Transport of bile acids in hepatic and non-hepatic tissues

2001 ◽  
Vol 204 (10) ◽  
pp. 1673-1686 ◽  
Author(s):  
M.V. St-Pierre ◽  
G.A. Kullak-Ublick ◽  
B. Hagenbuch ◽  
P.J. Meier
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Organic Anion ◽  
Cholesterol Homeostasis ◽  
Dietary Fats ◽  
Substrate Specificities ◽  
Molecular Defects ◽  
Biliary Epithelium ◽  
Bile Acid Transporters ◽  
Molecular Signals

Bile acids are steroidal amphipathic molecules derived from the catabolism of cholesterol. They modulate bile flow and lipid secretion, are essential for the absorption of dietary fats and vitamins, and have been implicated in the regulation of all the key enzymes involved in cholesterol homeostasis. Bile acids recirculate through the liver, bile ducts, small intestine and portal vein to form an enterohepatic circuit. They exist as anions at physiological pH and, consequently, require a carrier for transport across the membranes of the enterohepatic tissues. Individual bile acid carriers have now been cloned from several species. Na(+)-dependent transporters that mediate uptake into hepatocytes and reabsorption from the intestine and biliary epithelium and an ATP-dependent transporter that pumps bile acids into bile comprise the classes of transporter that are specific for bile acids. In addition, at least four human and five rat genes that code for Na(+)-independent organic anion carriers with broad multi-substrate specificities that include bile acids have been discovered. Studies concerning the regulation of these carriers have permitted identification of molecular signals that dictate eventual changes in the uptake or excretion of bile acids, which in turn have profound physiological implications. This overview summarizes and compares all known bile acid transporters and highlights findings that have identified diseases linked to molecular defects in these carriers. Recent advances that have fostered a more complete appreciation for the elaborate disposition of bile acids in humans are emphasized.

scholarly journals Regulation of Bile Acid and Cholesterol Metabolism by PPARs

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-15 ◽  
Author(s):  
Tiangang Li ◽  
John Y. L. Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholesterol Metabolism ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Major Pathway ◽  
Therapeutic Implications

Bile acids are amphipathic molecules synthesized from cholesterol in the liver. Bile acid synthesis is a major pathway for hepatic cholesterol catabolism. Bile acid synthesis generates bile flow which is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile acids are biological detergents that facilitate intestinal absorption of lipids and fat-soluble vitamins. Recent studies suggest that bile acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPARα, PPARγ, PPARδ) regulate lipoprotein metabolism, fatty acid oxidation, glucose homeostasis and inflammation, and therefore are used as anti-diabetic drugs for treatment of dyslipidemia and insulin insistence. Recent studies have shown that activation of PPARαalters bile acid synthesis, conjugation, and transport, and also cholesterol synthesis, absorption and reverse cholesterol transport. This review will focus on the roles of PPARs in the regulation of pathways in bile acid and cholesterol homeostasis, and the therapeutic implications of using PPAR agonists for the treatment of metabolic syndrome.

scholarly journals Evaluating Hepatobiliary Transport with 18F-Labeled Bile Acids: The Effect of Radiolabel Position and Bile Acid Structure on Radiosynthesis and In Vitro and In Vivo Performance

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Stef De Lombaerde ◽  
Ken Kersemans ◽  
Sara Neyt ◽  
Jeroen Verhoeven ◽  
Christian Vanhove ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Membrane Vesicles ◽  
Hepatic Uptake ◽  
Hepatobiliary Transport ◽  
Bile Acid Transporters ◽  
Significant Difference ◽  
The Impact

