    The effect of dietary guar gum (GG, 7.5%) on lipid metabolism and on bile acid secretion and reabsorption was investigated in rats adapted to cholesterol-free or 0.3% cholesterol diets. Compared with controls (fiber-free/cholesterol-free), rats fed cholesterol had significantly elevated plasma and liver cholesterol and triglyceride. In these rats, GG had a potent plasma cholesterol-lowering effect and also counteracted the liver accumulation of triglyceride and cholesterol esters. Fecal excretion of sterols, the major route of cholesterol elimination, was markedly enhanced by GG, especially in rats fed the cholesterol-containing diet (P < 0.001). The biliary bile acid flux into the small intestine was enhanced by dietary cholesterol (+30%) or GG (+52%) or both (P < 0.001). The fecal excretion of bile acids was significantly elevated by GG alone (+74%) and by dietary cholesterol (+190%). Small intestine reabsorption of bile acids appears to be significantly enhanced by GG, which also enhanced the transfer of bile acids into the large intestine, hence a greater fecal loss of steroids, although bile acid reabsorption was very effective in the cecum. GG feeding induced liver hydroxymethyl-glutaryl coenzyme A (HMG CoA) reductase, even in cholesterol-fed rats, as well as cholesterol 7 alpha-hydroxylase (P < 0.001). The cholesterol-lowering effect of GG thus appears to be mediated by an accelerated fecal excretion of steroids and a rise in the intestinal pool and biliary production of bile acids. Although liver HMG CoA reductase and cholesterol 7 alpha-hydroxylase are induced in parallel, this is not sufficient to compensate for fecal steroid losses. PMID:9187619

  10. NMR-based modeling and binding studies of a ternary complex between chicken liver bile acid binding protein and bile acids.

    PubMed

    Tomaselli, Simona; Ragona, Laura; Zetta, Lucia; Assfalg, Michael; Ferranti, Pasquale; Longhi, Renato; Bonvin, Alexandre M J J; Molinari, Henriette

    2007-10-01

    Chicken liver bile acid binding protein (cL-BABP) is involved in bile acid transport in the liver cytosol. A detailed study of the mechanism of binding and selectivity of bile acids binding proteins towards the physiological pool of bile salts is a key issue for the complete understanding of the role of these proteins and their involvement in cholesterol homeostasis. In the present study, we modeled the ternary complex of cL-BABP with two molecules of bile salts using the data driven docking program HADDOCK on the basis of NMR and mass spectrometry data. Docking resulted in good 3D models, satisfying the majority of experimental restraints. The docking procedure represents a necessary step to help in the structure determination and in functional analysis of such systems, in view of the high complexity of the 3D structure determination of a ternary complex with two identical ligands. HADDOCK models show that residues involved in binding are mainly located in the C-terminal end of the protein, with two loops, CD and EF, playing a major role in ligand binding. A spine, comprising polarresidues pointing toward the protein interior and involved in motion communication, has a prominent role in ligand interaction. The modeling approach has been complemented with NMR interaction and competition studies of cL-BABP with chenodeoxycholic and cholic acids. A higher affinity for chenodeoxycholic acid was observed and a Kd upper limit estimate was obtained. The binding is highly cooperative and no site selectivity was detected for the different bile salts, thus indicating that site selectivity and cooperativity are not correlated. Differences in physiological pathways and bile salt pools in different species is discussed in light of the binding results thus enlarging the body of knowledge of BABPs biological functions. PMID:17607743

  11. Genomic and genetic characterization of the bile stress response of probiotic Lactobacillus reuteri ATCC 55730.

    PubMed

    Whitehead, Kristi; Versalovic, James; Roos, Stefan; Britton, Robert A

    2008-03-01

    Probiotic bacteria encounter various stresses after ingestion by the host, including exposure to the low pH in the stomach and bile in the small intestine. The probiotic microorganism Lactobacillus reuteri ATCC 55730 has previously been shown to survive in the human small intestine. To address how L. reuteri can resist bile stress, we performed microarray experiments to determine gene expression changes that occur when the organism is exposed to physiological concentrations of bile. A wide variety of genes that displayed differential expression in the presence of bile indicated that the cells were dealing with several types of stress, including cell envelope stress, protein denaturation, and DNA damage. Mutations in three genes were found to decrease the strain's ability to survive bile exposure: lr1864, a Clp chaperone; lr0085, a gene of unknown function; and lr1516, a putative esterase. Mutations in two genes that form an operon, lr1584 (a multidrug resistance transporter in the major facilitator superfamily) and lr1582 (unknown function), were found to impair the strain's ability to restart growth in the presence of bile. This study provides insight into the possible mechanisms that L. reuteri ATCC 55730 may use to survive and grow in the presence of bile in the small intestine. PMID:18245259

  12. Evaluation of Streptococcus pneumoniae in bile samples: A case series review.

    PubMed

    Itoh, Naoya; Kawamura, Ichiro; Tsukahara, Mika; Mori, Keita; Kurai, Hanako

    2016-06-01

    Although Streptococcus pneumoniae is an important pathogen of humans, pneumococcal cholangitis is rare because of the rapid autolysis of S. pneumoniae. The aim of this case series was to review patients with bile cultures positive for S. pneumoniae. This study was a single center retrospective case series review of patients with S. pneumoniae in their bile at a tertiary-care cancer center between September 2002 and August 2015. Subjects consisted of all patients in whom S. pneumoniae was isolated in their bile during the study period. Bile specimens for culture were obtained from biliary drainage procedures such as endoscopic retrograde biliary drainage, endoscopic nasobiliary drainage, and percutaneous transhepatic biliary drainage. There were 20 patients with bile cultures positive for S. pneumoniae during the study period. All patients presented with extrahepatic obstructive jaundice due to hepatopancreatobiliary tumors. Nineteen of 20 patients underwent the placement of plastic intrabiliary tubes. The mean time between the first-time drainage and the positive culture was 26 days (range 0-313 days). Although 12 of 20 patients met our definition of cholangitis, 5 were clinically treated with antibiotics based on a physician's assessment of whether there was a true infection. The present study is the largest case series of patients with S. pneumoniae in their bile. Based on our findings, the isolation of S. pneumoniae from bile may be attributed to the placement of biliary drainage devices. PMID:27025902

  13. The adsorption-desorption behaviour and structure function relationships of bile salts.

    PubMed

    Parker, Roger; Rigby, Neil M; Ridout, Michael J; Gunning, A Patrick; Wilde, Peter J

    2014-09-14

    The digestion of dietary components in the human gastrointestinal (GI) tract is a complex, dynamic, inherently heterogeneous process. A key aspect of the digestion of lipid in the GI tract is the combined action of bile salts, lipase and colipase in hydrolysing and solubilising dispersed lipid. The bile salts are a mixture of steroid acid conjugates with surfactant properties. In order to examine whether the different bile salts have different interfacial properties their dynamic interfacial behaviour was characterised. Differences in the adsorption behaviour to solid hydrophobic surfaces of bile salt species were studied using dual polarisation interferometry and atomic force microscopy (AFM) under physiological conditions. Specifically, the cholates adsorbed more slowly and a significant proportion were irreversibly adsorbed following buffer rinsing; whereas the deoxycholates and chenodeoxycholates adsorbed more rapidly and desorbed to a greater extent following buffer rinsing. The conjugating groups (taurine, glycine) did not influence the behaviour. AFM showed that the interfacial structures that remained following buffer rinsing were also different between these two groups. In addition, the adsorption-desorption behaviour affected the adsorption of colipase to a solid surface. This supports the idea that cooperative adsorption occurs between certain bile salts and colipase to facilitate the adsorption and activity of pancreatic lipase in order to restore lipolytic activity in the presence of bile salts. This study provides insights into how differences in bile salt structure could affect lipase activity and solubilisation of lipolysis products and other lipid-soluble bioactive molecules. PMID:25008989

  14. Bile acid salt binding with colesevelam HCl is not affected by suspension in common beverages.

    PubMed

    Hanus, Martin; Zhorov, Eugene

    2006-12-01

    It has been previously reported that anions in common beverages may bind to bile acid sequestrants (BAS), reducing their capacity for binding bile acid salts. This study examined the ability of the novel BAS colesevelam hydrochloride (HCl), in vitro, to bind bile acid sodium salts following suspension in common beverages. Equilibrium binding was evaluated under conditions of constant time and varying concentrations of bile acid salts in simulated intestinal fluid (SIF). A stock solution of sodium salts of glycochenodeoxycholic acid (GCDC), taurodeoxycholic acid (TDC), and glycocholic acid (GC), was added to each prepared sample of colesevelam HCl. Bile acid salt binding was calculated by high-performance liquid chromatography (HPLC) analysis. Kinetics experiments were conducted using constant initial bile acid salt concentrations and varying binding times. The affinity, capacity, and kinetics of colesevelam HCl binding for GCDC, TDC, and GC were not significantly altered after suspension in water, carbonated water, Coca-Cola, Sprite, grape juice, orange juice, tomato juice, or Gatorade. The amount of bile acid sodium salt bound as a function of time was unchanged by pretreatment with any beverage tested. The in vitro binding characteristics of colesevelam HCl are unchanged by suspension in common beverages. PMID:16937334

  15. Effects of Cholestasis on Learning and Locomotor Activity in Bile Duct Ligated Rats

    PubMed Central

    HOSSEINI, Nasrin; ALAEI, Hojjatallah; NASEHI, Mohammad; RADAHMADI, Maryam; Mohammad Reza, ZARRINDAST

    2014-01-01

    Background: Cognitive functions are impaired in patients with liver disease. Bile duct ligation causes cholestasis that impairs liver function. This study investigated the impact of cholestasis progression on the acquisition and retention times in the passive avoidance test and on the locomotor activity of rats. Methods: Cholestasis was induced in male Wistar rats by ligating the main bile duct. Locomotor activity, learning and memory were assessed by the passive avoidance learning test at day 7, day 14, and day 21 post-bile duct ligation. The serum levels of bilirubin, alanine aminotransferase, and alkaline phosphatase were measured. Results: The results showed that acquisition time and locomotor activity were not affected at day 7 and day 14, but they were significantly (P < 0.05) impaired at day 21 post-bile duct ligation compared with the results for the control group. Additionally, memory was significantly impaired on day 7 (P < 0.01), day 14, and day 21 (P < 0.001) compared with the control groups. The levels of total bilirubin, direct bilirubin, indirect bilirubin, alanine aminotransferase, and alkaline phosphatase were significantly higher at day 7, day 14, and day 21 post-bile duct ligation compared with the levels in the sham group. Conclusion: Based on these findings, both liver and memory function were affected in the early stage of cholestasis (7 days after bile duct ligation), while learning and locomotor activity were impaired at 21 days after bile duct ligation following the progression of cholestasis. PMID:24639608

  16. Neuroendocrine carcinoma of the extrahepatic bile duct: A case report

    PubMed Central

    Oshiro, Yukio; Gen, Ryozo; Hashimoto, Shinji; Oda, Tatsuya; Sato, Taiki; Ohkohchi, Nobuhiro

    2016-01-01

    Neuroendocrine carcinoma (NEC) originating from the gastrointestinal hepatobiliary-pancreas is a rare, invasive, and progressive disease, for which the prognosis is extremely poor. The patient was a 72-year-old man referred with complaints of jaundice. He was diagnosed with middle extrahepatic cholangiocarcinoma (cT4N1M0, cStage IV). He underwent a right hepatectomy combined with extrahepatic bile duct and portal vein resection after percutaneous transhepatic portal vein embolization. Microscopic examination showed a large-cell neuroendocrine carcinoma according to the WHO criteria for the clinicopathologic classification of gastroenteropancreatic neuroendocrine tumors. Currently, the patient is receiving combination chemotherapy with cisplatin and etoposide for postoperative multiple liver metastases. Although NEC is difficult to diagnose preoperatively, it should be considered an uncommon alternative diagnosis. PMID:27570432

  17. Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery

    PubMed Central

    Noel, Olivier F.; Still, Christopher D.; Argyropoulos, George; Edwards, Michael; Gerhard, Glenn S.

