ae3 In humans the two primary bile acids CA

In humans, the two primary bile acids CA and CDCA make up approximately 70%–80% of the total bile ae3 pool. DCA is the major secondary bile acid, which may account for approximately 20% of the total bile acid pool. Among all bile acid species, the secondary bile acid LCA is highly toxic. LCA is efficiently detoxified, and only trace amounts of LCA are found in the bile. In mice and rats, CDCA and UDCA are converted to α-muricholic acids (MCA) and βMCA, respectively. MCAs have a hydroxyl group at the C-6 position and are more hydrophilic than CDCA. In C57BL6J mice, the bile acid pool contains roughly 50% MCA, ∼40% CA and ∼10% CDCA. A recent study revealed that murine CYP2C70 was involved in MCA formation in mice. Humans do not appear to have a homolog of murine CYP2C70, which may explain the different bile acid composition between mice and humans.
Bile acid receptors in the regulation of metabolism and inflammation Bile acid exerts its regulatory function by activating a number of nuclear receptors and signal transduction pathways in hepatic and extrahepatic tissues. Nuclear receptors are intracellular ligand-activated transcription factors. A typical nuclear receptor consists of a DNA-binding domain and a ligand-binding domain. Most nuclear receptors bind to the consensus DNA sequences in their target gene promoters and regulate gene transcription in a ligand-dependent manner. Bile acids are endogenous ligands of three nuclear receptors: the farnesoid X receptor (FXR), the pregnane X receptor and the vitamin D receptor. These bile acid receptors sense bile acid concentrations in the enterohepatic system and in turn regulate bile acid homeostasis and detoxification mechanisms. Pregnane X and vitamin D receptor activation induces many phase-I cytochrome p450s, phase II conjugating enzymes and phase-III transporters that are involved in bile acid and drug detoxification in the hepatocyte and the intestine (reviewed in). In this review, we will primarily focus our discussion on the role of FXR in the regulation of bile acid, lipid and glucose metabolism. Bile acids also activate cell surface receptors, such as the G protein-coupled receptor TGR5 and the sphingosine-1-phosphate receptor 2. TGR5 is expressed in the intestine and colon as well as metabolically active tissues, including skeletal muscle and brown adipose tissue, and is involved in the regulation of glucose and energy metabolism. Finally, bile acid-activated FXR induces the growth hormone fibroblast growth factor (FGF) 15 in mice and its ortholog FGF19 in humans. Recent studies revealed a novel role of FGF15/19 in the regulation of postprandial glucose metabolism in the liver.
Conclusion Extensive studies over the past two decades have significantly expanded our knowledge of the physiological and pathophysiological functions of bile acid metabolism and signaling. Bile acids are no longer considered merely physiological detergent molecules that facilitate nutrient absorption, but are also important regulators of various cellular processes in lipid, glucose and energy metabolism and immune responses. Under normal physiology, bile acid signaling plays a role in integrating nutrient sensing to the regulation of metabolic homeostasis. Dysregulation of bile acid homeostasis may underlie the pathogenesis of many human diseases. Importantly, new mechanistic understanding of bile acid signaling action in the liver and extrahepatic tissues to date has laid the groundwork for the development of promising bile acid-based drug therapies for the treatment of liver and metabolic diseases. Indeed, bile acid sequestrants have been used for a long time as a cholesterol-lowering therapy in addition to statins. More recently, the bile acid sequestrant colesevelam has been approved to be used in combination therapies to improve glycemic control in type 2 diabetes because of its effects on inducing gut GLP-1 production. Additionally, the FXR agonist obeticholic acid has been approved for primary biliary cholangitis treatment. Obeticholic acid treatment has also been shown to significantly improve fibrosis and NAFLD Activity Score in a completed Phase 2b FLINT trial. Other bile acid-based therapies, such as the selective TGR5 agonist and the FXR and TGR5 dual agonist, are being tested in preclinical studies and phase 1 trials as potential therapies for metabolic and inflammatory diseases.