Pleiotropic Roles of Bile Acids in Metabolism

Enzymatic oxidation of cholesterol generates numerous distinct bile acids which function both as detergents that facilitate the digestion and absorption of dietary lipids and as hormones that activate five distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility, bacterial growth, inflammation, and in the liver-gut axis. This review focuses on the present knowledge regarding the physiologic and pathologic role of bile acids and their immunomodulatory role, with particular attention to bacterial lipopolysaccharides (endotoxins) and bile acid and immunological disorders. The specific role that bile acids play in the regulation of innate immunity, various systemic inflammations, inflammatory bowel diseases, allergy, psoriasis, cholestasis, obesity, metabolic syndrome, alcoholic liver disease, and colon cancer will be reviewed.

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

What Can We Learn From Mouse Models About Bile Acid-Mediated Changes After Bariatric Surgery?

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Role of the bile acid receptor TGR5 (Gpbar-1) in liver damage and regeneration

A comprehensive study of cholesterol, bile acid, and lipoprotein metabolism was undertaken in two strains of hamster that differed markedly in their response to a sucrose-rich/low fat diet. Under basal conditions, hamsters from the LPN strain differed from Janvier hamsters by a lower cholesterolemia, a higher postprandial insulinemia, a more active cholesterogenesis in both liver [3- to 4-fold higher 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoAR) activity and mRNA] and small intestine, and a lower hepatic acyl-coenzyme A:cholesterol acyltransferase activity. Cholesterol saturation indices in the gallbladder bile were similar for both strains, but the lipid concentration was 2-fold higher in LPN than in Janvier hamsters. LPN hamsters had a lower capacity to transform cholesterol into bile acids, shown by the smaller fraction of endogenous cholesterol converted into bile acids prior to fecal excretion (0.34 vs. 0.77). In LPN hamsters, the activities of cholesterol 7alpha-hydroxylase (C7OHase) and sterol 27-hydroxylase (S27OHase), the two rate-limiting enzymes of bile acid synthesis, were disproportionably lower (by 2-fold) to that of HMG-CoAR. When fed a sucrose-rich diet, plasma lipids increased, dietary cholesterol absorption improved, hepatic activities of HMG-CoA reductase, C7Ohase, and S27OHase were reduced, and intestinal S27OHase was inhibited in both strains. Despite a similar increase in the biliary hydrophobicity index due to the bile acid enrichment in chenodeoxycholic acid and derivatives, only LPN hamsters had an increased lithogenic index and developed cholesterol gallstones (75% incidence), whereas Janvier hamsters formed pigment gallstones (79% incidence). These studies indicate that LPN hamsters have a genetic predisposition to sucrose-induced cholesterol gallstone formation related to differences in cholesterol and bile acid metabolism.

Bile acids promote bile formation and facilitate dietary lipid absorption. Animal and human studies showing disturbed bile acid metabolism in diabetes mellitus suggest a link between bile acids and glucose control. Bile acids are activating ligands of the farnesoid X receptor (FXR), a nuclear receptor with an established role in bile acid and lipid metabolism. Evidence suggests a role for FXR also in maintenance of glucose homeostasis. Animal and human studies employing bile acid sequestrants (bile acid binding agents), which interrupt the enterohepatic circulation of bile acids and effectively reduce plasma cholesterol, support a link between bile acid and glucose metabolism. In lipid-lowering trials, bile acid sequestrants, such as colesevelam hydrochloride, colestyramine (cholestyramine) and colestilan (colestimide), have also been shown to lower plasma glucose and glycosylated haemoglobin levels, suggesting the utility of these agents as a potential therapy for type 2 diabetes. In this article, we review the relationship between bile acid metabolism and glucose homeostasis, and present data demonstrating the utility of bile acid sequestrants in the management of diabetes.