    2016-01-01

    Overweight and obesity represent major risk factors for diabetes and related metabolic diseases. Obesity is associated with a chronic and progressive inflammatory response leading to the development of insulin resistance and type 2 diabetes (T2D) mellitus, although the precise mechanism mediating this inflammatory process remains poorly understood. The most effective intervention for the treatment of obesity, bariatric surgery, leads to glucose normalization and remission of T2D. Recent work in both clinical studies and animal models supports bile acids (BAs) as key mediators of these effects. BAs are involved in lipid and glucose homeostasis primarily via the farnesoid X receptor (FXR) transcription factor. BAs are also involved in regulating genes involved in inflammation, obesity, and lipid metabolism. Here, we review the novel role of BAs in bariatric surgery and the intersection between BAs and immune, obesity, weight loss, and lipid metabolism genes. PMID:27006824

  18. Laparoscopic injuries to the bile duct. A cause for concern.

    PubMed Central

    Moossa, A R; Easter, D W; Van Sonnenberg, E; Casola, G; D'Agostino, H

    1992-01-01

    The authors report six patients who had injuries to their common hepatic bile duct at laparoscopic cholecystectomy over a 16-month period. Five of the six complications could be attributed to laser injuries during dissection in the region of Calot's triangle. The authors discuss the possible mechanism of these injuries, their perioperative management, and the methods of surgical reconstruction. The follow-up period ranges from 3 months to 21 months. Liver function parameters and isotope biliary excretion scans are back to normal in all six patients. The potential hazards of laparoscopic surgery demand that extraordinary care be used not only during the actual surgical procedure, but also in the preoperative decision concerning the dissection method to be employed. Images FIG. 2. FIG. 3. FIG. 4. FIG. 5. FIG. 6. PMID:1531914

  19. Nuclear bile acid signaling through the farnesoid X receptor.

    PubMed

    Mazuy, Claire; Helleboid, Audrey; Staels, Bart; Lefebvre, Philippe

    2015-05-01

    Bile acids (BAs) are amphipathic molecules produced from cholesterol by the liver. Expelled from the gallbladder upon meal ingestion, BAs serve as fat solubilizers in the intestine. BAs are reabsorbed in the ileum and return via the portal vein to the liver where, together with nutrients, they provide signals to coordinate metabolic responses. BAs act on energy and metabolic homeostasis through the activation of membrane and nuclear receptors, among which the nuclear receptor farnesoid X receptor (FXR) is an important regulator of several metabolic pathways. Highly expressed in the liver and the small intestine, FXR contributes to BA effects on metabolism, inflammation and cell cycle control. The pharmacological modulation of its activity has emerged as a potential therapeutic strategy for liver and metabolic diseases. This review highlights recent advances regarding the mechanisms by which the BA sensor FXR contributes to global signaling effects of BAs, and how FXR activity may be regulated by nutrient-sensitive signaling pathways. PMID:25511198

  20. LC-MS/MS method for the determination of haemanthamine in rat plasma, bile and urine and its application to a pilot pharmacokinetic study.

    PubMed

    Hroch, Miloš; Mičuda, Stanislav; Havelek, Radim; Cermanová, Jolana; Cahlíková, Lucie; Hošťálková, Anna; Hulcová, Daniela; Řezáčová, Martina

    2016-07-01

    Evidence gathered in various studies points to the fact that haemanthamine, an isoquinoline alkaloid, has multiple medicinally interesting characteristics, including antitumor, antileukemic, antioxidant, antiviral, anticonvulsant and antimalarial activity. This work presents, for the first time, a universal LC-MS/MS method for analysis of haemanthamine in plasma, bile and urine which has been verified in a pilot pharmacokinetic experiment on rats. Chromatographic separation was performed on a pentafluorophenyl core-shell column in gradient elution mode with a mobile phase consisting of acetonitrile-methanol-ammonium formate buffer. A sample preparation based on liquid-liquid extraction with methyl tert-butyl ether was employed with ambelline used as an internal standard. Quantification was performed using LC-MS-ESI(+) in Selected Reaction Monitoring mode. The method was validated according to the European Medicines Agency guideline in a concentration range of 0.1-10 μmol/L in plasma, bile and urine. The concentration-time profiles of haemanthamine in plasma, bile and urine after a single i.v. bolus of 10 mg/kg have been described for the first time. The presented study addresses the lack of information on haemanthamine pharmacokinetics and also introduces a new universal method of haemanthamine analysis in complex biological matrices. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26577707

  1. Crystal structure of bile salt hydrolase from Lactobacillus salivarius.

    PubMed

    Xu, Fuzhou; Guo, Fangfang; Hu, Xiao Jian; Lin, Jun

    2016-05-01

    Bile salt hydrolase (BSH) is a gut-bacterial enzyme that negatively influences host fat digestion and energy harvesting. The BSH enzyme activity functions as a gateway reaction in the small intestine by the deconjugation of glycine-conjugated or taurine-conjugated bile acids. Extensive gut-microbiota studies have suggested that BSH is a key mechanistic microbiome target for the development of novel non-antibiotic food additives to improve animal feed production and for the design of new measures to control obesity in humans. However, research on BSH is still in its infancy, particularly in terms of the structural basis of BSH function, which has hampered the development of BSH-based strategies for improving human and animal health. As an initial step towards the structure-function analysis of BSH, C-terminally His-tagged BSH from Lactobacillus salivarius NRRL B-30514 was crystallized in this study. The 1.90 Å resolution crystal structure of L. salivarius BSH was determined by molecular replacement using the structure of Clostridium perfringens BSH as a starting model. It revealed this BSH to be a member of the N-terminal nucleophile hydrolase superfamily. Crystals of apo BSH belonged to space group P21212, with unit-cell parameters a = 90.79, b = 87.35, c = 86.76 Å (PDB entry 5hke). Two BSH molecules packed perfectly as a dimer in one asymmetric unit. Comparative structural analysis of L. salivarius BSH also identified potential residues that contribute to catalysis and substrate specificity. PMID:27139829

  2. Limits of Surgical Resection for Bile Duct Cancer

    PubMed Central

    Bartsch, Fabian; Heinrich, Stefan; Lang, Hauke

    2015-01-01

    Introduction Perihilar cholangiocarcinoma is the most frequent cholangiocarcinoma and poses difficulties in preoperative evaluation. For its therapy, often major hepatic resections as well as resection and reconstruction of the hepatic artery or the portal vein are necessary. In the last decades, great advances were made in both the surgical procedures and the perioperative anesthetic management. In this article, we describe from our point of view which facts represent the limits for curative (R0) resection in perihilar cholangiocarcinoma. Methods Retrospective data of a 6-year period (2008-2014) was collected in an SPSS 22 database and further analyzed with focus on the surgical approach and the postoperative as well as histological results. Results Out of 96 patients in total we were able to intend a curative resection in 73 patients (76%). In 58/73 (79.5%) resections an R0 situation could be reached (R1 n = 14; R2 n = 1). 23 patients were irresectable because of peritoneal carcinosis (n = 8), broad infiltration of major blood vessels (n = 8), bilateral advanced tumor growth to the intrahepatic bile ducts (n = 3), infiltration of the complete liver hilum (n = 2), infiltration of the gallbladder (n = 1), and liver cirrhosis (n = 1). Patients with a T4 stadium were treated with curative intention twice, and in each case an R1 resection was achieved. Most patients with irresectable tumors can be suspected to have a T4 stadium as well. In a T3 situation (n = 6) we could establish five R0 resections and one R1 resection. Conclusion The limit of surgical resection for bile duct cancer is the advanced tumor stage (T stadium). While in a T3 stadium an R0 resection is possible in most cases, we were not able to perform an R0 resection in a T4 stadium. From our point of view, early T stadium cannot usually be estimated through expanded diagnostics but only through surgical exploration. PMID:26468314

  3. Iatrogenic bile duct injury with loss of confluence

    PubMed Central

    Mercado, Miguel-Angel; Vilatoba, Mario; Contreras, Alan; Leal-Leyte, Pilar; Cervantes-Alvarez, Eduardo; Arriola, Juan-Carlos; Gonzalez, Bruno-Adonai

    2015-01-01

    AIM: To describe our experience concerning the surgical treatment of Strasberg E-4 (Bismuth IV) bile duct injuries. METHODS: In an 18-year period, among 603 patients referred to our hospital for surgical treatment of complex bile duct injuries, 53 presented involvement of the hilar confluence classified as Strasberg E4 injuries. Imagenological studies, mainly magnetic resonance imaging showed a loss of confluence. The files of these patients were analyzed and general data were recorded, including type of operation and postoperative outcome with emphasis on postoperative cholangitis, liver function test and quality of life. The mean time of follow-up was of 55.9 ± 52.9 mo (median = 38.5, minimum = 2, maximum = 181.2). All other patients with Strasberg A, B, C, D, E1, E2, E3, or E5 biliary injuries were excluded from this study. RESULTS: Patients were divided in three groups: G1 (n = 21): Construction of neoconfluence + Roux-en-Y hepatojejunostomy. G2 (n = 26): Roux-en-Y portoenterostomy. G3 (n = 6): Double (right and left) Roux-en-Y hepatojejunostomy. Cholangitis was recorded in two patients in group 1, in 14 patients in group 2, and in one patient in group 3. All of them required transhepatic instrumentation of the anastomosis and six patients needed live transplantation. CONCLUSION: Loss of confluence represents a surgical challenge. There are several treatment options at different stages. Roux-en-Y bilioenteric anastomosis (neoconfluence, double-barrel anastomosis, portoenterostomy) is the treatment of choice, and when it is technically possible, building of a neoconfluence has better outcomes. When liver cirrhosis is shown, liver transplantation is the best choice. PMID:26527428

  4. Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity

    PubMed Central

    James, Laura; Yan, Ke; Pence, Lisa; Simpson, Pippa; Bhattacharyya, Sudeepa; Gill, Pritmohinder; Letzig, Lynda; Kearns, Gregory; Beger, Richard

    2015-01-01

    Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001), glycodeoxycholic acid (R=0.581; p<0.001), and glycochenodeoxycholic acid (R=0.571; p<0.001). Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury. PMID:26208104

  5. Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity.

    PubMed

    James, Laura; Yan, Ke; Pence, Lisa; Simpson, Pippa; Bhattacharyya, Sudeepa; Gill, Pritmohinder; Letzig, Lynda; Kearns, Gregory; Beger, Richard

    2015-01-01

    Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001), glycodeoxycholic acid (R=0.581; p<0.001), and glycochenodeoxycholic acid (R=0.571; p<0.001). Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury. PMID:26208104

  6. Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse.

    PubMed

    Wang, David Q-H; Tazuma, Susumu; Cohen, David E; Carey, Martin C

    2003-09-01

    We explored the influence of the hydrophilic-hydrophobic balance of a series of natural bile acids on cholesterol absorption in the mouse. Male C57L/J mice were fed standard chow or chow supplemented with 0.5% cholic; chenodeoxycholic; deoxycholic; dehydrocholic; hyocholic; hyodeoxycholic; alpha-, beta-, or omega-muricholic; ursocholic; or ursodeoxycholic acids for 7 days. Biliary bile salts were measured by reverse-phase HPLC, and hydrophobicity indices were estimated by Heuman's method. Cholesterol absorption efficiency was determined by a plasma dual-isotope ratio method. In mice fed chow, natural proportions of tauro-beta-muricholate (42 +/- 6%) and taurocholate (50 +/- 7%) with a hydrophobicity index of -0.35 +/- 0.04 produced cholesterol absorption of 37 +/- 5%. Because bacterial and especially hepatic biotransformations of specific bile acids occurred, hydrophobicity indices of the resultant bile salt pools differed from fed bile acids. We observed a significant positive correlation between hydrophobicity indices of the bile salt pool and percent cholesterol absorption. The principal mechanism whereby hydrophilic bile acids inhibit cholesterol absorption appears to be diminution of intraluminal micellar cholesterol solubilization. Gene expression of intestinal sterol efflux transporters Abcg5 and Abcg8 was upregulated by feeding cholic acid but not by hydrophilic beta-muricholic acid nor by hydrophobic deoxycholic acid. We conclude that the hydrophobicity of the bile salt pool predicts the effects of individual fed bile acids on intestinal cholesterol absorption. Natural alpha- and beta-muricholic acids are the most powerful inhibitors of cholesterol absorption in mice and might act as potent cholesterol-lowering agents for prevention of cholesterol deposition diseases in humans. PMID:12748061

  7. Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity.

