scholarly journals The role of conjugation reactions in enhancing biliary secretion of bile acids

1983 ◽  
Vol 214 (3) ◽  
pp. 923-927 ◽  
Author(s):  
D A Vessey ◽  
J Whitney ◽  
J L Gollan
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Hepatic Uptake ◽  
Biliary Secretion ◽  
Side Chain ◽  
Isolated Perfused Rat Liver ◽  
Rat Livers ◽  
Kinetics Of ◽  
Methylene Group

Shortening the five-carbon carboxylic acid side chain of cholic acid by one methylene group gave rise to a bile acid (norcholate) that was not a substrate for the bile acid-conjugating enzymes. The metabolism and biliary secretion of norcholate in intact liver was examined in the isolated perfused rat liver system. When rat livers were perfused with 14-20 microM solutions of norcholate for 10 min, norcholate was found in the unconjugated form in liver, venous effluent and bile. Neither tauronorcholate nor glyconorcholate was detectable by high-pressure liquid chromatography or fast-atom-bombardment mass spectrometry. The kinetics of hepatic uptake and biliary secretion of norcholate was compared with that for cholate, taurocholate and chemically synthesized tauronorcholate. The latter three bile acids were completely cleared from the perfusate and efficiently secreted into the bile. However, norcholate was incompletely extracted from the perfusate, and this was shown to be at least partially due to its relatively lower rate of hepatic uptake. Furthermore, the rate of norcholate secretion into bile was greatly reduced relative to the secretion of cholate or chemically synthesized tauronorcholate, even though the concentration of norcholate in the liver was comparatively high. These data demonstrate that the conjugation of bile acids greatly facilitates their secretion into bile.

Influence of side-chain charge on hepatic transport of bile acids and bile acid analogues

1985 ◽  
Vol 249 (4) ◽  
pp. G479-G488 ◽  
Author(s):  
M. S. Anwer ◽  
E. R. O'Maille ◽  
A. F. Hofmann ◽  
R. A. DiPietro ◽  
E. Michelotti
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Liver Cell ◽  
Hepatic Uptake ◽  
Biliary Secretion ◽  
Side Chain ◽  
Bile Fistula ◽  
Bile Acid Derivatives ◽  
Derivatives Of ◽  
Secretion Rates

The importance of side-chain charge on hepatic uptake and biliary secretion of bile acids and analogues was studied using the isolated, perfused rat liver and the anesthetized rat with a bile fistula. Derivatives of cholic acid with negative, neutral, zwitterionic, or positive charges on the side chain were synthesized and studied. Hepatic uptake by the isolated perfused liver, determined by measuring the rate of disappearance of a single 20-mumol bolus added to the perfusate, was strongly influenced by side-chain charge. A fully positively charged bile acid derivative (cholylcholamine) and two fully zwitterionic bile acid derivatives (CHAPS and cholyllysine) showed no appreciable uptake (less than 1% of the uptake rate of cholyltaurine). Bile acid derivatives existing mostly in cationic form (cholylamine) at pH 7.4, in neutral form (cholylglycylhistamine), or in divalent anion form (cholylaspartate and cholylcysteate) had an uptake rate that was greater but only 7-19% that of cholyltaurine. Side-chain charge also appeared to influence the rate of secretion into bile. Bile acids existing in mono- or dianionic form were well secreted (greater than 95% of dose in 2 h) into the bile, but all other derivatives had much lower secretion rates (less than 20% of dose in 2 h). When the biliary secretion of each bile acid derivative was expressed in relation to the amount that had entered the liver, relative secretion rates (presumably from liver cell) into bile decreased in the following order: cholyltaurine greater than cholylaspartate and cholylcysteate greater than CHAPS greater than cholyllysine greater than cholylglycylhistamine approximately equal to cholylamine. In bile fistula rats, cholylaspartate was quantitatively secreted into bile when infused at rates below its secretory maximum, whereas only very low biliary secretion rates of CHAPS were observed even during relatively high infusion rates; cholylamine was cholestatic. The above data show that, although uncharged and anionic derivatives of cholic acid may be taken up by the liver at a moderate rate, only anionic derivatives (both monovalent and divalent) are well secreted from within the liver cell into bile. A single negative charge on the side chain appears to be required for optimal transport of a bile acid from sinusoidal blood to bile.

