A proposed nomenclature for bile acids.

A proposal is made for a system of nomenclature of the more common unconjugated and conjugated bile acids. Acceptable trivial names for bile acids are tabulated, and guidelines are proposed for using these existing trivial names as roots to create acceptable semi-systematic names for other bile acids, as well as for new natural bile acids that will be discovered in the future. The term alpha-hyocholic is recommended to replace hyocholic, and beta-hyocholic to replace omega-muricholic. The term murideoxycholic acid is recommended for 3 alpha,6 beta-dihydroxy-5 beta-cholan-24-oic acid. Proposals are also made for bile acids with epimeric hydroxy groups, for unsaturated bile acids, and for bile acids with oxo- and/or hydroxy-oxo- substituents on the nucleus and/or on the side chain. For conjugated bile acids, the term "aminoacyl amidates" is recommended to replace "amidates" for bile acids conjugated in N-acyl linkage with amino acids. Nomenclature for other types of conjugates (sulfates, glucuronides, glucosides) is included as well as abbreviations. It is recommended that the historic tradition of naming a newly discovered bile acid after the species from which it was isolated be abandoned, and that in the future such a bile acid should be named using the principles contained in this paper.     

Differential binding of glycine- and taurine-conjugated bile acids to insoluble calcium phosphate.

It is demonstrated that bile acids bind to insoluble calcium phosphate at pH values beyond 5.5. Significant binding occurs with glycine-conjugated dihydroxy bile acids. Results indicate that these bile acids are bound in a micellar mode. Taurine conjugation almost completely inhibits the binding of these bile acids to insoluble calcium phosphate. Since glycine-conjugated dihydroxy bile acids are predominant in the rabbit, but not in the rat, our results suggest an explanation for the intriguing species-dependence of casein-induced hypercholesterolaemia, which is high in the rabbit but absent in the rat.     

Bile acids and their receptors in regulation of gut health and diseases

It is well established that bile acids play important roles in lipid metabolism. In recent decades, bile acids have also been shown to function as signaling molecules via interacting with various receptors. Bile acids circulate continuously through the enterohepatic circulation and go through microbial transformation by gut microbes, and thus bile acids metabolism has profound effects on the liver and intestinal tissues as well as the gut microbiota. Farnesoid X receptor and G protein-coupled bile acid receptor 1 are two pivotal bile acid receptors that highly expressed in the intestinal tissues, and they have emerged as pivotal regulators in bile acids metabolism, innate immunity and inflammatory responses. There is considerable interest in manipulating the metabolism of bile acids and the expression of bile acid receptors as this may be a promising strategy to regulate intestinal health and disease. This review aims to summarize the roles of bile acids and their receptors in regulation of gut health and diseases.     

Further studies on the properties of bile acids. II. Effect of bile acids on the reactivity of adrenergic and cholinergic receptors in rat intestine

The effects of bile acids (deoxycholic, cholic and dehydrocholic) were studied on the action of certain autonomic system drugs (isoprenaline, adrenaline, noradrenaline and acetylcholine). It was also tried to explain the causes of these changes in the light of the results of experiments with the widely used antagonists of adrenergic and cholinergic receptors. The experiments were carried out on isolated rat intestine by the method of Magnus. It was found that bile acids decreased the relaxing effect of isoprenaline and caused inversion of the action of adrenaline and noradrenaline on the intestine. Changes in the action of catecholamines are caused by stimulation of alpha-adrenergic receptors enhanced by bile acids, with a simultaneous decreased stimulation of beta-receptors. Bile acids cause also an increase of the effect of acetylcholine on the intestine.     

Bile acid regulation of hepatic physiology: III. Bile acids and nuclear receptors

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.     

Bile acid sulfates in serum bile acids determination.

Some bile acid sulfates were synthesized and characterized. The configuration of sulfate groups at C-3, C-7 and C-12 positions was confirmed by Nuclear Magnetic Resonance analysis. These sulfates were utilized in a study of their chemical behaviour in different analytical procedures currently used for serum bile acids determination. Procedures for bile acids extraction from serum with ethanol or Amberlite XAD-2 result in an important loss of the most polar sulfated bile acids. Complete separation of unsulfated from sulfated bile acids on Sephadex LH-20 is not achieved when deconjugation of the most polar bile acid sulfate is slow but does not produce artifacts. Enzymatic determination of bile acids gives positive response with some bile acid sulfates. The current procedures of serum bile acids determination are discussed in consideration of these results.     

Highly simplified method for gas-liquid chromatographic quantitation of bile acids and sterols in human stool.

A simple method for the gas-liquid chromatographic quantitation of human fecal bile acids and sterols is described where bile acids are subjected to n-butyl ester derivatization, without prior isolation from the stool, followed by trimethylsilylation of the sterols and bile acids. Under these conditions, bile acid derivatives are well resolved from each other and from the trimethylsilyl ether derivatives of fecal sterols and no overlap occurs. The method was shown to be highly reproducible and recoveries were similar to those obtained with other methods used for fecal bile acid analysis. Application of the method for bile acid and sterol analysis in human stool is described.     

