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Systemic bile acids induce insulin resistance in a TGR5-independent manner.
Syring KE, Cyphert TJ, Beck TC, Flynn CR, Mignemi NA, McGuinness OP
(2019) Am J Physiol Endocrinol Metab 316: E782-E793
MeSH Terms: Animals, Bile Acids and Salts, Cholagogues and Choleretics, Cholic Acids, Deoxycholic Acid, Gene Expression Profiling, Gluconeogenesis, Glucose Clamp Technique, Hep G2 Cells, Hepatocytes, Humans, Insulin Resistance, Liver, Mice, Mice, Knockout, Obesity, Primary Cell Culture, Receptors, G-Protein-Coupled, Taurocholic Acid
Show Abstract · Added April 15, 2019
Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.
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19 MeSH Terms
Apolipoprotein A-V is present in bile and its secretion increases with lipid absorption in Sprague-Dawley rats.
Zhang LS, Sato H, Yang Q, Ryan RO, Wang DQ, Howles PN, Tso P
(2015) Am J Physiol Gastrointest Liver Physiol 309: G918-25
MeSH Terms: Animals, Apolipoprotein A-V, Apolipoproteins, Bile, Biliary Fistula, Chylomicrons, Disease Models, Animal, Duodenum, Emulsions, Fasting, Intestinal Absorption, Liver, Lymph, Male, Phosphatidylcholines, Phospholipids, Rats, Sprague-Dawley, Soybean Oil, Taurocholic Acid, Time Factors, Up-Regulation
Show Abstract · Added December 8, 2015
Apolipoprotein (apo) A-V is a protein synthesized only in the liver that dramatically modulates plasma triglyceride levels. Recent studies suggest a novel role for hepatic apoA-V in regulating the absorption of dietary triglycerides, but its mode of action on the gut remains unknown. The aim of this study was to test for apoA-V in bile and to determine whether its secretion is regulated by dietary lipids. After an overnight recovery, adult male Sprague-Dawley bile fistula rats indeed secreted apoA-V into bile at a constant rate under fasting conditions. An intraduodenal bolus of intralipid (n = 12) increased the biliary secretion of apoA-V but not of other apolipoproteins, such as A-I, A-IV, B, and E. The lipid-induced increase of biliary apoA-V was abolished under conditions of poor lymphatic lipid transport, suggesting that the stimulation is regulated by the magnitude of lipids associated with chylomicrons transported into lymph. We also studied the secretion of apoA-V into bile immediately following bile duct cannulation. Biliary apoA-V increased over time (∼6-fold increase at hour 16, n = 8) but the secretions of other apolipoproteins remained constant. Replenishing luminal phosphatidylcholine and taurocholate (n = 9) only enhanced apoA-V secretion in bile, suggesting that the increase was not due to depletion of phospholipids or bile salts. This is the first study to demonstrate that apoA-V is secreted into bile, introducing a potential route of delivery of hepatic apoA-V to the gut lumen. Our study also reveals the uniqueness of apoA-V secretion into bile that is regulated by mechanisms different from other apolipoproteins.
Copyright © 2015 the American Physiological Society.
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21 MeSH Terms
Ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibit bile acid transport in human and rat hepatocytes.
McRae MP, Lowe CM, Tian X, Bourdet DL, Ho RH, Leake BF, Kim RB, Brouwer KL, Kashuba AD
(2006) J Pharmacol Exp Ther 318: 1068-75
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 11, ATP-Binding Cassette Transporters, Adolescent, Adult, Aged, Aged, 80 and over, Animals, Anti-HIV Agents, Benzoxazines, Biological Transport, Cells, Cultured, Child, Hepatocytes, Humans, Male, Middle Aged, Nevirapine, Organic Anion Transporters, Organic Anion Transporters, Sodium-Dependent, Oxazines, Rats, Ritonavir, Saquinavir, Symporters, Taurocholic Acid
Show Abstract · Added March 5, 2014
Human immunodeficiency virus-infected patients on antiretroviral drug therapy frequently experience hepatotoxicity, the underlying mechanism of which is poorly understood. Hepatotoxicity from other compounds such as bosentan and troglitazone has been attributed, in part, to inhibition of hepatocyte bile acid excretion. This work tested the hypothesis that antiretroviral drugs modulate hepatic bile acid transport. Ritonavir (28 microM), saquinavir (15 microM), and efavirenz (32 microM) inhibited [(3)H]taurocholate transport in bile salt export pump expressing Sf9-derived membrane vesicles by 90, 71, and 33%, respectively. In sandwich-cultured human hepatocytes, the biliary excretion index (BEI) of [(3)H]taurocholate was maximally decreased 59% by ritonavir, 39% by saquinavir, and 20% by efavirenz. Likewise, in sandwich-cultured rat hepatocytes, the BEI of [(3)H]taurocholate was decreased 100% by ritonavir and 94% by saquinavir. Sodium-dependent and -independent initial uptake rates of [(3)H]taurocholate in suspended rat hepatocytes were significantly decreased by ritonavir, saquinavir, and efavirenz. [(3)H]Taurocholate transport by recombinant NTCP and Ntcp was inhibited by ritonavir (IC(50) = 2.1 and 6.4 microM in human and rat, respectively), saquinavir (IC(50) = 6.7 and 20 microM, respectively), and efavirenz (IC(50) = 43 and 97 microM, respectively). Nevirapine (75 microM) had no effect on bile acid transport in any model system. In conclusion, ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibited both the hepatic uptake and biliary excretion of taurocholate.