    PubMed

    Herraez, Elisa; Macias, Rocio I R; Vazquez-Tato, Jose; Hierro, Carlos; Monte, Maria J; Marin, Jose J G

    2009-08-15

    Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreased basal (-60%) and TCA-stimulated bile flow (-55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion (<5%) of tauro-BALU-1 was detected. BALU-1 did not inhibit the biliary secretion of endogenous bile acids. When highly choleretic bile acids, - ursodeoxycholic (UDCA) and dehydrocholic acid (DHCA) - were administered, they were found less efficient than BALU-1 in preventing phalloidin-induced cholestasis. Biliary phalloidin elimination was low but it was increased by BALU-1>TCA>DHCA>UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin. PMID:19409403

  8. Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity

    SciTech Connect

    Herraez, Elisa; Macias, Rocio I.R.; Vazquez-Tato, Jose; Hierro, Carlos; Monte, Maria J.; Marin, Jose J.G.

    2009-08-15

    Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreased basal (- 60%) and TCA-stimulated bile flow (- 55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion (< 5%) of tauro-BALU-1 was detected. BALU-1 did not inhibit the biliary secretion of endogenous bile acids. When highly choleretic bile acids, - ursodeoxycholic (UDCA) and dehydrocholic acid (DHCA) - were administered, they were found less efficient than BALU-1 in preventing phalloidin-induced cholestasis. Biliary phalloidin elimination was low but it was increased by BALU-1 > TCA > DHCA > UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin.

  9. The association of bile acid excretion and atherosclerotic coronary artery disease

    PubMed Central

    Charach, Gideon; Grosskopf, Itamar; Rabinovich, Alexander; Shochat, Michael; Weintraub, Moshe; Rabinovich, Pavel

    2011-01-01

    Background: Excess cholesterol is usually eliminated from the body by conversion to bile acids excreted in feces as bile salts. The excretion of large amounts of bile protects against atherosclerosis, while diminished excretion may lead to coronary artery disease (CAD). Objective: To investigate a relationship between CAD and bile acid excretion. Methods: Bile acid excretion was compared between 36 patients with proven CAD and 37 CAD-free individuals (controls). The groups were comparable for demographics and selected risk factors. All subjects received a 4-day standard diet that included ∼500 mg of cholesterol. Fecal bile acids from 24-hour stool collections were measured by gas liquid chromatography. Results: CAD patients excreted lower amounts of total bile acids (358 ± 156 mg) than controls (617 ± 293 mg; p < 0.01) and less deoxycholic acid (188.29 ± 98.12 mg versus 325.96 ± 198.57 mg; p < 0.0001) and less lithocholic acid (115.43 ± 71.89 mg versus 197.27 ± 126.87 mg; p < 0.01). Advanced age, male gender, left ventricular ejection fraction and total bile acid levels were significant independent factors that predicted CAD (p < 0.05). Mortality, CAD and cerebrovascular accident development rates were significantly lower for the controls at the 13-year follow up. Conclusion: CAD patients have significantly decreased bile acid excretion levels than non-CAD patients. An impaired ability to excrete cholesterol may be an additional risk factor for CAD development. PMID:21694811

  10. Characteristic transport of lactoferrin from the intestinal lumen into the bile via the blood in piglets.

    PubMed

    Harada, E; Itoh, Y; Sitizyo, K; Takeuchi, T; Araki, Y; Kitagawa, H

    1999-11-01

    Lactoferrin is a major iron-binding protein in milk from several species, such as humans, monkeys, mice and sows. Using neonatal and weaner piglets, the characteristic transfer of lactoferrin from intestinal lumen into bile via the circulation was investigated. Bovine lactoferrin (1 or 3 g/kg body weight) was infused into the stomach through a polyethylene tube or into the duodenum through a duodenal catheter over 5 min. Peripheral blood and bile samples were collected after the infusion. Lactoferrin absorbed into plasma and bile were assayed quantitatively by double-antibody enzyme-linked immunosorbent assay, and homogeneity of bovine lactoferrin in plasma and bile was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting methods. Morphological investigation was carried out according to the peroxidase anti-peroxidase method. Following oral administration in neonatal pigs, bovine lactoferrin appeared in the blood circulation and reached a peak level after 2 h. It was confirmed immunohistochemically that lactoferrin was transported by endocytosis via the epithelial cells. Lactoferrin absorbed into the blood was also detected in the bile and reached a peak value 12 h after oral administration. Transportation of lactoferrin from the intestinal lumen into the bile via the bloodstream was also observed in weaner piglets. Lactoferrin transported into plasma and bile was confirmed to be the same substance as administrated lactoferrin by electrophoresis and immunoblotting methods. Lactoferrin transported into bile was re-absorbed into the blood in neonatal pigs. These results demonstrate that lactoferrin contained in milk is transported into the circulation from the intestinal lumen and excreted into the bile, suggesting the possibility of entero-hepatic circulation of lactoferrin in neonatal pigs. PMID:10665381

  11. Effects of dose, flow rate, and bile acid on diclofenac disposition in the perfused rat liver.

    PubMed

    Uraki, Misato; Kawase, Atsushi; Matsushima, Yuka; Iwaki, Masahiro

    2016-06-01

    An in situ perfused rat liver system is useful for studying the hepatic disposition of drugs and their metabolites. However, the effects of the perfusion conditions on drug disposition are unclear. We examined the effects of conditions such as flow rate (13 or 26 mL/min) and bile acid on disposition of diclofenac (DF) as a model drug and DF metabolites [diclofenac-1-O-acyl glucuronide (DF-Glu) or 4'-hydroxydiclofenac (DF-4'OH)] in the absence of albumin. DF, DF-Glu, and DF-4'OH concentrations in the perfusate and cumulative amounts of DF-Glu excreted in bile were measured using high-performance liquid chromatography methods. DF in the perfusate was rapidly eliminated as the perfusate flow rate increased. The area under the plasma concentration-time curve from 0 to 60 min (AUC0-60) for DF-Glu and DF-4'OH in a perfusate containing bile acid was lower at a flow rate of 26 and 13 mL/min, respectively. The bile flow rate at 26 mL/min with 24 μM of bile acid in the perfusate was significantly higher (ca. 3.5 times) compared with that at 13 mL/min without bile acid. Cumulative biliary DF-Glu excretion was also dramatically affected by the flow rate and addition of bile acid. This study indicated that the flow rate and bile acid in the perfused rat liver were key factors for bile flow rate and DF, DF-Glu, and DF-4'OH disposition in the absence of albumin. PMID:25656736

  12. Bio-relevant media to assess drug permeability: sodium taurocholate and lecithin combination or crude bile?

    PubMed

    Berginc, Katja; Trontelj, Jurij; Kristl, Albin

    2012-06-15

    The assessment of in vivo drug absorption with in vitro permeability models demands the use of transport media with surface acting compounds. With the aim to establish their influence on in vitro permeability of 30 drugs through Caco-2 monolayers, cell vitality/integrity and micellar drug entrapment, taurocholate/lecithin (NaTC/Leci) and pig crude bile were applied. Drug permeabilities were correlated to fraction of drugs absorbed and appropriate NaTC/Leci and bile concentrations were proposed to simulate fasted/fed conditions in vitro (bile in the concentration range 1-5 v/v% or 0.2/0.05mM NaTC/Leci for fasted; 10 v/v% bile or 3/0.75mM NaTC/Leci for fed conditions) without detrimental effects on monolayer integrity/vitality (NaTC/Leci was more toxic than bile). Surfactants exerted different affinities for drugs; free drug concentration (c(free)) of some was significantly lowered only by bile, while for the others NaTC/Leci and bile significantly diminished c(free). For some substances NaTC/Leci and bile significantly increased their permeabilities (i.e. more than 3-times) in spite of profound c(free) decrease indicating the existence of an alternative absorption mechanism. Based on these data, the impact of bile on in vitro drug permeability and micellar drug entrapment cannot be adequately simulated by NaTC/Leci, because their effects on drug absorption differ. PMID:22449411

  13. Characterization of the role of ABCG2 as a bile acid transporter in liver and placenta.

    PubMed

    Blazquez, Alba G; Briz, Oscar; Romero, Marta R; Rosales, Ruben; Monte, Maria J; Vaquero, Javier; Macias, Rocio I R; Cassio, Doris; Marin, Jose J G

    2012-02-01

    ABCG2 is involved in epithelial transport/barrier functions. Here, we have investigated its ability to transport bile acids in liver and placenta. Cholylglycylamido fluorescein (CGamF) was exported by WIF-B9/R cells, which do not express the bile salt export pump (BSEP). Sensitivity to typical inhibitors suggested that CGamF export was mainly mediated by ABCG2. In Chinese hamster ovary (CHO cells), coexpression of rat Oatp1a1 and human ABCG2 enhanced the uptake and efflux, respectively, of CGamF, cholic acid (CA), glycoCA (GCA), tauroCA, and taurolithocholic acid-3-sulfate. The ability of ABCG2 to export these bile acids was confirmed by microinjecting them together with inulin in Xenopus laevis oocytes expressing this pump. ABCG2-mediated bile acid transport was inhibited by estradiol 17β-d-glucuronide and fumitremorgin C. Placental barrier for bile acids accounted for <2-fold increase in fetal cholanemia despite >14-fold increased maternal cholanemia induced by obstructive cholestasis in pregnant rats. In rat placenta, the expression of Abcg2, which was much higher than that of Bsep, was not affected by short-term cholestasis. In pregnant rats, fumitremorgin C did not affect uptake/secretion of GCA by the liver but inhibited its fetal-maternal transfer. Compared with wild-type mice, obstructive cholestasis in pregnant Abcg2(-/-) knockout mice induced similar bile acid accumulation in maternal serum but higher accumulation in placenta, fetal serum, and liver. In conclusion, ABCG2 is able to transport bile acids. The importance of this function depends on the relative expression in the same epithelium of other bile acid exporters. Thus, ABCG2 may play a key role in bile acid transport in placenta, as BSEP does in liver. PMID:22096226

  14. A New Insight into the Physiological Role of Bile Salt Hydrolase among Intestinal Bacteria from the Genus Bifidobacterium

    PubMed Central

    Jarocki, Piotr; Podleśny, Marcin; Glibowski, Paweł; Targoński, Zdzisław

    2014-01-01

    This study analyzes the occurrence of bile salt hydrolase in fourteen strains belonging to the genus Bifidobacterium. Deconjugation activity was detected using a plate test, two-step enzymatic reaction and activity staining on a native polyacrylamide gel. Subsequently, bile salt hydrolases from B. pseudocatenulatum and B. longum subsp. suis were purified using a two-step chromatographic procedure. Biochemical characterization of the bile salt hydrolases showed that the purified enzymes hydrolyzed all of the six major human bile salts under the pH and temperature conditions commonly found in the human gastrointestinal tract. Next, the dynamic rheometry was applied to monitor the gelation process of deoxycholic acid under different conditions. The results showed that bile acids displayed aqueous media gelating properties. Finally, gel-forming abilities of bifidobacteria exhibiting bile salt hydrolase activity were analyzed. Our investigations have demonstrated that the release of deconjugated bile acids led to the gelation phenomenon of the enzymatic reaction solution containing purified BSH. The presented results suggest that bile salt hydrolase activity commonly found among intestinal microbiota increases hydrogel-forming abilities of certain bile salts. To our knowledge, this is the first report showing that bile salt hydrolase activity among Bifidobacterium is directly connected with the gelation process of bile salts. In our opinion, if such a phenomenon occurs in physiological conditions of human gut, it may improve bacterial ability to colonize the gastrointestinal tract and their survival in this specific ecological niche. PMID:25470405

  15. Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure.