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

2014 ◽  
Vol 307 (11) ◽  
pp. G1130-G1143 ◽  
Author(s):  
Gregory G. Martin ◽  
Barbara P. Atshaves ◽  
Kerstin K. Landrock ◽  
Danilo Landrock ◽  
Stephen M. Storey ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Physiological Role ◽  
Hdl Cholesterol ◽  
Hepatic Uptake ◽  
Biliary Secretion ◽  
Bile Acid Metabolism ◽  
Fatty Acid Binding ◽  
Bile Acid Concentration ◽  
Biliary Bile Acid

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.

scholarly journals Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1104
Author(s):  
Cong Xie ◽  
Weikun Huang ◽  
Richard L. Young ◽  
Karen L. Jones ◽  
Michael Horowitz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Peptide Yy ◽  
Glycogen Synthesis ◽  
Hormone Secretion ◽  
Gastrointestinal Hormones ◽  
Farnesoid X Receptor ◽  
Gastrointestinal Hormone ◽  
Bile Acid Sequestrants

Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge regarding bile acid physiology and metabolic health. Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulates the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome. These effects may contribute to the metabolic benefits of bile acid sequestrants, metformin, and bariatric surgery. This review focuses on the role of bile acids in energy intake and body weight, particularly their effects on gastrointestinal hormone secretion, the changes in obesity and T2D, and their potential relevance to the management of metabolic disorders.

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.

Effects of ion substitution on transport and choleretic effect of ouabain

1987 ◽  
Vol 252 (3) ◽  
pp. G357-G364
Author(s):  
M. S. Anwer
Keyword(s):  
Choline Chloride ◽  
Inorganic Ions ◽  
Hepatic Uptake ◽  
Isolated Perfused Rat Liver ◽  
Electrolyte Excretion ◽  
Hepatic Transport ◽  
Osmotic Effect ◽  
Ion Substitution ◽  
Choleretic Effect

The role of inorganic ions in hepatic transport and choleretic effect of ouabain was studied in isolated perfused rat liver to verify whether Na+-coupled ouabain uptake into hepatocytes is responsible for the choleretic effect. Hepatic uptake and clearance of ouabain were not significantly affected when perfusate Na+ was replaced by Li+ or choline+, chloride by nitrate or isethionate, or bicarbonate by tricine. However, these ion substitutions, with the exception of Li+, significantly reduced ouabain-induced choleresis and biliary electrolyte excretion. When ouabain was infused at different rates followed by perfusion without ouabain, changes in bile flow paralleled biliary excretion of ouabain rather than hepatic uptake. These results indicate that hepatic uptake of ouabain is not Na+ dependent and that the osmotic effect of biliary excreted ouabain is responsible for its choleretic effect. A part of the choleretic effect (30%) must also involve other mechanisms, since a permeable anion-like nitrate failed to substitute for perfusate chloride. Results of infusion studies also showed that ouabain was concentrated in liver (liver/perfusate = 30) and in bile (bile/liver = 15), indicating that ouabain is transported against its concentration gradient across both sinusoidal and canalicular membranes.

scholarly journals Role of Bile Acids in Dysbiosis and Treatment of Nonalcoholic Fatty Liver Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Caihua Wang ◽  
Chunpeng Zhu ◽  
Liming Shao ◽  
Jun Ye ◽  
Yimin Shen ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Bile Acids ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver ◽  
Bile Acid Receptors

Nonalcoholic fatty liver disease (NAFLD) is a major health threat around the world and is characterized by dysbiosis. Primary bile acids are synthesized in the liver and converted into secondary bile acids by gut microbiota. Recent studies support the role of bile acids in modulating dysbiosis and NAFLD, while the mechanisms are not well elucidated. Dysbiosis may alter the size and the composition of the bile acid pool, resulting in reduced signaling of bile acid receptors such as farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). These receptors are essential in lipid and glucose metabolism, and impaired bile acid signaling may cause NAFLD. Bile acids also reciprocally regulate the gut microbiota directly via antibacterial activity and indirectly via FXR. Therefore, bile acid signaling is closely linked to dysbiosis and NAFLD. During the past decade, stimulation of bile acid receptors with their agonists has been extensively explored for the treatment of NAFLD in both animal models and clinical trials. Early evidence has suggested the potential of bile acid receptor agonists in NAFLD management, but their long-term safety and effectiveness need further clarification.

scholarly journals Bile Acid Uptake Transporters as Targets for Therapy

2017 ◽  
Vol 35 (3) ◽  
pp. 251-258 ◽  
Author(s):  
Davor Slijepcevic ◽  
Stan F.J. van de Graaf
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Energy Homeostasis ◽  
Sodium Taurocholate ◽  
Hepatic Uptake ◽  
Farnesoid X Receptor ◽  
Acid Uptake ◽  
Bile Acid Uptake ◽  
Uptake Transporters ◽  
Conjugated Bile Acids

Background: Bile acids are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via the bile acid receptors farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). The sodium taurocholate cotransporting polypeptide (NTCP) and the apical sodium dependent bile acid transporter (ASBT) ensure an effective circulation of (conjugated) bile acids. The modulation of these transport proteins affects bile acid localization, dynamics and signaling. The NTCP-specific pharmacological inhibitor myrcludex B inhibits hepatic uptake of conjugated bile acids. Multiple ASBT-inhibitors are already in clinical trials to inhibit intestinal bile acid uptake. Here, we discuss current insights into the consequences of targeting bile acid uptake transporters on systemic and intestinal bile acid dynamics and discuss the possible therapeutic applications that evolve as a result.

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