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25 MeSH Terms
Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics.
Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, Wang Y, Kim RB
(2006) Gastroenterology 130: 1793-806
MeSH Terms: Animals, Base Sequence, Biological Transport, Cells, Cultured, Fluorobenzenes, Gene Expression Regulation, Hepatocytes, Humans, Male, Molecular Sequence Data, Organic Anion Transporters, Sodium-Dependent, Organic Anion Transporters, Sodium-Independent, Pharmacogenetics, Probability, Pyrimidines, RNA, Messenger, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Rosuvastatin Calcium, Species Specificity, Sulfonamides, Symporters, Taurocholic Acid
Show Abstract · Added March 5, 2014
BACKGROUND & AIMS - The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, target liver HMG-CoA and are of proven benefit in the prevention of coronary heart disease. Rosuvastatin is an effective statin notable for liver selectivity and lack of significant metabolism. We assessed the extent and relevance of hepatic transporters to rosuvastatin uptake.
METHODS - Transporters involved in rosuvastatin uptake were determined through heterologous expression of multiple human and rat uptake transporters. Human organic anion transporting polypeptide (OATP) 1B1 and sodium-dependent taurocholate cotransporting polypeptide (NTCP) allelic variants were also assessed. Expression of OATP and NTCP messenger RNA and protein was determined from a bank of human liver samples.
RESULTS - Multiple OATP family members, including 1B1, 1B3, 2B1, and 1A2, were capable of rosuvastatin transport. Naturally occurring polymorphisms in OATP1B1, including *5, *9, *15, and *18, were associated with profound loss of activity toward rosuvastatin. Interestingly, the major human hepatic bile acid uptake transporter NTCP, but not rat Ntcp, also transported rosuvastatin. Human hepatocyte studies suggested that NTCP alone accounted for approximately 35% of rosuvastatin uptake. Remarkably, NTCP*2, a variant known to have a near complete loss of function for bile acids, exhibited a profound gain of function for rosuvastatin. Quantitative messenger RNA analysis revealed marked intersubject variability in expression of OATPs and NTCP.
CONCLUSIONS - Multiple transporters mediate the overall hepatic uptake of rosuvastatin, and NTCP may be a heretofore unrecognized transporter important to the disposition of rosuvastatin and possibly other drugs/statins in clinical use. Accordingly, transporter expression and polymorphisms may be key determinants of intersubject variability in response to statin therapy in general.
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24 MeSH Terms
Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition.
Ho RH, Leake BF, Roberts RL, Lee W, Kim RB
(2004) J Biol Chem 279: 7213-22
MeSH Terms: African Continental Ancestry Group, Alleles, Amino Acid Sequence, Asian Continental Ancestry Group, Bile Acids and Salts, Biological Transport, Biotinylation, Carrier Proteins, Cell Line, Cell Membrane, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, European Continental Ancestry Group, Gene Frequency, Genotype, Glycosylation, HeLa Cells, Hepatocytes, Hispanic Americans, Humans, Microscopy, Confocal, Molecular Sequence Data, Organic Anion Transporters, Sodium-Dependent, Plasmids, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Protein Binding, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Substrate Specificity, Symporters, Taurocholic Acid, Vaccinia virus
Show Abstract · Added March 5, 2014
The key transporter responsible for hepatic uptake of bile acids from portal circulation is Na+-taurocholate cotransporting polypeptide (NTCP, SLC10A1). This transporter is thought to be critical for the maintenance of enterohepatic recirculation of bile acids and hepatocyte function. Therefore, functionally relevant polymorphisms in this transporter would be predicted to have an important impact on bile acid homeostasis/liver function. However, little is known regarding genetic heterogeneity in NTCP. In this study, we demonstrate the presence of multiple single nucleotide polymorphisms in NTCP in populations of European, African, Chinese, and Hispanic Americans. Specifically four nonsynonymous single nucleotide polymorphisms associated with a significant loss of transport function were identified. Cell surface biotinylation experiments indicated that the altered transport activity of T668C (Ile223-->Thr), a variant seen only in African Americans, was due at least in part to decreased plasma membrane expression. Similar expression patterns were observed when the variant alleles were expressed in HepG2 cells, and plasma membrane expression was assessed using immunofluorescence confocal microscopy. Interestingly the C800T (Ser267-->Phe) variant, seen only in Chinese Americans, exhibited a near complete loss of function for bile acid uptake yet fully normal transport function for the non-bile acid substrate estrone sulfate, suggesting this position may be part of a region in the transporter critical and specific for bile acid substrate recognition. Accordingly, our study indicates functionally important polymorphisms in NTCP exist and that the likelihood of being carriers of such polymorphisms is dependent on ethnicity.