    PubMed

    McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew; Ashfaq, Samir; de los Santos, Mario; Grant, Stephanie; DeMorrow, Sharon

    2016-02-01

    Hepatic encephalopathy is a serious neurological complication of liver failure. Serum bile acids are elevated after liver damage and may disrupt the blood-brain barrier and enter the brain. Our aim was to assess the role of serum bile acids in the neurological complications after acute liver failure. C57Bl/6 or cytochrome p450 7A1 knockout (Cyp7A1(-/-)) mice were fed a control, cholestyramine-containing, or bile acid-containing diet before azoxymethane (AOM)-induced acute liver failure. In parallel, mice were given an intracerebroventricular infusion of farnesoid X receptor (FXR) Vivo-morpholino before AOM injection. Liver damage, neurological decline, and molecular analyses of bile acid signaling were performed. Total bile acid levels were increased in the cortex of AOM-treated mice. Reducing serum bile acids via cholestyramine feeding or using Cyp7A1(-/-) mice reduced bile acid levels and delayed AOM-induced neurological decline, whereas cholic acid or deoxycholic acid feeding worsened AOM-induced neurological decline. The expression of bile acid signaling machinery apical sodium-dependent bile acid transporter, FXR, and small heterodimer partner increased in the frontal cortex, and blocking FXR signaling delayed AOM-induced neurological decline. In conclusion, circulating bile acids may play a pathological role during hepatic encephalopathy, although precisely how they dysregulate normal brain function is unknown. Strategies to minimize serum bile acid concentrations may reduce the severity of neurological complications associated with liver failure. PMID:26683664

  16. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

    PubMed Central

    Hofmann, Alan F.; Hagey, Lee R.

    2014-01-01

    During the last 80 years there have been extraordinary advances in our knowledge of the chemistry and biology of bile acids. We present here a brief history of the major achievements as we perceive them. Bernal, a physicist, determined the X-ray structure of cholesterol crystals, and his data together with the vast chemical studies of Wieland and Windaus enabled the correct structure of the steroid nucleus to be deduced. Today, C24 and C27 bile acids together with C27 bile alcohols constitute most of the bile acid “family”. Patterns of bile acid hydroxylation and conjugation are summarized. Bile acid measurement encompasses the techniques of GC, HPLC, and MS, as well as enzymatic, bioluminescent, and competitive binding methods. The enterohepatic circulation of bile acids results from vectorial transport of bile acids by the ileal enterocyte and hepatocyte; the key transporters have been cloned. Bile acids are amphipathic, self-associate in solution, and form mixed micelles with polar lipids, phosphatidylcholine in bile, and fatty acids in intestinal content during triglyceride digestion. The rise and decline of dissolution of cholesterol gallstones by the ingestion of 3,7-dihydroxy bile acids is chronicled. Scientists from throughout the world have contributed to these achievements. PMID:24838141

  17. Steam Cooking Significantly Improves In Vitro Bile Acid Binding of Collard Greens, Kale, Mustard Greens, Broccoli, Green Bell Pepper and Cabbage

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bile acid binding capacity has been related to the cholesterol-lowering potential of foods and food fractions. Lowering recirculating bile acids results in utilization of cholesterol to synthesize bile acid and reduced fat absorption. Secondary bile acids have been associated with increasing the r...

  18. Evaluating the Beneficial and Detrimental Effects of Bile Pigments in Early and Later Life

    PubMed Central

    Dennery, Phyllis A.

    2012-01-01

    The heme degradation pathway has been conserved throughout phylogeny and allows for the removal of a pro-oxidant and the generation of unique molecules including bile pigments with important cellular functions. The impact of bile pigments on health and disease are reviewed, as is the special circumstance of neonatal hyperbilirubinemia. In addition, the importance of promoter polymorphisms in the UDP-glucuronosyl transferase gene (UGTA1), which is key to the elimination of excess bilirubin and to the prevention of its toxicity, are discussed. Overall, the duality of bile pigments as either cytoprotective or toxic molecules is highlighted. PMID:22737125

  19. Cloning and analysis of bile salt hydrolase genes from Lactobacillus plantarum CGMCC No. 8198.

    PubMed

    Gu, Xiang-Chao; Luo, Xue-Gang; Wang, Chong-Xi; Ma, De-Yun; Wang, Yan; He, Ying-Ying; Li, Wen; Zhou, Hao; Zhang, Tong-Cun

    2014-05-01

    Genes coding for bile salt hydrolase of Lactobacillus plantarum CGMCC 8198, a novel probiotic strain isolated from silage, were identified, analyzed and cloned. L. plantarum strongly resisted the inhibitory effects of bile salts and also decreased serum cholesterol levels by 20% in mice with hypercholesterolemia. Using RT-PCR analysis, bsh2, bsh3 and bsh4 were upregulated by bile salts in a dose-dependent manner. All three bsh genes had high similarity with those of other Lactobacillus strains. All three recombinant BSHs had high activities for the hydrolysis of glycodeoxycholic acids and taurodeoxycholic acids. PMID:24375235

  20. Polarized light microscopic examination of human bile in the diagnosis of microlithiasis of the gallbladder.

    PubMed

    Gogna, A; Kar, P; Acharya, N R; Anand, V J; Kapoor, R

    1989-01-01

    Of the 20 cases with biliary colics who had normal OCG and ultrasound, 11 (55%) showed microlithiasis in the form of cholesterol monohydrate crystals and/or calcium bilirubinate granules on polarized light microscopy of the duodenal bile. Microlithiasis was noted in gallbladder bile of all (100%) the cases with proven gallstones but in none of the duodenal bile samples from healthy subjects. This study suggests that polarized microscopy may be a useful method to detect microlithiasis in patients with repeated biliary colics who have normal OCG and ultrasound examination. PMID:2815325

  1. Spontaneous perforation of the common bile-duct in the neonate: imaging and treatment.

    PubMed

    Ford, W D; Sen, S; Morris, L; LeQuesne, G

    1988-10-01

    The presence of bile in the peritoneal cavity and obstructive jaundice without liver derangement in the neonatal period is pathognomonic of spontaneous perforation of the bile-ducts. These features can be demonstrated preoperatively with ultrasound, nuclide imaging and liver function tests, without recourse to paracentesis, and the risk of contaminating the bile ascites. Furthermore, the presence of isotope in the general peritoneal cavity will exclude the diagnosis of a choledochal cyst so that jejunum should not be anastamosed to the 'false capsule' of a spontaneous perforation. PMID:3067698

  2. Evolutionary diversity of bile salts in reptiles and mammals, including analysis of ancient human and extinct giant ground sloth coprolites

    PubMed Central

    2010-01-01

    Background Bile salts are the major end-metabolites of cholesterol and are also important in lipid and protein digestion and in influencing the intestinal microflora. We greatly extend prior surveys of bile salt diversity in both reptiles and mammals, including analysis of 8,000 year old human coprolites and coprolites from the extinct Shasta ground sloth (Nothrotherium shastense). Results While there is significant variation of bile salts across species, bile salt profiles are generally stable within families and often within orders of reptiles and mammals, and do not directly correlate with differences in diet. The variation of bile salts generally accords with current molecular phylogenies of reptiles and mammals, including more recent groupings of squamate reptiles. For mammals, the most unusual finding was that the Paenungulates (elephants, manatees, and the rock hyrax) have a very different bile salt profile from the Rufous sengi and South American aardvark, two other mammals classified with Paenungulates in the cohort Afrotheria in molecular phylogenies. Analyses of the approximately 8,000 year old human coprolites yielded a bile salt profile very similar to that found in modern human feces. Analysis of the Shasta ground sloth coprolites (approximately 12,000 years old) showed the predominant presence of glycine-conjugated bile acids, similar to analyses of bile and feces of living sloths, in addition to a complex mixture of plant sterols and stanols expected from an herbivorous diet. Conclusions The bile salt synthetic pathway has become longer and more complex throughout vertebrate evolution, with some bile salt modifications only found within single groups such as marsupials. Analysis of the evolution of bile salt structures in different species provides a potentially rich model system for the evolution of a complex biochemical pathway in vertebrates. Our results also demonstrate the stability of bile salts in coprolites preserved in arid climates

  3. Bile-induced DNA strand breaks and biochemical analysis of bile acids in an experimental model of anomalous arrangement of the pancreaticobiliary ducts.

    PubMed

    Masamune, K; Kunitomo, K; Sasaki, K; Yagi, K; Komi, N; Tashiro, S

    1997-08-01

    A canine experimental model for the anomalous arrangement of the pancreaticobiliary ducts (APBD) was made to investigate the effects of bile acids on carcinogenesis. Seven adult mongrel dogs underwent dorsal pancreatico-cholecystostomy to serve as a functional model for APBD, and six dogs underwent the same procedure with the pancreatic duct ligated as a control group. Bile from the gallbladder was taken 14 months after surgery for bile acid analysis by HPLC. DNA strand breaks in HeLa cells induced by the bile were also investigated in situ by nick translation method. As a result, the fraction of cholic acid tended to be lower, and that of deoxycholic acid slightly higher in APBD-dogs (N.S.). The ursodeoxycholic acid percentage in APBD-dogs significantly decreased compared with that in the control and normal dogs (p < 0.05). Extremely high frequency of DNA strand breaks was shown in only two out of seven APBD-dogs. In those two dogs, the cholic acid percentage decreased and that of deoxycholic acid increased extremely. These findings suggest that the alteration of the bile composition in APBD caused frequent DNA strand breaks and repair which might lead to gene mutation and biliary tract carcinoma. PMID:9395717

  4. Structure of human NAPE-PLD: regulation of fatty-acid ethanolamide biosynthesis by bile acids

    PubMed Central

    Magotti, Paola; Bauer, Inga; Igarashi, Miki; Babagoli, Masih; Marotta, Roberto; Piomelli, Daniele; Garau, Gianpiero

    2015-01-01

    SUMMARY The fatty-acid ethanolamides (FAEs) are lipid mediators present in all organisms and involved in highly conserved biological functions such as innate immunity, energy balance and stress control. They are produced from membrane N-acylphosphatidylethanolamines (NAPEs) and include agonists for G protein-coupled receptors (e.g. cannabinoid receptors) and nuclear receptors (e.g. PPAR-α). Here we report the crystal structure of human NAPE-hydrolyzing phospholipase D (NAPE-PLD) at 2.65 Å resolution, a membrane enzyme that catalyzes FAE formation in mammals. NAPE-PLD forms homodimers partly separated by an internal ~9 Å-wide channel and uniquely adapted to associate with phospholipids. A hydrophobic cavity provides an entryway for NAPE into the active site, where a binuclear Zn2+ center orchestrates its hydrolysis. Bile acids bind with high affinity to selective pockets in this cavity, enhancing dimer assembly and enabling catalysis. These elements offer multiple targets for the design of small-molecule NAPE-PLD modulators with potential applications in inflammation and metabolic disorders. PMID:25684574