Introduction. An in vivo determination of bile acid hepatobiliary transport efficiency can be of use in liver disease and preclinical drug development. Given the increased interest in bile acid Positron Emission Tomography- (PET-) imaging, a further understanding of the impact of 18-fluorine substitution on bile acid handling in vitro and in vivo can be of significance. Methods. A number of bile acid analogues were conceived for nucleophilic substitution with [18F]fluoride: cholic acid analogues of which the 3-, 7-, or 12-OH function is substituted with a fluorine atom (3α-[18F]FCA; 7β-[18F]FCA; 12β-[18F]FCA); a glycocholic and chenodeoxycholic acid analogue, substituted on the 3-position (3β-[18F]FGCA and 3β-[18F]FCDCA, resp.). Uptake by the bile acid transporters NTCP and OATP1B1 was evaluated with competition assays in transfected CHO and HEK cell lines and efflux by BSEP in membrane vesicles. PET-scans with the tracers were performed in wild-type mice (n=3 per group): hepatobiliary transport was monitored and compared to a reference tracer, namely, 3β-[18F]FCA. Results. Compounds 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA were synthesized in moderate radiochemical yields (4–10% n.d.c.) and high radiochemical purity (>99%); 7β-[18F]FCA and 12β-[18F]FCA could not be synthesized and included further in this study. In vitro evaluation showed that 3α-FCA, 3β-FGCA, and 3β-FCDCA all had a low micromolar Ki-value for NTCP, OATP1B1, and BSEP. In vivo, 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA displayed hepatobiliary transport with varying efficiency. A slight yet significant difference in uptake and efflux rate was noticed between the 3α-[18F]FCA and 3β-[18F]FCA epimers. Conjugation of 3β-[18F]FCA with glycine had no significant effect in vivo. Compound 3β-[18F]FCDCA showed a significantly slower hepatic uptake and efflux towards gallbladder and intestines. Conclusion. A set of 18F labeled bile acids was synthesized that are substrates of the bile acid transporters in vitro and in vivo and can serve as PET-biomarkers for hepatobiliary transport of bile acids.

Interaction of bumetanide derivatives with hepatocellular bile acid uptake

1993 ◽  
Vol 265 (5) ◽  
pp. G942-G954
Author(s):  
E. Petzinger ◽  
W. Follmann ◽  
M. Blumrich ◽  
R. Schermuly ◽  
S. Schulz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Model Building ◽  
Organic Anion ◽  
Rat Hepatocytes ◽  
Salt Transport ◽  
Acid Uptake ◽  
Ligand Interaction ◽  
Isolated Rat Hepatocytes ◽  
Bile Acid Uptake

The loop diuretic bumetanide is an organic monocarboxylic organic anion assumed to be transported into hepatocytes by a transport system for bile acids. The structural requirements of 22 bumetanide analogues were analyzed for an interaction with bile acid uptake into isolated rat hepatocytes. Whereas bumetanide inhibited the hepatocellular uptake of [14C]cholate to the same degree as its own uptake, derivatization altered affinity and specificity and yielded compounds that selectively inhibited either cholate or taurocholate uptake or uptake of both. No correlation was found between the diuretic potency of bumetanide derivatives, reflecting the affinity to the Na(+)-K(+)-Cl- cotransporter, and their affinity to hepatic bile salt transport. Computer-aided model building combined with the calculation of potential energy maps showed a strictly amphipathic charge separation in bumetanide analogues as in bile acids. Ranking bumetanide compounds by their mean inhibitory concentration values, inhibition constants, and their type of competition, we conclude that at least three binding domains in the proteins are essential for recognition by bile acid transporters, namely two hydrophobic and an anionic side, and that for the anionic binding region a carbonyl atom in the ligands as an electron donor group is sufficient for ligand interaction.

Bile duct cells: a novel in vitro model for the study of lipid metabolism and bile acid production

1999 ◽  
Vol 276 (2) ◽  
pp. G407-G414 ◽  
Author(s):  
Monika Zoltowska ◽  
Edgard E. Delvin ◽  
Khazal Paradis ◽  
Ernest Seidman ◽  
Emile Levy
Keyword(s):  
Bile Acid ◽  
Bile Duct ◽  
Bile Acids ◽  
Cytokeratin 19 ◽  
Sterol Metabolism ◽  
Hmg Coa Reductase ◽  
Biliary Epithelium ◽  
Duct Cells ◽  
Coa Reductase

