Abstract
In addition to their classical roles as detergents to aid in the process of digestion, bile acids have been identified as important signaling molecules that function through various nuclear and G protein-coupled receptors to regulate a myriad of cellular and molecular functions across both metabolic and nonmetabolic pathways. Signaling via these pathways will vary depending on the tissue and the concentration and chemical structure of the bile acid species. Important determinants of the size and composition of the bile acid pool are their efficient enterohepatic recirculation, their host and microbial metabolism, and the homeostatic feedback mechanisms connecting hepatocytes, enterocytes, and the luminal microbiota. This review focuses on the mammalian intestine, discussing the physiology of bile acid transport, the metabolism of bile acids in the gut, and new developments in our understanding of how intestinal metabolism, particularly by the gut microbiota, affects bile acid signaling.
Highlights
In addition to their classical roles as detergents to aid in the process of digestion, bile acids have been identified as important signaling molecules that function through various nuclear and G protein-coupled receptors to regulate a myriad of cellular and molecular functions across both metabolic and nonmetabolic pathways
The best studied of these pathways include those regulated via direct ligand-mediated activation of the nuclear receptors farnesoid X receptor (FXR) (NR1H4), pregnane X receptor (PXR) (NR1I2), and vitamin D receptor (VDR)
Bile acids act through other receptors including muscarinic receptors, the sphingosine-1-phosphate receptor 2, ␣5,1-integrin, through signal transduction pathways such as those mediated by Jun Nterminal kinase (JNK), ERK, and Akt [3, 6,7,8], and through posttranslational interactions with proteins [9]
Summary
Bile acids are synthesized from cholesterol primarily in pericentral hepatocytes through a series of sterol ring hydroxylations and side chain oxidation steps. The newly synthesized bile acids are N-acyl amidated on the side chain with glycine or taurine at a ratio of approximately 3 to 1 in humans and almost exclusively with taurine (>95%) in mice After their synthesis, bile acids undergo an enterohepatic circulation where they are secreted by the liver along with other biliary constituents, pass into the small intestine, are reabsorbed from the intestinal lumen, and are carried back in the portal circulation to the liver for efficient extraction and secretion into bile [20]. Bile acids solubilize nonpolar lipids such as cholesterol and fat-soluble vitamins, increasing their water-solubility and promoting their diffusion across the unstirred water layer for delivery to the intestinal epithelium [33] Absorption of these other dietary and biliary lipids begins in the proximal and mid-intestine, whereas bile acids are absorbed primarily in the distal small intestine (ileum), with only about 5% of intestinal bile acids escaping reabsorption to undergo fecal elimination. In all vertebrates examined to date, including primitive vertebrates such as the little skate (Leucoraja erinacea) and sea lamprey (Petromyzon marinus) [38], the ileal epithelium maintains an efficient transport system for the active reclamation of bile acids [39]
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