Bile acids (BAs) are a family of steroidal molecules derived from cholesterol and biosynthesised in the pericentral hepatocytes of the liver. Structurally they may be regarded as consisting of two components, a rigid steroid nucleus and a short aliphatic side chain terminating in an alcohol or carboxyl group. Traditionally BAs are known for their ability to act as solubilising agents in the gut, aiding in the absorption of dietary lipids through the formation of mixed micelles. However the identification of BAs as ligands of the farnesoid X receptor (FXR) has lead to the realisation that these molecules have a wider range of biological effects. BAs regulate lipid and glucose homeostasis through activation of the FXR and the G-protein coupled receptor, TGR5. They can activate apoptotic, inflammatory and carcinogenic signalling pathways. BAs have also been shown to have anti-inflammatory effects. Interestingly, BAs are not restricted to the hepatic-intestinal system. Plasma BAs regulate BA synthesis and metabolism. BAs have recently been identified in cerebrospinal fluid. The BA, ursodeoxycholic acid has a potential role as a neuroprotectant in Huntington's disease and its taurine conjugate exhibits neuro-protective effects in vitro that may be relevant to Alzheimer's disease. This renaissance in BA biology has lead to the development of numerous medicinal chemistry programmes with different therapeutic targets, using BAs as lead structures. BA derivatives with increased efficacy and potency for FXR and TGR5 hold significant promise for the treatment of metabolic disorders. The peculiar effects of BAs on cell viability have been exploited for the design of selective cytocidal agents for treatment of various cancers. BA derivatives have also been screened with much success for anti-microbial and antifungal properties. Other targets include carbonic anhydrase for treatment of glaucoma and the glucocorticoid receptor for antiinflammatory effects. In this review interesting recent developments in the medicinal chemistry of these eclectic substances will be discussed.

Bile acids (BAs) are amphipathic molecules synthetized in the liver. They are primarily involved in the digestion of nutrients. Apart from their role in dietary lipid absorption, BAs have progressively emerged as key regulators of systemic metabolism and inflammation. In the last decade, it became evident that BAs are particularly important for the regulation of glucose, lipid, and energy metabolism. Indeed, the interest in role of BA in metabolism homeostasis is further increased due to the global public health increase in obesity and related complications and a large number of research postulating that there is a close mutual relationship between BA and metabolic disorders. This strong relationship seems to derive from the role of BAs as signaling molecules involved in the regulation of a wide spectrum of metabolic pathways. These actions are mediated by different receptors, particularly nuclear farnesoid X receptor (FXR) and Takeda G protein coupled receptor 5 (TGR5), which are probably the major effectors of BA actions. These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in BA, lipid and carbohydrate metabolism, energy expenditure, and inflammation. The large correlation between BAs and metabolic disorders offers the possibility that modulation of BAs could be used as a therapeutic approach for the treatment of metabolic diseases, including obesity itself. The aim of this review is to describe the main physiological and metabolic actions of BA, focusing on its signaling pathways, which are important in the regulation of metabolism and might provide new BA -based treatments for metabolic diseases.

We present a method using a combination of enzymatic deconjugation and targeted LC-multiple reaction monitoring (MRM)-MS analysis for analyzing all common bile acids (BAs) in piglet urine, and in particular, for detecting conjugated BAs either in the absence of their standards, or when present in low concentrations. Initially, before enzymatic deconjugation, 19 unconjugated BAs (FBAs) were detected where the total concentration of the detected FBAs was 9.90 μmol/l. Sixty-seven conjugated BAs were identified by LC-MRM-MS analysis before and after enzymatic deconjugation. Four enzymatic assays were used to deconjugate the BA conjugates. FBAs in urine after cholylglycine hydrolase/sulfatase treatment were 33.40 μmol/l, indicating the urinary BAs were comprised of 29.75% FBAs and 70.25% conjugated BAs in single and multiple conjugated forms. For the conjugates in single form, released FBAs from cholylglycine hydrolase deconjugation indicated that the conjugates with amino acids were 14.54% of urinary BAs, 16.27% glycosidic conjugates were found by β-glucuronidase treatment, and sulfatase with glucuronidase inhibitor treatment liberated FBAs that constituted 16.67% of urinary BAs. Notably, chenodeoxycholic acid (CDCA) was initially detected only in trace amounts in urine, but was found at significant levels after the enzymatic assays above. These results support that CDCA is a precursor of γ-muricholic acid in BA biosynthesis in piglets.