Immortalized bile duct cells (BDC), derived from transgenic mice harboring the SV40 thermosensitive immortalizing mutant gene ts458, were utilized to investigate the role of the biliary epithelium in lipid and sterol metabolism. This cell model closely resembles the in vivo situation because it expresses the specific phenotypic marker cytokeratin 19 (CK-19), exhibits the formation of bile duct-like structures, and displays well-formed microvilli projected from the apical side to central lumen. The BDC were found to incorporate [14C]oleic acid (in nmol/mg protein) into triglycerides (121 ± 6), phospholipids (PL; 59 ± 3), and cholesteryl ester (16 ± 1). The medium lipid content represented 5.90 ± 0.16% ( P < 0.005) of the total intracellular production, indicating a limited lipid export capacity. Analysis of PL composition demonstrated the synthesis of all classes of polar lipids, with phosphatidylcholine and phosphatidylethanolamine accounting for 60 ± 1 and 24 ± 1%, respectively, of the total. Differences in PL distribution were apparent between cells and media. Substantial cholesterol synthesis was observed in BDC, as determined by the incorporation of [14C]acetate suggesting the presence of hydroxymethylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. With the use of [14C]acetate and [14C]cholesterol as precursors, both tauro- and glycoconjugates of bile acids were synthesized, indicating the presence of cholesterol 7α- and 26R-hydroxylases, the key enzymes involved in bile acid formation. The transport of bile acids was not limited, as shown by their marked accumulation in the medium (>6-fold of cell content). HMG-CoA reductase (53.0 ± 6.7), cholesterol 7α-hydroxylase (15.5 ± 0.5), and acyl-CoA:cholesterol acyltransferase (ACAT; 201.7 ± 10.2) activities (in pmol ⋅ min−1 ⋅ mg protein−1) were present in the microsomal fractions. Our data show that biliary epithelial cells actively synthesize lipids and may directly contribute bile acids to the biliary fluid in vivo. This BDC line thus represents an efficient experimental tool to evaluate biliary epithelium sterol metabolism and to study biliary physiology.

III. Bile acids and nuclear receptors

2003 ◽  
Vol 284 (3) ◽  
pp. G349-G356 ◽  
Author(s):  
John Y. L. Chiang
Keyword(s):  
Bile Acid ◽  
Cardiovascular Diseases ◽  
Bile Acids ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Regulatory Genes ◽  
Cholesterol Homeostasis ◽  
Physiological Pathways ◽  
Bile Acid Receptor

Bile acids are physiological detergents that facilitate excretion, absorption, and transport of fats and sterols in the intestine and liver. Recent studies reveal that bile acids also are signaling molecules that activate several nuclear receptors and regulate many physiological pathways and processes to maintain bile acid and cholesterol homeostasis. Mutations of the principal regulatory genes in bile acid biosynthetic pathways have recently been identified in human patients with hepatobiliary and cardiovascular diseases. Genetic manipulation of key regulatory genes and bile acid receptor genes in mice have been obtained. These advances have greatly improved our understanding of the molecular mechanisms underlying complex liver physiology but also raise many questions and controversies to be resolved. These developments will lead to early diagnosis and discovery of drugs for treatment of liver and cardiovascular diseases.

scholarly journals Increased cholesterol 7α-hydroxylase expression and size of the bile acid pool in the lactating rat

2008 ◽  
Vol 294 (4) ◽  
pp. G1009-G1016 ◽  
Author(s):  
Clavia Ruth Wooton-Kee ◽  
David E. Cohen ◽  
Mary Vore
Keyword(s):  
Bile Acid ◽  
Protein Expression ◽  
Mrna Expression ◽  
Bile Acids ◽  
Fold Increase ◽  
Bile Acid Pool ◽  
Hydrophobicity Index ◽  
Acid Pool ◽  
Bile Acid Transporters ◽  
Cholic Acids