  5. Radical-mediated dehydrogenation of bile acids by means of hydrogen atom transfer to triplet carbonyls.

    PubMed

    Miro, P; Marin, M L; Miranda, M A

    2016-03-01

    The aim of the present paper is to explore the potential of radical-mediated dehydrogenation of bile salts (BSs), which is reminiscent of the enzymatic action of hydroxysteroid dehydrogenase enzymes (HSDH). The concept has been demonstrated using triplet carbonyls that can be efficiently generated upon selective UVA-excitation. Hydrogen atom transfer (HAT) from BSs to triplet benzophenone (BP) derivatives gave rise to radicals, ultimately leading to reduction of the BP chromophore with concomitant formation of the oxo-analogs of the corresponding BSs. The direct reactivity of triplet BP with BSs in the initial step was evaluated by determining the kinetic rate constants using laser flash photolysis (LFP). The BP triplet decay was monitored (λmax = 520 nm) upon addition of increasing BS concentrations, and the obtained rate constant values indicated a reactivity of the methine hydrogen atoms in the order of C-3 < C-12 < C-7. The steady-state kinetics of the overall process, monitored through the disappearance of the typical BP absorption band at 260 nm, was much faster under N2 than under O2, also supporting the role of the oxygen-quenchable triplet in the dehydrogenation process. Furthermore, irradiation of deaerated aqueous solutions of sodium cholate in the presence of KPMe provided the oxo-analogs, 3[O],7[O]-CA, 3[O]-CA and 7[O]-CA, arising from the HAT process. PMID:26833240

  6. Changes in bile acids, FGF-19 and sterol absorption in response to bile salt hydrolase active L. reuteri NCIMB 30242.

    PubMed

    Martoni, Christopher J; Labbé, Alain; Ganopolsky, Jorge G; Prakash, Satya; Jones, Mitchell L

    2015-01-01

    The size and composition of the circulating bile acid (BA) pool are important factors in regulating the human gut microbiota. Disrupted regulation of BA metabolism is implicated in several chronic diseases. Bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242, previously shown to decrease LDL-cholesterol and increase circulating BA, was investigated for its dose response effect on BA profile in a pilot clinical study. Ten otherwise healthy hypercholesterolemic adults, recruited from a clinical trial site in London, ON, were randomized to consume delayed release or standard release capsules containing L. reuteri NCIMB 30242 in escalating dose over 4 weeks. In another aspect, 4 healthy normocholesterolemic subjects with LDL-C below 3.4 mmol/l received delayed release L. reuteri NCIMB 30242 at a constant dose over 4 weeks. The primary outcome measure was the change in plasma BA profile over the intervention period. Additional outcomes included circulating fibroblast growth factor (FGF)-19, plant sterols and LDL-cholesterol as well as fecal microbiota and bsh gene presence. After one week of intervention subjects receiving delayed release L. reuteri NCIMB 30242 increased total BA by 1.13 ± 0.67 μmol/l (P = 0.02), conjugated BA by 0.67 ± 0.39 μmol/l (P = 0.02) and unconjugated BA by 0.46 ± 0.43 μmol/l (P = 0.07), which represented a greater than 2-fold change relative to baseline. Increases in BA were largely maintained post-week 1 and were generally correlated with FGF-19 and inversely correlated with plant sterols. This is the first clinical support showing that a BSH-active probiotic can significantly and rapidly influence BA metabolism and may prove useful in chronic diseases beyond hypercholesterolemia. PMID:25612224

  7. Changes in bile acids, FGF-19 and sterol absorption in response to bile salt hydrolase active L. reuteri NCIMB 30242

    PubMed Central

    Martoni, Christopher J; Labbé, Alain; Ganopolsky, Jorge G; Prakash, Satya; Jones, Mitchell L

    2015-01-01

    The size and composition of the circulating bile acid (BA) pool are important factors in regulating the human gut microbiota. Disrupted regulation of BA metabolism is implicated in several chronic diseases. Bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242, previously shown to decrease LDL-cholesterol and increase circulating BA, was investigated for its dose response effect on BA profile in a pilot clinical study. Ten otherwise healthy hypercholesterolemic adults, recruited from a clinical trial site in London, ON, were randomized to consume delayed release or standard release capsules containing L. reuteri NCIMB 30242 in escalating dose over 4 weeks. In another aspect, 4 healthy normocholesterolemic subjects with LDL-C below 3.4 mmol/l received delayed release L. reuteri NCIMB 30242 at a constant dose over 4 weeks. The primary outcome measure was the change in plasma BA profile over the intervention period. Additional outcomes included circulating fibroblast growth factor (FGF)-19, plant sterols and LDL-cholesterol as well as fecal microbiota and bsh gene presence. After one week of intervention subjects receiving delayed release L. reuteri NCIMB 30242 increased total BA by 1.13 ± 0.67 μmol/l (P = 0.02), conjugated BA by 0.67 ± 0.39 μmol/l (P = 0.02) and unconjugated BA by 0.46 ± 0.43 μmol/l (P = 0.07), which represented a greater than 2-fold change relative to baseline. Increases in BA were largely maintained post-week 1 and were generally correlated with FGF-19 and inversely correlated with plant sterols. This is the first clinical support showing that a BSH-active probiotic can significantly and rapidly influence BA metabolism and may prove useful in chronic diseases beyond hypercholesterolemia. PMID:25612224

  8. Prevention of Bile Leak after Liver Surgery: A Fool-proof Method

    PubMed Central

    Pujahari, Aswini K.

    2009-01-01

    Background/Aim: Bile leak is not uncommon after liver surgeries. There is no adequate method described to prevent this morbid complication. Materials and Methods: At the end of the liver procedure, transcystic normal saline was injected under pressure with distal clamping. Leaking saline on the cut surface of the liver was sutured. The process was repeated till no leaking was observed. A suction drain was kept for any bile leak. Results: Open liver resection and hydatid cyst surgery cases were included. There were 24 cases, with 13 males and 11 females. The age range was from 4 to 80 years, with a mean of 48 years (SD ± 17.7). The number of leak sites that could be sutured were 0-4 (mean of 2.3 ± 0.5). None had bile leak postoperatively. Conclusion: Transcystic injection under pressure with distal clamping demonstrates the leak sites. Suturing them prevents the postoperative bile leak. PMID:19568579

  9. Se-75-labeled bile acid analogs, new radiopharmaceuticals for investigating the enterohepatic circulation. [Rats

    SciTech Connect

    Boyd, G.S.; Merrick, M.V.; Monks, R.; Thomas, I.L.

    1981-08-01

    Four selenium-labeled free bile acids and four selenium-labeled conjugated bile acids, labeled with Se-75 at the C-19, C-22, C-23, or C-24 position, have been synthesized and their absorption and excretion compared with that of (24-/sup 14/C)cholic acid, following both oral and intravenous administration. All but one of the compounds is absorbed and excreted in bile to a significant extent. One compound, SeHCAT, has been selected for particular study. It is quantitatively absorbed from the gut at the same rate as cholic acid, and both are excreted into the bile at the same rate. It remains almost entirely confined to the enterohepatic circulation (the gut, liver, and biliary tree) and excretion is exclusively fecal. Such a compound offers the possibility of a simple, novel, and aesthetically acceptalbe method investigating small-bowel disease.

  10. Using resin to generate a non-invasive intestinal bile-depleted rat model was unsuccessful.

    PubMed

    Holm, René; Hesselkilde, Janne Z; Jørgensen, Erling B; Müllertz, Anette

    2012-09-29

    The purpose of this study was to evaluate if a rat model, based upon co-administration of the anion-exchanging resin, cholestyramine, could replace surgery when evaluating the importance of bile on drug absorption. Two different formulations were used for the administration of halofantrine; polyethylene glycol 400 (PEG 400) and PEG 400/polysorbate 80 (50:50, w/w%), as a positive and negative control on the dependency of bile. No significant effect of the resin was detected after evaluation of three different pre-dosing regimes, but in line with previous studies the formulation containing polysorbate 80 showed a significant increase in the absorption of halofantrine. This study therefore demonstrates that the pre-dosing of rats with Cholestyramine can not replace surgical bile duct cannulation if a formulation needs to be evaluated for its bile dependency. PMID:22732256

  11. Evaluating Healthful Properties of Cereals and Cereal Fractions by Their Bile-Acid-Binding Potential

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The healthful, cholesterol-lowering (atherosclerosis amelioration) or detoxification of harmful metabolites (cancer prevention) potential of cereals and cereal fractions could be predicted by evaluating their in vitro bile acid binding under physiological conditions. Using equal dry matter per incu...

  12. Relief of common bile duct obstruction during the course of hepatobiliary scintigraphy.

    PubMed

    Jacobson, A F

    1995-10-01

    Hepatobiliary scintigraphy performed in a patient suspected of having common bile duct obstruction showed persistence of the hepatic parenchymal phase and no bile duct or gallbladder activity during the first hour of imaging. On endoscopic retrograde cholangiopancreatography examination several hours later, an obstructing gallstone was identified in the common bile duct, and the stone was extracted in conjunction with a papillotomy. Delayed scintigraphic images at 6 hours were unchanged from the earlier views, but imaging at 24 hours showed tracer activity in the small bowel and colon along with persistent hepatic parenchymal activity. These results demonstrate that hepatobiliary radiopharmaceuticals remain in an excretable form in the liver in patients with complete common duct obstruction, but that resumption of bile flow and tracer excretion does not occur until a number of hours after relief of the obstruction. PMID:8616993

  13. Evaluation of two enzymatic methods of determining unsulphated serum bile acids.

    PubMed

    Hedenborg, G; Norman, A; Samuelson, K

    1984-12-01

    Two enzymatic methods of determining unsulphated 3 alpha-hydroxylated and 7 alpha-hydroxylated bile acids, respectively, were evaluated. Both methods are based on a coupled enzyme reaction involving a coloured redox indicator and absorbance measurement as the final step. Recovery and specificity were tested on human serum pools containing different bile acids added in various amounts, and by comparison of the results with those obtained by gas-liquid chromatography after group separation of bile acids from patient sera. Results from the two enzymatic methods were also compared with those determined with radioimmunoassay on a large number of patient sera. The results indicate that the enzymatic methods are useful for serum bile acid screening but more sensitive methods are necessary for investigations within the normal range. PMID:6597529

  14. Proteomic and transcriptomic analysis of the response to bile stress of Lactobacillus casei BL23.

    PubMed

    Alcántara, Cristina; Zúñiga, Manuel

    2012-05-01

    Lactobacillus casei is a lactic acid bacterium commonly found in the gastrointestinal tract of animals, and some strains are used as probiotics. The ability of probiotic strains to survive the passage through the gastrointestinal tract is considered a key factor for their probiotic action. Therefore, tolerance to bile salts is a desirable feature for probiotic strains. In this study we have characterized the response of L. casei BL23 to bile by a transcriptomic and proteomic approach. The analysis revealed that exposure to bile induced changes in the abundance of 52 proteins and the transcript levels of 67 genes. The observed changes affected genes and proteins involved in the stress response, fatty acid and cell wall biosynthesis, metabolism of carbohydrates, transport of peptides, coenzyme levels, membrane H(+)-ATPase, and a number of uncharacterized genes and proteins. These data provide new insights into the mechanisms that enable L. casei BL23 to cope with bile stress. PMID:22322960

  15. Heterogeneity of bile pigment conjugates as revealed by chromatography of their anthranilate azopigments

    PubMed Central

    Heirwegh, K. P. M.; Van Hees, G. P.; Leroy, P.; Van Roy, F. P.; Jansen, F. H.

