Pleiotropic roles of bile acids in metabolism

Abstract

Enzymatic oxidation of cholesterol generates numerous distinct bile acids that function both as detergents that facilitate digestion and absorption of dietary lipids, and as hormones that activate four 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 and bacterial growth, inflammation, liver regeneration, and hepatocarcinogenesis. This review covers the roles of specific bile acids, synthetic agonists, and their cognate receptors in controlling these diverse functions, as well as their current use in treating human diseases.

Figure 1. Synthesis of Bile Acids and the Bile Acid Pool

(A) The conversion of the 27 carbon cholesterol to primary and secondary 24 carbon bile acids by liver enzymes and the microbiome/gut flora is shown. Representative primary and secondary bile acids together with the orientation of the hydroxyls are indicated. (B) Relative bile acid composition in the human (modified from Hofmann, 2010) and mouse bile acid pool (modified from Kerr et al., 2002).

Figure 2. Bile Acid Metabolism in Liver and Intestine

(A) A cartoon of hepatocytes showing the classic (neutral) and alternative (acidic) bile acid biosynthetic pathways that generate glycine- or taurine- conjugated bile acids (BA), including cholic, chenodeoxycholic and muricholic acids (inset). The location of the lipid transporters BSEP, MDR2/3 and ABCG5/ABCG8 on the apical membrane, and the location of NTCP and OATP transporters that facilitate recovery of bile acids from the blood are also shown. FGF15, secreted into the portal blood from the intestine, is shown bound to FGFR4/β-Klotho, leading to suppression of bile acid (BA) synthesis. Three representative FXR target genes (SHP, BSEP and MDR2) are shown in the nucleus. (B) A cartoon of enterocytes in the distal ileum showing bile acid absorption from the lumen occurring via ASBT and bile acid efflux out of the cell via OSTα/OSTβ. Representative FXR target genes (SHP, FGF15, IBABP, OSTα and OSTβ) are shown as well as the secretion of FGF15 into the portal blood.