Maximal bile acid secretory rates and expression of bile acid transporters in liver and ileum are increased in lactation, possibly to facilitate increased enterohepatic recirculation of bile acids. We determined changes in the size and composition of the bile acid pool and key enzymes of the bile acid synthetic pathway [cholesterol 7α-hydroxylase (Cyp7a1), sterol 27-hydroxylase (Cyp27a1), and sterol 12α-hydroxylase (Cyp8b1)] in lactating rats relative to female virgin controls. The bile acid pool increased 1.9 to 2.5-fold [postpartum (PP) days 10, 14, and 19–23], compared with controls. A 1.5-fold increase in cholic acids and a 14 to 20% decrease in muricholic acids in lactation significantly increased the hydrophobicity index. In contrast, the hepatic concentration of bile acids and small heterodimer partner mRNA were unchanged in lactation. A 2.8-fold increase in Cyp7a1 mRNA expression at 16 h (10 h of light) demonstrated a shift in the diurnal rhythm at day 10 PP; Cyp7a1 protein expression and cholesterol 7α-hydroxylase activity were significantly increased at this time and remained elevated at day 14 PP but decreased to control levels by day 21 PP. There was an overall decrease in Cyp27a1 mRNA expression and a 20% decrease in Cyp27a1 protein expression, but there was no change in Cyp8b1 mRNA or protein expression at day 10 PP. The increase in Cyp7a1 expression PP provides a mechanism for the increase in the bile acid pool.

scholarly journals OATP1B3-1B7, a novel organic anion transporting polypeptide, is modulated by FXR ligands and transports bile acids

2019 ◽  
Vol 317 (6) ◽  
pp. G751-G762 ◽  
Author(s):  
Vanessa Malagnino ◽  
Janine Hussner ◽  
Ali Issa ◽  
Angela Midzic ◽  
Henriette E. Meyer zu Schwabedissen
Keyword(s):  
Endoplasmic Reticulum ◽  
Bile Acid ◽  
Bile Acids ◽  
Smooth Endoplasmic Reticulum ◽  
Organic Anion ◽  
Farnesoid X Receptor ◽  
Organic Anion Transporter ◽  
Organic Anion Transporting Polypeptide ◽  
Anion Transporter ◽  
Solute Carrier

Organic anion transporting polypeptide (OATP) 1B3–1B7 (LST-3TM12) is a member of the OATP1B [solute carrier organic anion transporter ( SLCO) 1B] family. This transporter is not only functional but also expressed in the membrane of the smooth endoplasmic reticulum of hepatocytes and enterocytes. OATP1B3–1B7 is a splice variant of SLCO1B3 in which the initial part is encoded by SLCO1B3, whereas the rest of the mRNA originates from the gene locus of SLCO1B7. In this study, we not only showed that SLCO1B3 and the mRNA encoding for OATP1B3–1B7 share the 5′ untranslated region but also that silencing of an initial SLCO1B3 exon lowered the amount of SLCO1B3 and of SLCO1B7 mRNA in Huh-7 cells. To validate the assumption that both transcripts are regulated by the same promoter we tested the influence of the bile acid sensor farnesoid X receptor (FXR) on their transcription. Treatment of Huh-7 and HepaRG cells with activators of this known regulator of OATP1B3 not only increased SLCO1B3 but also OATP1B3–1B7 mRNA transcription. Applying a heterologous expression system, we showed that several bile acids interact with OATP1B3–1B7 and that taurocholic acid and lithocholic acid are OATP1B3–1B7 substrates. As OATP1B3–1B7 is located in the smooth endoplasmic reticulum, it may grant access to metabolizing enzymes. In accordance are our findings showing that the OATP1B3–1B7 inhibitor bromsulphthalein significantly reduced uptake of bile acids into human liver microsomes. Taken together, we report that OATP1B3–1B7 transcription can be modulated with FXR agonists and antagonists and that OATP1B3–1B7 transports bile acids. NEW & NOTEWORTHY Our study on the transcriptional regulation of the novel organic anion transporting polypeptide (OATP) 1B3–1B7 concludes that the promoter of solute carrier organic anion transporter ( SLCO) 1B3 governs SLCO1B3–1B7 transcription. Moreover, the transcription of OATP1B3–1B7 can be modulated by farnesoid X receptor (FXR) agonists and antagonists. FXR is a major regulator in bile acid homeostasis that links OATP1B3–1B7 to this physiological function. Findings in transport studies with OATP1B3–1B7 suggest that this transporter interacts with the herein tested bile acids.