    1970-01-01

    1. Azopigments derived from conjugated bile pigments by coupling with the diazonium salt of ethyl anthranilate are analysed conveniently by quantitative t.l.c. or by column chromatography on CM-cellulose. 2. By chromatographic studies combined with a series of chemical tests six groups of azopigments were demonstrable in preparations from bile and from icteric urine of man. Azobilirubin and its β-d-monoglucuronide have hitherto been considered to be the only major derivatives that can be obtained from human bile pigments. In the present work, other azopigments accounted for 30–40% of the total azopigment material, and the amounts of these showed considerable variation among biological fluids. 3. The divergence of the present results from earlier work is probably related to the use of milder diazotization conditions and of chromatographic techniques with a high resolving power. 4. The thin-layer chromatographic systems developed allow rapid and quantitative analysis of azopigments derived from bile pigments. PMID:5500353

  16. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

    PubMed Central

    Gomez-Ospina, Natalia; Potter, Carol J.; Xiao, Rui; Manickam, Kandamurugu; Kim, Mi-Sun; Kim, Kang Ho; Shneider, Benjamin L.; Picarsic, Jennifer L.; Jacobson, Theodora A.; Zhang, Jing; He, Weimin; Liu, Pengfei; Knisely, A. S.; Finegold, Milton J.; Muzny, Donna M.; Boerwinkle, Eric; Lupski, James R.; Plon, Sharon E.; Gibbs, Richard A.; Eng, Christine M.; Yang, Yaping; Washington, Gabriel C.; Porteus, Matthew H.; Berquist, William E.; Kambham, Neeraja; Singh, Ravinder J.; Xia, Fan; Enns, Gregory M.; Moore, David D.

    2016-01-01

    Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection. PMID:26888176

  17. Common bile duct perforation sealed with a metal fully-covered stent.

    PubMed

    García-Cano, Jesús; Ferri-Bataller, Ramón; Gómez-Ruiz, Carmen Julia

    2016-08-01

    A common bile duct perforation due to sphincteroplasty is reported. It was managed by temporary insertion of a metal fully covered stent with good outcomes. Images from the procedure are provided. PMID:27554382

  18. Determination of total and hexavalent chromium in bile after intravenous administration of potassium dichromate in rats

    SciTech Connect

    Cavalleri, A.; Minoia, C.; Richelmi, P.; Baldi, C.; Micoli, G.

    1985-08-01

    Total and hexavalent chromium were measured in bile samples obtained from cannulated bile ducts of male rats iv administered with potassium dichromate at various doses corresponding to 0.1, 0.5, and 1 mg of chromium. The evaluation of the hexavalent form was performed by separation with a liquid anion exchanger and electrothermal atomization-atomic absorption spectrophotometric determination. Within 2 hr 1.35-2.23% of the chromium injected was recovered in bile as total chromium, the hexavalent form accounting for less than 1% of the total chromium collected, which seems almost entirely excreted as trivalent chromium. Since Cr(VI) administered iv was quickly reduced to Cr(III) in blood, the possibility exists for chromium in trivalent form to penetrate into the liver cells and to be excreted in the bile, possibly by binding to a carrier such as the low-molecular-weight substances described by Yamamoto et al.

  19. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

    PubMed Central

    Porez, Geoffrey; Prawitt, Janne; Gross, Barbara; Staels, Bart

    2012-01-01

    Dyslipidemia is an important risk factor for cardiovascular disease (CVD) and atherosclerosis. When dyslipidemia coincides with other metabolic disorders such as obesity, hypertension, and glucose intolerance, defined as the metabolic syndrome (MS), individuals present an elevated risk to develop type 2 diabetes (T2D) as well as CVD. Because the MS epidemic represents a growing public health problem worldwide, the development of therapies remains a major challenge. Alterations of bile acid pool regulation in T2D have revealed a link between bile acid and metabolic homeostasis. The bile acid receptors farnesoid X receptor (FXR) and TGR5 both regulate lipid, glucose, and energy metabolism, rendering them potential pharmacological targets for MS therapy. This review discusses the mechanisms of metabolic regulation by FXR and TGR5 and the utility relevance of natural and synthetic modulators of FXR and TGR5 activity, including bile acid sequestrants, in the treatment of the MS. PMID:22550135

  20. Resolving bile reflux by lanreotide in patients with Roux-en-Y gastrojejunostomy.

    PubMed

    Moubax, K; Mana, F; Urbain, D

    2014-12-01

    Reflux into the esophagus after partial or total gastrectomy is a well known problem. Even a Roux-en-Y reconstruction is not always a definitive solution. Bile reflux might occur and cause disabling symptoms, unresponsive to the classic anti-acid or anti-reflux therapy. Endoscopy and a Tc-99m-BrIDA hepatobiliary (HIDA) scan can be used to make the diagnosis. Clinical studies have shown that lanreotide (somatuline), which strongly inhibits many gastro-intestinal hormones, reduces the bile salts outputs. We present a case of a patient with bile reflux after Roux-en-Y. After administration of lanreotide he had a good clinical improvement and mucosal healing on endoscopy. Lanreotide can be a good treatment option for bile reflux when classic treatment fails, but clinical trials with more patients will have to confirm this. PMID:25682623

  1. Laparoscopic common bile duct exploration for extraction of a round worm.

    PubMed

    Moirangthem, G S; Singh, C Arunkumar; Lokendra, K; Singh, L Deban

    2006-01-01

    A 35 years old lady presented with fever, biliary colic, mild jaundice, indigestion and flatulence. The upper abdominal ultrasonography revealed cholecystitis with sludge and a round worm in the common bile duct. Laparoscopic cholecystectomy and exploration of the bile duct for the removal of round worm was performed. The post-operative period was uneventful and the patient was discharged fit on the 4th post-operative day. PMID:17542295

  2. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice.

    PubMed

    Wagner, Martin; Halilbasic, Emina; Marschall, Hanns-Ulrich; Zollner, Gernot; Fickert, Peter; Langner, Cord; Zatloukal, Kurt; Denk, Helmut; Trauner, Michael

    2005-08-01

    Induction of hepatic phase I/II detoxification enzymes and alternative excretory pumps may limit hepatocellular accumulation of toxic biliary compounds in cholestasis. Because the nuclear xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate involved enzymes and transporters, we aimed to induce adaptive alternative pathways with different CAR and PXR agonists in vivo. Mice were treated with the CAR agonists phenobarbital and 1,4-bis-[2-(3,5-dichlorpyridyloxy)]benzene, as well as the PXR agonists atorvastatin and pregnenolone-16alpha-carbonitrile. Hepatic bile acid and bilirubin-metabolizing/detoxifying enzymes (Cyp2b10, Cyp3a11, Ugt1a1, Sult2a1), their regulatory nuclear receptors (CAR, PXR, farnesoid X receptor), and bile acid/organic anion and lipid transporters (Ntcp, Oatp1,2,4, Bsep, Mrp2-4, Mdr2, Abcg5/8, Asbt) in the liver and kidney were analyzed via reverse-transcriptase polymerase chain reaction and Western blotting. Potential functional relevance was tested in common bile duct ligation (CBDL). CAR agonists induced Mrp2-4 and Oatp2; PXR agonists induced only Mrp3 and Oatp2. Both PXR and CAR agonists profoundly stimulated bile acid-hydroxylating/detoxifying enzymes Cyp3a11 and Cyp2b10. In addition, CAR agonists upregulated bile acid-sulfating Sult2a1 and bilirubin-glucuronidating Ugt1a1. These changes were accompanied by reduced serum levels of bilirubin and bile acids in healthy and CBDL mice and by increased levels of polyhydroxylated bile acids in serum and urine of cholestatic mice. Atorvastatin significantly increased Oatp2, Mdr2, and Asbt, while other transporters and enzymes were moderately affected. In conclusion, administration of specific CAR or PXR ligands results in coordinated stimulation of major hepatic bile acid/bilirubin metabolizing and detoxifying enzymes and hepatic key alternative efflux systems, effects that are predicted to counteract cholestasis. PMID:15986414

  3. Normothermic machine perfusion reduces bile duct injury and improves biliary epithelial function in rat donor livers.

    PubMed

    Op den Dries, Sanna; Karimian, Negin; Westerkamp, Andrie C; Sutton, Michael E; Kuipers, Michiel; Wiersema-Buist, Janneke; Ottens, Petra J; Kuipers, Jeroen; Giepmans, Ben N; Leuvenink, Henri G D; Lisman, Ton; Porte, Robert J

    2016-07-01

    Bile duct injury may occur during liver procurement and transplantation, especially in livers from donation after circulatory death (DCD) donors. Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury compared to static cold storage (SCS). However, it is unknown whether NMP provides better preservation of bile ducts. The aim of this study was to determine the impact of NMP on bile duct preservation in both DCD and non-DCD livers. DCD and non-DCD livers obtained from Lewis rats were preserved for 3 hours using either SCS or NMP, followed by 2 hours ex vivo reperfusion. Biomarkers of bile duct injury (gamma-glutamyltransferase and lactate dehydrogenase in bile) were lower in NMP-preserved livers compared to SCS-preserved livers. Biliary bicarbonate concentration, reflecting biliary epithelial function, was 2-fold higher in NMP-preserved livers (P < 0.01). In parallel with this, the pH of the bile was significantly higher in NMP-preserved livers (7.63 ± 0.02 and 7.74 ± 0.05 for non-DCD and DCD livers, respectively) compared with SCS-preserved livers (7.46 ± 0.02 and 7.49 ± 0.04 for non-DCD and DCD livers, respectively). Scanning and transmission electron microscopy of donor extrahepatic bile ducts demonstrated significantly decreased injury of the biliary epithelium of NMP-preserved donor livers (including the loss of lateral interdigitations and mitochondrial injury). Differences between NMP and SCS were most prominent in DCD livers. Compared to conventional SCS, NMP provides superior preservation of bile duct epithelial cell function and morphology, especially in DCD donor livers. By reducing biliary injury, NMP could have an important impact on the utilization of DCD livers and outcome after transplantation. Liver Transplantation 22 994-1005 2016 AASLD. PMID:26946466

  4. Biliary bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid.

    PubMed

    Combes, B; Carithers, R L; Maddrey, W C; Munoz, S; Garcia-Tsao, G; Bonner, G F; Boyer, J L; Luketic, V A; Shiffman, M L; Peters, M G; White, H; Zetterman, R K; Risser, R; Rossi, S S; Hofmann, A F

    1999-06-01

    Bile acid composition in fasting duodenal bile was assessed at entry and at 2 years in patients with primary biliary cirrhosis (PBC) enrolled in a randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) (10-12 mg/kg/d) taken as a single bedtime dose. Specimens were analyzed by a high-pressure liquid chromatography method that had been validated against gas chromatography. Percent composition in bile (mean +/- SD) for 98 patients at entry for cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA), lithocholic (LCA), and ursodeoxycholic (UDCA) acids, respectively, were 57.4 +/- 18.6, 31.5 +/- 15.5, 8.0 +/- 9.3, 0.3 +/- 1.0, and 0.6 +/- 0.9. Values for CA were increased, whereas those for CDCA, DCA, LCA, and UDCA were decreased when compared with values in normal persons. Bile acid composition of the major bile acids did not change after 2 years on placebo medication. By contrast, in patients receiving UDCA for 2 years, bile became enriched with UDCA on average to 40.1%, and significant decreases were noted for CA (to 32.2%) and CDCA (to 19.5%). No change in percent composition was observed for DCA and LCA. Percent composition at entry and changes in composition after 2 years on UDCA were similar in patients with varying severity of PBC. In patients whose bile was not enriched in UDCA (entry and placebo-treated specimens), CA, CDCA, DCA, and the small amount of UDCA found in some of these specimens were conjugated to a greater extent with glycine (52%-64%) than with taurine (36%-48%). Treatment with UDCA caused the proportion of all endogenous bile acids conjugated with glycine to increase to 69% to 78%, while the proportion conjugated with taurine (22%-31%) fell (P <.05). Administered UDCA was also conjugated predominantly with glycine (87%). PMID:10347103

  5. Eleven-year experience on the endoscopic treatment of post-cholecystectomy bile leaks

    PubMed Central

    Fasoulas, Kostas; Zavos, Christos; Chatzimavroudis, Grigoris; Trakateli, Christina; Vasiliadis, Themistoklis; Ioannidis, Aristidis; Kountouras, Jannis; Katsinelos, Panagiotis