Is CYP2C70 the key to new mouse models to understand bile acids in humans?

Bile acids are detergents and important signaling molecules that activate the nuclear receptor FXR to control key metabolic processes, including feedback mechanisms to maintain bile acid homeostasis. FXR is the central rheostat of bile acid metabolism, and activation of FXR decreases the mRNA levels of bile acid synthetic genes, including Cyp 7 a 1 , the gene encoding the rate-limiting enzyme of bile acid synthesis. We show that Cyp 7 a 1 mRNA levels were rapidly reduced after pharmacologic FXR activation in wild-type, but not Fxr – / – or liver-specific Fxr knockout mice ( Fxr L - KO ). The rapid decrease in Cyp 7 a 1 mRNA suggested a previously unidentified post-transcriptional mechanism. To identify the mechanism, we used synthetic and endogenous FXR agonists and found the RNA binding protein ZFP36L1 as a novel FXR target gene. ZFP36L1 mRNA and protein levels were increased as early as 30 minutes after FXR activation. ZFP36L1 is a bona - fide RNA binding protein that promotes degradation of mRNA targets by binding to AU-rich elements (AREs) in the 3’ UTR. We generated in vivo and in vitro gain-of-function models and we used reporter assays to show that ZFP36L1 targets the Cyp7a1 UTR . In mice, hepatic overexpression of ZFP36L1 decreased Cyp 7 a 1 mRNA and protein and decreased bile acid levels. To complement our gain-of-function studies, we generated liver-specific Zfp 36 l 1 knockout mice ( Zfp 36 l 1 L - KO ) and we show that loss of Zfp 36 l 1 resulted in elevated Cyp 7 a 1 mRNA and protein, and increased bile acid levels. Given that bile acids are important metabolites that control lipid absorption and signaling, we investigated whether loss of hepatic Zfp 36 l 1 resulted in more broad metabolic dysfunction. Western diet fed Zfp 36 l 1 L - KO mice had reduced body weight gain, specifically in adipose tissue depots compared to littermate Zfp 36 l 1 flox-flox mice. The differences in adiposity and steatosis were attributed to reduced lipid absorption, as Zfp 36 l 1 L - KO mice have increased fecal caloric content and reduced triglyceride absorption as determined by an intragastric fat tolerance test. The decreased lipid absorption is consistent with an altered bile acid metabolism. Thus, we have identified a novel pathway that controls Cyp 7 a 1 and bile acid metabolism but may also have wider implications in diseases such as obesity and hepatosteatosis.

Bile Acids as Modulators of Gut Microbiota Linking Dietary Habits and Inflammatory Bowel Disease: A Potentially Dangerous Liaison

Primary bile acids are the end product of cholesterol catabolism synthesized in the liver and excreted into bile. Secondary bile acids are derived after modifications of primary bile acids by intestinal microbiota. Historically BAs have been viewed as emulsifying agents facilitating the digestion and absorption of dietary lipids and damaging tissue through their detergent activity. More recent studies have uncovered the hormone-like signaling functions of bile acids that modulate a myriad of metabolic and inflammatory pathways in multiple cell types and tissues via dedicated bile acid receptors in the nucleus (e.g., FXR) and plasma membrane (e.g., TGR5). Accumulating evidence suggests that bilirubin also has active signaling roles in immune cells beyond its well-established antioxidant effects. Deregulated bile acid and bilirubin metabolism and transport have been implicated in the pathogenesis of a variety of diseases including cholestatic and metabolic liver diseases, hepatic malignancies, and inflammatory bowel disease. Although the functions of bile acids and bilirubin in the regulation of inflammation and immunity are only beginning to be appreciated, targeting bile acids and their cellular receptors (e.g., FXR, TGR5) represents an important and highly promising area of drug discovery.