Bile acid regulation of hepatic physiology: IV. Bile acids and death receptors

Toxic bile acids facilitate Fas and tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) death-receptor oligomerization and activation. Bile acid modulation of death-receptor signaling is multifactorial and includes trafficking of Fas to the cell surface, enhancing TRAIL-R2/DR5 expression, and suppression of function of cFLIP, an antiapoptotic protein modulating death-receptor function. Because bile acid-associated death receptor-mediated apoptosis is a common mechanism for cholestatic hepatocyte injury, inhibition of death receptors and their cascades may prove useful in attenuating liver injury during cholestasis.     

Bile acid regulation of hepatic physiology: I. Hepatocyte transport of bile acids

Bile acids are cholesterol derivatives that serve as detergents in bile and the small intestine. Approximately 95% of bile acids secreted by hepatocytes into bile are absorbed from the distal ileum into the portal venous system. Extraction from the portal circulation by the hepatocyte followed by reexcretion into the bile canaliculus completes the enterohepatic circulation of these compounds. Over the past few years, candidate bile acid transport proteins of the sinusoidal and canalicular plasma membranes of the hepatocyte have been identified. The physiology of hepatocyte bile acid transport and its relationship to these transport proteins is the subject of this Themes article.     

Bile acid synthesis: down-regulation by monohydroxy bile acids

The regulation of bile acid synthesis was studied in rabbits after interruption of the enterohepatic circulation by choledochoureteral anastomosis. Total daily bile acid output was 772 +/- 130 (SD) mumol/24 h, of which greater than 95% was glycocholic acid. Administration of deoxycholic or cholic acid or their conjugates (300-800 mumol) or gall-bladder bile failed to down-regulate endogenous bile acid synthesis. In contrast, chenodeoxycholic acid administration did down-regulate bile acid synthesis, but this effect was related to the formation and excretion of lithocholic acid. This observation was confirmed by the finding that i.v. infusion of 10-20 mumol of either lithocholic acid or 3 beta-hydroxy-5-cholenoic acid significantly reduced cholic acid synthesis. Thus monohydroxy bile acids, derived from either hepatic or intestinal sources, participate in the down-regulation of bile acid synthesis.     

Bile acids. XLIX. Allocholic acid, the major bile acid of Uromastix hardwickii.

Tauroallocholate is the major bile salt of the lizard, Uromastix hardwickii. Alkaline hydrolysis of bile from 25 gallbladders provided 1.21 g of acidic material, about 90% of which was allocholic acid. Analyses by gas-liquid chromatography, and mass spectrometry verified the presence of almost 10% of deoxycholic acid and smaller amounts of other 5alpha and 5beta-bile acids.     

Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease

The nuclear receptor Farnesoid X Receptor (FXR) critically regulates nascent bile formation and bile acid enterohepatic circulation. Bile acids and FXR play a pivotal role in regulating hepatic inflammation and regeneration as well as in regulating extent of inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. Recent evidence suggests, that the bile acid–FXR interaction is involved in the pathophysiology of a wide range of diseases of the liver, biliary and gastrointestinal tract, such as cholestatic and inflammatory liver diseases and hepatocellular carcinoma, inflammatory bowel disease and inflammation-associated cancer of the colon and esophagus. In this review we discuss current knowledge of the role the bile acid–FXR interaction has in (patho)physiology of the liver, biliary and gastrointestinal tract, and proposed underlying mechanisms, based on in vitro data and experimental animal models. Given the availability of highly potent synthetic FXR agonists, we focus particularly on potential relevance for human disease.     

Bile acid sulfates. III. Synthesis of 7- and 12-monosulfates of bile acids and their conjugates using a sulfur trioxide-triethylamine complex.

The 7- and 12-monosulfates of chenodeoxycholic acid, deoxycholic acid, and cholic acid were prepared by sulfation of the protected bile acids with sulfur trioxide-triethylamine in pyridine overnight and were isolated by precipitation as the p-toluidinium salt after removing the protecting group(s). The taurine conjugates were obtained by conjugating the bile acid sulfates with taurine in hot dimethylformamide (DMF) in the presence of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). A new procedure of preparing glycine conjugated bile acid sulfates by direct conjugation of the bile acid sulfate triethylammonium salt with ethyl glycinate in boiling chloroform in the presence of EEDQ is also described. The advantage of these procedures over other procedures are their simplicity and their higher yields (tyically above 90%) The thin layer chromatographic mobilities of these sulfates are presented. The influence of side chain and hydroxyl group configurations on the properties of bile acid sulfates is briefly discussed.     

Bile acid glucuronides, III[1, 2]. Chemical synthesis and characterization of glucuronic acid coupled mono-, di- and trihydroxy bile acids.

The synthesis of bile acid-3-beta-D-monoglucuronides has been accomplished via the Koenigs-Knorr condensation reaction using methyl 2, 3, 4-tri-O-acetyl-1-deoxy-alpha-bromo-D-glucopyranuronate as coupling reagent. Chemical characteristics as melting points, elemental analyses, IR-spectra, isobutane-chemical ionization mass spectra and, in case of the derivative of 3alpha-hydroxy=5beta-cholanoate, NMR-spectra were recorded and can serve as a means of identification of these recently detected naturally occurring derivatives of bile acids in isolation procedures from biological sources.