    2011-01-01

    Background Bile leak is a common and serious complication of cholecystectomy with endotherapy being an established method of treatment. This retrospective study presents the 11-year experience of a referral center in endoscopic management of post-cholecystectomy bile leaks. Methods During the period between January 2000 and December 2010, records of patients who had undergone endoscopic retrograde cholangiopancreatography (ERCP) for suspected post-cholecystectomy bile leaks were reviewed for evidence of clinical presentation of bile leaks, cholangiographic findings, type of endoscopic intervention, procedural complications and post-procedure follow-up. Results Seventy-one patients with suspected post-cholecystectomy bile leak were referred for ERCP. Common bile duct (CBD) cannulation was successful in 70 patients (98.59%). Complete transection of CBD was diagnosed in 4 patients; they were treated with surgery. A leak from the cystic duct stump was demonstrated in 49 patients (74.24%), from the ducts of Luschka in 4 (6.06%), from the gallbladder bed in 2 (3.03%), from the CBD in 7 (10.61%) and from the common hepatic duct (CHD) in 4 patients (6.06%). Endoscopic sphincterotomy (ES) plus endoprosthesis was performed in 64 patients (96.97%). A 12-year-old girl with a leak from cystic duct stump was successfully treated with stenting without ES and one patient with leak from gallbladder bed underwent only ES. Endoscopic intervention failed to treat a leak from CHD in one patient. During the follow-up, three patients developed bile duct stricture. Two were treated endoscopically and one with hepaticojejunostomy. Conclusions ES plus large-bore straight plastic biliary stent placement is a safe and effective intervention in post-cholecystectomy bile leaks. PMID:24713781

  6. A rapid and sensitive method for HPLC cholesterol determination in bile.

    PubMed

    Bocos, C; Castro, M; Orozco, E; Contreras, J A; Herrera, E

    1992-09-01

    A relatively little time consuming simple method based on the treatment of bile with cholesterol oxidase and subsequent high performance liquid chromatography measurement of the 3-ketocholesterol produced in order to determine the level of the cholesterol concentration is described. The method avoids bilirubin interferences, has high reproducibility and recovery assays give 100% values. It is highly sensitive and suitable for use in the determination of cholesterol concentrations in bile and other bilirubin containing biological fluids. PMID:1301638

  7. Effect of bile diversion on satiety and fat absorption from liquid and solid dietary sources

    SciTech Connect

    Doty, J.E.; Gu, Y.G.; Meyer, J.H.

    1988-12-01

    In previous studies, liquid fat has been used to determine the effect of bile diversion on fat absorption. Since protein digests, in addition to bile salts, are capable of solubilizing lipids, we hypothesized that fat incorporated in the protein-rich matrix of solid food would be less sensitive to bile diversion than fat ingested as an oil or liquid. Using (3H)glycerol triether as a nonabsorbable fat recovery marker, we determined how much (14C)triolein was absorbed from solid (chicken liver) and liquid (margarine) dietary sources. After a standard liquid/solid meal with either the chicken liver or margarine labeled, midintestinal chyme was collected for 6 hr, extracted, and counted for 14C and 3H activity. Zero, eighty, or one hundred percent of endogenous bile was diverted. Fat absorption from both chicken liver and margarine was nearly complete by midintestine with 0% diversion and was little affected by diversion of 80% of bile. Complete biliary diversion significantly decreased fat absorption from margarine (87.9 +/- 4.4 to 37.2 +/- 9.2%, P less than 0.05) but reduced (14C)triolein absorption from chicken liver less consistently and insignificantly (78.8 +/- 6.9 to 43.9 +/- 10.6%). These data indicate that fat absorption is not solely dependent on bile and support the hypothesis that fat ingested in a cellular matrix is less dependent on bile than liquid fat. Using these same animals but with the midintestinal cannulas plugged to expose the distal intestine to unabsorbed luminal nutrients, we also demonstrated that bile diversion of an initial meal reduced food consumption at a meal offered 3 hr later.

  8. Biliary excretion of pravastatin and taurocholate in rats with bile salt export pump (Bsep) impairment.

    PubMed

    Cheng, Yaofeng; Freeden, Chris; Zhang, Yueping; Abraham, Pamela; Shen, Hong; Wescott, Debra; Humphreys, W Griffith; Gan, Jinping; Lai, Yurong

    2016-07-01

    The bile salt export pump (BSEP) is expressed on the canalicular membrane of hepatocytes regulating liver bile salt excretion, and impairment of BSEP function may lead to cholestasis in humans. This study explored drug biliary excretion, as well as serum chemistry, individual bile acid concentrations and liver transporter expressions, in the SAGE Bsep knockout (KO) rat model. It was observed that the Bsep protein in KO rats was decreased to 15% of that in the wild type (WT), as quantified using LC-MS/MS. While the levels of Ntcp and Mrp2 were not significantly altered, Mrp3 expression increased and Oatp1a1 decreased in KO animals. Compared with the WT rats, the KO rats had similar serum chemistry and showed normal liver transaminases. Although the total plasma bile salts and bile flow were not significantly changed in Bsep KO rats, individual bile acids in plasma and liver demonstrated variable changes, indicating the impact of Bsep KO. Following an intravenous dose of deuterium labeled taurocholic acid (D4-TCA, 2 mg/kg), the D4-TCA plasma exposure was higher and bile excretion was delayed by approximately 0.5 h in the KO rats. No differences were observed for the pravastatin plasma concentration-time profile or the biliary excretion after intravenous administration (1 mg/kg). Collectively, the results revealed that these rats have significantly lower Bsep expression, therefore affecting the biliary excretion of endogenous bile acids and Bsep substrates. However, these rats are able to maintain a relatively normal liver function through the remaining Bsep protein and via the regulation of other transporters. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27059119

  9. Distinct Plasma Bile Acid Profiles of Biliary Atresia and Neonatal Hepatitis Syndrome.

    PubMed

    Zhou, Kejun; Wang, Jun; Xie, Guoxiang; Zhou, Ying; Yan, Weihui; Pan, Weihua; Che, Yanran; Zhang, Ting; Wong, Linda; Kwee, Sandi; Xiao, Yongtao; Wen, Jie; Cai, Wei; Jia, Wei

    2015-11-01

    Biliary atresia (BA) is a severe chronic cholestasis disorder of infants that leads to death if not treated on time. Neonatal hepatitis syndrome (NHS) is another leading cause of neonatal cholestasis confounding the diagnosis of BA. Recent studies indicate that altered bile acid metabolism is closely associated with liver injury and cholestasis. In this study, we systematically measured the bile acid metabolome in plasma of BA, NHS, and healthy controls. Liver bile acids were also measured using biopsy samples from 48 BA and 16 NHS infants undergoing operative cholangiography as well as 5 normal adjacent nontumor liver tissues taken from hepatoblastoma patients as controls. Both BA and NHS samples had significantly elevated bile acid levels in plasma compared to normal controls. BA patients showed a distinct bile acid profile characterized by the higher taurochenodeoxycholic acid (TCDCA) level and lower chenodeoxycholic acid (CDCA) level than those in NHS patients. The ratio of TCDCA to CDCA in plasma was significantly higher in BA compared to healthy infants (p < 0.001) or NHS (p < 0.001). The area under receiver operating characteristic curve for TCDCA/CDCA to differentiate BA from NHS was 0.923 (95% CI: 0.862-0.984). These findings were supported by significantly altered expression levels of bile acid transporters and nuclear receptors in liver including farnesoid X receptor (FXR), small heterodimer partner (SHP), bile salt export pump (BSEP), and multidrug resistant protein 3 (MDR3) in BA compared to NHS. Taken together, the plasma bile acid profiles are distinct in BA, NHS, and normal infants, as characterized by the ratio of TCDCA/CDCA differentially distributed among the three groups of infants. PMID:26449593

  10. Primary Patency of Wallstents in Malignant Bile Duct Obstruction: Single vs. Two or More Noncoaxial Stents

    SciTech Connect

    Maybody, Majid Brown, Karen T.; Brody, Lynn A.; Covey, Anne M.; Sofocleous, Constantinos T.; Thornton, Raymond H.; Getrajdman, George I.

    2009-07-15

    The purpose of this study was to determine the primary patency of two or more noncoaxial self-expanding metallic Wallstents (Boston Scientific, Natick, MA) and to compare this with the primary patency of a single stent in malignant bile duct obstruction. From August 2002 to August 2004, 127 patients had stents placed for malignant bile duct obstruction. Forty-five patients were treated with more than one noncoaxial self-expanding metallic stents and 82 patients had a single stent placed. Two patients in the multiple-stent group were lost to follow-up. The primary patency period was calculated from the date of stenting until the first poststenting intervention for stent occlusion, death, or the time of last documented follow-up. The patency of a single stent was significantly different from that of multiple stents (P = 0.0004). In the subset of patients with high bile duct obstruction, the patency of a single stent remained significantly different from that of multiple stents (P = 0.02). In the single-stent group, there was no difference in patency between patients with high vs. those with low bile duct obstruction (P = 0.43). The overall median patency for the multistent group and the single-stent group was 201 and 261 days, respectively. In conclusion, the patency of a single stent placed for malignant low or high bile duct obstruction is similar, and significantly longer than, that of multiple stents placed for malignant high bile duct obstruction. Given the median patency of 201 days, when indicated, percutaneous stenting of multiple bile ducts is an effective palliative measure for patients with malignant high bile duct obstruction.

  11. Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high-cholesterol-fed rats.

    PubMed

    Murakami, Shigeru; Fujita, Michiko; Nakamura, Masakazu; Sakono, Masanobu; Nishizono, Shoko; Sato, Masao; Imaizumi, Katsumi; Mori, Mari; Fukuda, Nobuhiro

    2016-03-01

    This study was designed to investigate the effects of dietary taurine on cholesterol metabolism in high-cholesterol-fed rats. Male Sprague-Dawley rats were randomly divided into two dietary groups (n = 6 in each group): a high-cholesterol diet containing 0.5% cholesterol and 0.15% sodium cholate, and a high-cholesterol diet with 5% (w/w) taurine. The experimental diets were given for 2 weeks. Taurine supplementation reduced the serum and hepatic cholesterol levels by 37% and 32%, respectively. Faecal excretion of bile acids was significantly increased in taurine-treated rats, compared with untreated rats. Biliary bile acid concentrations were also increased by taurine. Taurine supplementation increased taurine-conjugated bile acids by 61% and decreased glycine-conjugated bile acids by 53%, resulting in a significant decrease in the glycine/taurine (G/T) ratio. Among the taurine-conjugated bile acids, cholic acid and deoxycholic acid were significantly increased. In the liver, taurine supplementation increased the mRNA expression and enzymatic activity of hepatic cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme for bile acid synthesis, by three- and two-fold, respectively. Taurine also decreased the enzymatic activity of acyl-CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). These observations suggest that taurine supplementation increases the synthesis and excretion of taurine-conjugated bile acids and stimulates the catabolism of cholesterol to bile acid by elevating the expression and activity of CYP7A1. This may reduce cholesterol esterification and lipoprotein assembly for very low density lipoprotein (VLDL) secretion, leading to reductions in the serum and hepatic cholesterol levels. PMID:26710098

  12. Effects of conjugated and unconjugated bile acids on the activity of the Vibrio cholerae porin OmpT.

    PubMed

    Pagel, Melissa; Delcour, Anne H

    2011-01-01

    During infection, the enteric pathogen Vibrio cholerae encounters a bile-containing environment. Previous studies have shown that bile and/or bile acids exert several effects on the virulence and physiology of the bacterial cells. These observations have led to the suggestion that bile acids may play a signaling role in infection. We have previously reported that the bile component deoxycholic acid blocks the general diffusion porin OmpT in a dose-dependent manner, presumably as it transits through the pore. V. cholerae colonizes the distal jejunum and ileum, where a mixture of various conjugated and unconjugated bile acids are found. In this work, we have used patch clamp electrophysiology to investigate the effects of six bile acids on OmpT. Two bile acids (deoxycholic and chenodeoxycholic acids) were found to block OmpT at physiological concentrations below 1 mM, while glycodeoxycholic acid was mildly effective and cholic, lithocholic and taurodeoxycholic acids were ineffective in this range. The block was also voltage-dependent. These observations suggest the presence of a specific binding site inside the OmpT pore. Since deconjugation is due to the activity of the endogenous flora, the preferential uptake of some unconjugated bile acids by OmpT may signal the presence of a hospitable environment. The results are also discussed in terms of the possible molecular interactions between the penetrating bile acid molecule and the channel wall. PMID:21067451

  13. Characterization of a novel bile-inducible operon encoding a two-component regulatory system in Lactobacillus acidophilus.