Bile acids and their receptors in metabolic disorders

Bile acids are a large family of atypical steroids which exert their functions by binding to a family of ubiquitous cell membrane and nuclear receptors. There are two main bile acid activated receptors, FXR and GPBAR1, that are exclusively activated by bile acids, while other receptors CAR, LXRs, PXR, RORγT, S1PR2and VDR are activated by bile acids in addition to other more selective endogenous ligands. In the intestine, activation of FXR and GPBAR1 promotes the release of FGF15/19 and GLP1 which integrate their signaling with direct effects exerted by theother receptors in target tissues. This network is tuned in a time ordered manner by circadian rhythm and is critical for the regulation of metabolic process including autophagy, fast-to-feed transition, lipid and glucose metabolism, energy balance and immune responses. In the last decade FXR ligands have entered clinical trials but development of systemic FXR agonists has been proven challenging because their side effects including increased levels of cholesterol and Low Density Lipoproteins cholesterol (LDL-c) and reduced High-Density Lipoprotein cholesterol (HDL-c). In addition, pruritus has emerged as a common, dose related, side effect of FXR ligands. Intestinal-restricted FXR and GPBAR1 agonists and dual FXR/GPBAR1 agonists have been developed. Here we review the last decade in bile acids physiology and pharmacology.     

Nuclear receptors. II. Intestinal corticosteroid receptors

Two corticosteroid receptors have been cloned; they are the glucocorticoid receptor and the mineralocorticoid receptor. These receptors are members of the steroid/thyroid/retinoid receptor family of nuclear transactivating factors, which are characterized by two highly conserved zinc fingers in the central DNA binding domain, a COOH-terminal domain that encompasses the ligand binding site, and a variable NH(2)-terminal domain. In addition to these cloned receptors, other corticosteroid receptors have recently been identified in intestine. Steroid binding studies have identified two novel putative corticosteroid receptors in intestinal epithelia, and molecular cloning studies have detected two low-affinity receptors in small intestine that are activated by corticosteroids and induce CYP3A gene expression. This article focuses on the identification of these novel corticosteroid receptors and the potential role they may play in intestinal physiology.     

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.     

Phenolic 9,10-secosteroids as products of the catabolism of bile acids by a Pseudomonas sp.

The obligate aerobe, Pseudomonas putida ATCC 31752, efficiently utilises bile acids as a source of carbon and energy for growth and maintenance. When aeration is considerably restricted, a consequence to the catabolism of the bile acids in a fermentor is an accumulation of certain steroidal catabolites. Evidence is presented to show that among these are hydroxy-9,10-seco-1,3,5(10)-androstratriene-9,17-diones and those from four of the common bile acids, cholic, chenodeoxycholic, hyodeoxycholic and deoxycholic acids have been isolated and their structures determined. The product of catabolism of hyodeoxycholic acid appears to exist in a hemi-acetal form which readily forms an acetal during isolation procedures. All but one of these are described for the first time.     

Zone electrophoresis study of the bile lipoprotein complex.

Sucrose gradient column electrophoresis was performed with human hepatic and gallbladder bile. It is shown that bile phosphatidylcholines exhibit a more rapid anodic mobility than do bile salts and serum albumin. This high mobility of bile phosphatidylcholines is not due to the negatively charged lipids which are present in bile, i.e. bile salts or free fatty acids. It is demonstrated that phosphatidylcholines are associated with anionic polypeptides. Electrophoresis of reassociations between these purified polypeptides and dilaurylphosphatidylcholine showed that these anionic polypeptides are primarily responsible for the high anodic mobility of the bile lipoprotein complex. This work describes a procedure for the purification of the bile lipoprotein complex which can be useful for the study of other kinds of lipid-polypeptide associations.     

Partitioning of bile acids into subcellular organelles and the in vivo distribution of bile acids in rat liver.

1. The subcellular distribution of conjugates of cholic acid and chenodeoxycholic acid between cytosol, nuclei, mitochondria and microsomes in rat liver has been determined. 2. The partition coefficients for the distribution of these bile acids between subcellular fractions and buffer have been measured and used to construct a compartmental model of the amounts of conjugated bile acids present in the different subcellular organelles in vivo. 3. This model indicates that a large percentage of the bile acid in the rat liver is found in the nuclear fraction; 42% of the cholic acid conjugates and 27% of the chenodeoxycholic acid conjugates. Substantial amounts of bile acid are also present in microsomes and mitochondria suggesting that published estimates of the amounts of bile acids in these fractions are underestimates. 4. The model also allows the amount of bile acid which is in free solution in cytosol to be determined; 10.9% of the cholic acid conjugates and 4.1% of the chenodeoxycholic acid conjugates in rat liver were present in this fraction. Knowlege of the amount of free bile acid allows possible roles of the cytosolic bile binding proteins to be assessed.     

Bile acids. XXXV. Metabolism of 5 -cholestan-3 -ol in the Mongolian gerbil

The principal bile acid of Mongolian gerbil bile is cholic acid, although small amounts of chenodeoxycholic and lesser amounts of deoxycholic acids are identified. Muricholic acids were not found in gerbil bile. The ratio of trihydroxy to dihydroxy bile acids in gerbil bile is approximately 11:1. After administration of [4-(14)C]5alpha-cholestan-3beta-ol to gerbils with bile fistulas, 4-7% of the administered (14)C was recovered in bile and 16% in urine on the first 6 days. Alkaline hydrolysis of the bile afforded the biliary acids which were separated by partition chromatography. The (14)C ratio of trihydroxy to dihydroxy bile acids was 11:1. Allocholic acid was identified as the major acidic biliary metabolite. From analysis of (14)C retained in selected tissues, the adrenal gland appears to be an important site for retention of cholestanol or its metabolites.     

Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR

Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism.     

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.