Mechanism of bile acid facilitation of biliary protoporphyrin excretion in rat liver

1995 ◽  
Vol 268 (5) ◽  
pp. G754-G763 ◽  
Author(s):  
M. M. Berenson ◽  
M. Y. el-Mir ◽  
L. K. Zhang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Intracellular Transport ◽  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Canalicular Membrane ◽  
Rat Livers ◽  
Eisai Hyperbilirubinemic Rat

The mechanism(s) by which bile acids increase biliary protoporphyrin excretion was characterized using perfused rat livers. We determined 1) relationships between biliary bile acids, phospholipid, and protoporphyrin, using rapid kinetic analyses; 2) protoporphyrin excretion in livers with defective canalicular multispecific organic anion transport; 3) effects of intracellular vesicular transport inhibition with colchicine and monensin; and 4) the role of luminal bile acids, using retrograde intrabiliary taurocholate injections. Biliary protoporphyrin excretion peaked with phospholipid excretion 14-18 min after loading. Protoporphyrin excretion induced by taurocholate was not related to effects on intracellular transport, including colchicine- and monensin-inhibitable vesicular systems. Eisai hyperbilirubinemic rat livers excreted protoporphyrin similarly to controls. Retrograde intrabiliary taurocholate injections increased protoporphyrin output. Collectively, these data suggest that 1) intracellular protoporphyrin transport is mediated by nonvesicular carriers targeted to the canalicular membrane, and 2) bile acid facilitates protoporphyrin translocation into bile in the same manner it effects phospholipid excretion.

scholarly journals A novel bioluminescence-based method to investigate uptake of bile acids in living cells

2018 ◽  
Vol 315 (4) ◽  
pp. G529-G537 ◽  
Author(s):  
Alexander L. Ticho ◽  
Hyunjin Lee ◽  
Ravinder K. Gill ◽  
Pradeep K. Dudeja ◽  
Seema Saksena ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Real Time ◽  
Sodium Taurocholate ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Bile Acid Transporters ◽  
Sodium Dependent ◽  
Bile Acid Transporter ◽  
Acid Transporter

Bile acid transporters, including the ileal apical sodium-dependent bile acid transporter (ASBT) and the hepatic sodium-taurocholate cotransporting polypeptide (NTCP), are crucial for the enterohepatic circulation of bile acids. Our objective was to develop a method for measuring bile acid transporter activity in real time to precisely evaluate rapid changes in their function. We designed a reporter system relying on a novel probe: cholic acid attached to luciferin via a disulfide-containing, self-immolating linker (CA-SS-Luc). Incubation of human embryonic kidney-293 cells coexpressing luciferase and ASBT with different concentrations of CA-SS-Luc (0.01–1 μM) resulted in bioluminescence with an intensity that was concentration- and time-dependent. The bioluminescence measured during incubation with 1 μM CA-SS-Luc was dependent on the levels of ASBT or NTCP expressed in the cells. Coincubation of CA-SS-Luc with natural bile acids enhanced the bioluminescence in a concentration-dependent manner with kinetic parameters for ASBT similar to those previously reported using conventional methods. These findings suggest that this method faithfully assesses ASBT function. Further, incubation with tyrosine phosphatase inhibitor III (PTPIII) led to significantly increased bioluminescence in cells expressing ASBT, consistent with previous studies showing an increase in ASBT function by PTPIII. We then investigated CA-SS-Luc in isolated mouse intestinal epithelial cells. Ileal enterocytes displayed significantly higher luminescence compared with jejunal enterocytes, indicating a transport process mediated by ileal ASBT. In conclusion, we have developed a novel method to monitor the activity of bile acid transporters in real time that has potential applications both for in vitro and in vivo studies.NEW & NOTEWORTHY This article reports the development of a real-time method for measuring the uptake of bile acids using a bioluminescent bile acid-based probe. This method has been validated for measuring uptake via the apical sodium-dependent bile acid transporter and the sodium-taurocholate cotransporting polypeptide in cell culture and ex vivo intestinal models.

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