    PubMed

    Pfeiler, Erika A; Azcarate-Peril, M Andrea; Klaenhammer, Todd R

    2007-07-01

    Lactobacillus acidophilus NCFM is an industrially important strain used extensively as a probiotic culture. Tolerance of the presence of bile is an attribute important to microbial survival in the intestinal tract. A whole-genome microarray was employed to examine the effects of bile on the global transcriptional profile of this strain, with the intention of elucidating genes contributing to bile tolerance. Genes involved in carbohydrate metabolism were generally induced, while genes involved in other aspects of cellular growth were mostly repressed. A 7-kb eight-gene operon encoding a two-component regulatory system (2CRS), a transporter, an oxidoreductase, and four hypothetical proteins was significantly upregulated in the presence of bile. Deletion mutations were constructed in six genes of the operon. Transcriptional analysis of the 2CRS mutants showed that mutation of the histidine protein kinase (HPK) had no effect on the induction of the operon, whereas the mutated response regulator (RR) showed enhanced induction when the cells were exposed to bile. These results indicate that the 2CRS plays a role in bile tolerance and that the operon it resides in is negatively controlled by the RR. Mutations in the transporter, the HPK, the RR, and a hypothetical protein each resulted in loss of tolerance of bile. Mutations in genes encoding another hypothetical protein and a putative oxidoreductase resulted in significant increases in bile tolerance. This functional analysis showed that the operon encoded proteins involved in both bile tolerance and bile sensitivity. PMID:17449631

  14. Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

    PubMed Central

    Aleksunes, Lauren M.

    2010-01-01

    Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting β polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) α and β] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory

  15. Bile acids reduce endocytosis of high-density lipoprotein (HDL) in HepG2 cells.

    PubMed

    Röhrl, Clemens; Eigner, Karin; Fruhwürth, Stefanie; Stangl, Herbert

    2014-01-01

    High-density lipoprotein (HDL) transports lipids to hepatic cells and the majority of HDL-associated cholesterol is destined for biliary excretion. Cholesterol is excreted into the bile directly or after conversion to bile acids, which are also present in the plasma as they are effectively reabsorbed through the enterohepatic cycle. Here, we provide evidence that bile acids affect HDL endocytosis. Using fluorescent and radiolabeled HDL, we show that HDL endocytosis was reduced in the presence of high concentrations of taurocholate, a natural non-cell-permeable bile acid, in human hepatic HepG2 and HuH7 cells. In contrast, selective cholesteryl-ester (CE) uptake was increased. Taurocholate exerted these effects extracellularly and independently of HDL modification, cell membrane perturbation or blocking of endocytic trafficking. Instead, this reduction of endocytosis and increase in selective uptake was dependent on SR-BI. In addition, cell-permeable bile acids reduced HDL endocytosis by farnesoid X receptor (FXR) activation: chenodeoxycholate and the non-steroidal FXR agonist GW4064 reduced HDL endocytosis, whereas selective CE uptake was unaltered. Reduced HDL endocytosis by FXR activation was independent of SR-BI and was likely mediated by impaired expression of the scavenger receptor cluster of differentiation 36 (CD36). Taken together we have shown that bile acids reduce HDL endocytosis by transcriptional and non-transcriptional mechanisms. Further, we suggest that HDL endocytosis and selective lipid uptake are not necessarily tightly linked to each other. PMID:25010412

  16. Bile salt receptor complex activates a pathogenic type III secretion system

    PubMed Central

    Li, Peng; Rivera-Cancel, Giomar; Kinch, Lisa N; Salomon, Dor; Tomchick, Diana R; Grishin, Nick V; Orth, Kim

    2016-01-01

    Bile is an important component of the human gastrointestinal tract with an essential role in food absorption and antimicrobial activities. Enteric bacterial pathogens have developed strategies to sense bile as an environmental cue to regulate virulence genes during infection. We discovered that Vibrio parahaemolyticus VtrC, along with VtrA and VtrB, are required for activating the virulence type III secretion system 2 in response to bile salts. The VtrA/VtrC complex activates VtrB in the presence of bile salts. The crystal structure of the periplasmic domains of the VtrA/VtrC heterodimer reveals a β-barrel with a hydrophobic inner chamber. A co-crystal structure of VtrA/VtrC with bile salt, along with biophysical and mutational analysis, demonstrates that the hydrophobic chamber binds bile salts and activates the virulence network. As part of a family of conserved signaling receptors, VtrA/VtrC provides structural and functional insights into the evolutionarily conserved mechanism used by bacteria to sense their environment. DOI: http://dx.doi.org/10.7554/eLife.15718.001 PMID:27377244

  17. The human gut sterolbiome: bile acid-microbiome endocrine aspects and therapeutics

    PubMed Central

    Ridlon, Jason M.; Bajaj, Jasmohan S.

    2015-01-01

    The human body is now viewed as a complex ecosystem that on a cellular and gene level is mainly prokaryotic. The mammalian liver synthesizes and secretes hydrophilic primary bile acids, some of which enter the colon during the enterohepatic circulation, and are converted into numerous hydrophobic metabolites which are capable of entering the portal circulation, returned to the liver, and in humans, accumulating in the biliary pool. Bile acids are hormones that regulate their own synthesis, transport, in addition to glucose and lipid homeostasis, and energy balance. The gut microbial community through their capacity to produce bile acid metabolites distinct from the liver can be thought of as an “endocrine organ” with potential to alter host physiology, perhaps to their own favor. We propose the term “sterolbiome” to describe the genetic potential of the gut microbiome to produce endocrine molecules from endogenous and exogenous steroids in the mammalian gut. The affinity of secondary bile acid metabolites to host nuclear receptors is described, the potential of secondary bile acids to promote tumors, and the potential of bile acids to serve as therapeutic agents are discussed. PMID:26579434

  18. The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases.

    PubMed

    Nagahashi, Masayuki; Yuza, Kizuki; Hirose, Yuki; Nakajima, Masato; Ramanathan, Rajesh; Hait, Nitai C; Hylemon, Phillip B; Zhou, Huiping; Takabe, Kazuaki; Wakai, Toshifumi

    2016-09-01

    Based on research carried out over the last decade, it has become increasingly evident that bile acids act not only as detergents, but also as important signaling molecules that exert various biological effects via activation of specific nuclear receptors and cell signaling pathways. Bile acids also regulate the expression of numerous genes encoding enzymes and proteins involved in the synthesis and metabolism of bile acids, glucose, fatty acids, and lipoproteins, as well as energy metabolism. Receptors activated by bile acids include, farnesoid X receptor α, pregnane X receptor, vitamin D receptor, and G protein-coupled receptors, TGR5, muscarinic receptor 2, and sphingosine-1-phosphate receptor (S1PR)2. The ligand of S1PR2, sphingosine-1-phosphate (S1P), is a bioactive lipid mediator that regulates various physiological and pathophysiological cellular processes. We have recently reported that conjugated bile acids, via S1PR2, activate and upregulate nuclear sphingosine kinase 2, increase nuclear S1P, and induce genes encoding enzymes and transporters involved in lipid and sterol metabolism in the liver. Here, we discuss the role of bile acids and S1P signaling in the regulation of hepatic lipid metabolism and in hepatobiliary diseases. PMID:27459945

  19. Characterization of the bile and gall bladder microbiota of healthy pigs.

    PubMed

    Jiménez, Esther; Sánchez, Borja; Farina, Annarita; Margolles, Abelardo; Rodríguez, Juan M

    2014-12-01

    Bile is a biological fluid synthesized in the liver, stored and concentrated in the gall bladder (interdigestive), and released into the duodenum after food intake. The microbial populations of different parts of mammal's gastrointestinal tract (stomach, small and large intestine) have been extensively studied; however, the characterization of bile microbiota had not been tackled until now. We have studied, by culture-dependent techniques and a 16S rRNA gene-based analysis, the microbiota present in the bile, gall bladder mucus, and biopsies of healthy sows. Also, we have identified the most abundant bacterial proteins in the bile samples. Our data show that the gall bladder ecosystem is mainly populated by members of the phyla Proteobacteria, Firmicutes, and Bacteroidetes. Furthermore, fluorescent in situ hybridization (FISH) and transmission electron microscopy (TEM) allowed us to visualize the presence of individual bacteria of different morphological types, in close association with either the epithelium or the erythrocytes, or inside the epithelial cells. Our work has generated new knowledge of bile microbial profiles and functions and might provide the basis for future studies on the relationship between bile microbiota, gut microbiota, and health. PMID:25336405

  20. Bile acids are toxic for isolated cardiac mitochondria: a possible cause for hepatic-derived cardiomyopathies?

    PubMed

    Ferreira, Manuela; Coxito, Pedro M; Sardão, Vilma A; Palmeira, Carlos M; Oliveira, Paulo J

    2005-01-01

    Cholestasis and other liver diseases may affect the heart through the toxic effects of the retained bile acids on cardiac mitochondria, which could explain the origin of hepatic-derived cardiomyopathies. The objective of this work was to test the hypothesis that bile acids are toxic to heart mitochondria for concentrations that are relevant for cholestasis. Heart mitochondria were isolated from rat and subjected to incubation with selected bile acids (litocholic acid [LCA], deoxycholic acid [DCA], chenodeoxycholic acid [CDCA], glycochenodeoxycholic acid [GCDC], taurodeoxycholic acid [TDCA], and glycoursodeoxycholic acid [GUDC]). We observed that the most toxic bile acids were also the most lipophilic ones (LCA, DCA, and CDCA), inducing a decrease on state 3 respiration, respiratory control ratio, and membrane potential and causing the induction of the mitochondrial permeability transition. GUDC was the bile acid with lower indexes of toxicity on isolated heart mitochondria. The results of this research indicate that at toxicologically relevant concentrations, most bile acids (mainly the most lipophilic) alter mitochondrial bioenergetics. The impairment of cardiac mitochondrial function may be an important cause for the observed cardiac alterations during cholestasis. PMID:15738586

  1. Validated UPLC method for determination of unbound bile acids in colesevelam HCl tablets.

    PubMed

    Vallapragada, Venkata Vivekanand; Inti, Gopichand; Vidiyala, Sudhakar Rao; Jadi, Sreeramulu

    2015-01-01

    A simple, precise and accurate gradient reverse-phase ultra-performance liquid chromatographic method was developed for the quantitative determination of bile acids [glycocholic acid (GCA), glycochenodeoxycholic acid (GCDA) and taurodeoxycholic acid (TDCA)) in in vitro bile acid-binding study of Welchol tablets. The method was developed using Phenomenex Kinetex C18 (50 × 2.10 mm, 1.7 µm) column with mobile phase containing a gradient mixture of solvent A consisting of 0.02 M tetrabutylammonium phosphate (pH 7.5) and solvent B consists acetonitrile. The eluted compounds were monitored at 210 nm and the runtime was within 2 min. The binding parameter constants of Colesevelam HCl tablets 625 mg were determined using the Langmuir approximation at pH 6.8 by UPLC. The method is selective and capable of detecting bile acids in the presence of placebo matrix. The method has been validated with a lower limit of quantitation of 0.01 mM for bile acids. A linear response function was established for the range of concentrations 0.01-30.0 mM (r > 0.99) for GCA, GCDA and TDCA. The intra- and interday precision values for bile acids met the acceptance as per Food and Drug Administrations guidelines. The developed method was applied to in vitro bile acid-binding studies of Colesevelam HCl tablets. PMID:24795077