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33 MeSH Terms
Ontogeny of glutamine transport by rat liver plasma membrane vesicles.
Ghishan FK, Shewayhat W, Dykes W, Abumrad N
(1992) J Dev Physiol 18: 1-7
MeSH Terms: Aging, Amino Acids, Analysis of Variance, Animals, Animals, Suckling, Biological Transport, Active, Cell Membrane, Choline, Dose-Response Relationship, Drug, Glutamine, Hydrogen-Ion Concentration, Lithium, Liver, Membrane Potentials, Osmolar Concentration, Potassium, Rats, Rats, Sprague-Dawley, Sodium, Taurocholic Acid
Show Abstract · Added December 10, 2013
Glutamine metabolism in the liver is essential for gluconeogenesis and ureagenesis. During the suckling period there is high hepatic protein accretion and the portal vein glutamine concentration is twice that in the adult, whereas hepatic vein glutamine concentration is similar between adult and suckling rats. Therefore, we hypothesized that glutamine uptake by the liver could be greater in the suckling period compared to the adult period. The present studies were, therefore, designed to investigate the transport of glutamine by plasma membranes of rat liver during maturation (suckling--2-week old, weanling--3-week old and adult--12-week old). Glutamine uptake by the plasma membranes of the liver represented transport into an osmotically sensitive space in all age groups. Inwardly directed Na+ gradient resulted in an "overshoot" phenomenon compared to K+ gradient. The magnitude of the overshoot was greater in suckling rats plasma membranes compared to adult membranes. Glutamine uptake under Na+ gradient was electrogenic and maximal at pH 7.5, whereas uptake under K+ gradient was electroneutral. Glutamine uptake with various concentrations of glutamine under Na+ gradient was saturable in all age groups with a Vmax of 1.5 +/- 0.1, 0.7 +/- 0.1 and 0.5 +/- 0.06 nmoles/mg protein/10 seconds in suckling, weanling and adult rats, respectively (P < 0.01). Km values were 0.6 +/- 0.1, 0.5 +/- 0.1 and 0.5 +/- 0.1 mM respectively. Vmax for Na(+)-independent glutamine uptake were 0.6 +/- 0.1, 0.55 +/- 0.07 and 0.54 +/- 0.06 nmoles/mg protein with Km values of 0.54 +/- 0.2, 0. +/- 0.1 and 0.5 +/- 0.2 mM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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20 MeSH Terms
Hepatic lesions and hemolysis following administration of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oyl taurine to rats.
Hanson RF, Williams GC, Hachey D, Sharp HL
(1977) J Lab Clin Med 90: 536-48
MeSH Terms: Anemia, Hemolytic, Animals, Bile, Bile Acids and Salts, Cholic Acids, Endoplasmic Reticulum, Female, Hemoglobinuria, Humans, Liver, Liver Cirrhosis, Mitochondria, Liver, Rats, Taurine, Taurocholic Acid
Show Abstract · Added March 20, 2014
Patients with a metabolic block in the conversion of THCA into cholic acid develop cirrhosis and hemolysis, and die of hepatic failure. In these patients, THCA is largely conjugated to taurine (tauro-THCA) and excreted instead of being converted into cholic acid. In the present study, the effects of tauro-THCA on hemolysis, bile flow, and hepatic morphology were evaluated in bile fistula rats. All rats infused with tauro-THCA at rates of 0.25, 0.50 or 0.75 micronmol/min developed hemolysis with hemoglobinuria. A direct toxic effect of tauro-THCA on washed human red blood cell membranes was demonstrated at a concentration of 8 X 10(-4) M. Liver biopsy sections from rats infused for a 2 hr period with tauro-THCA were examined by electron microscopy and showed dilation of the rough endoplasmic reticulum and distortion of mitochondrial membranes. Cholestasis was not induced, since tauro-THCA actually caused a greater choleretic response for a given rate of bile salt excretion than did taurocholate. This study raises the possibility that the clinical liver disease seen in patients with a metabolic block in the conversion of THCA into cholic acid may be caused by tauro-THCA.
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15 MeSH Terms