Pharmacology of bile acid receptors: Evolution of bile acids from simple detergents to complex signaling molecules

Abstract

For many years, bile acids were thought to only function as detergents which solubilize fats and facilitate the uptake of fat-soluble vitamins in the intestine. Many early observations, however, demonstrated that bile acids regulate more complex processes, such as bile acids synthesis and immune cell function through activation of signal transduction pathways. These studies were the first to suggest that receptors may exist for bile acids. Ultimately, seminal studies by many investigators led to the discovery of several bile acid-activated receptors including the farnesoid X receptor, the vitamin D receptor, the pregnane X receptor, TGR5, α5 β1 integrin, and sphingosine-1-phosphate receptor 2. Several of these receptors are expressed outside of the gastrointestinal system, indicating that bile acids may have diverse functions throughout the body. Characterization of the functions of these receptors over the last two decades has identified many important roles for these receptors in regulation of bile acid synthesis, transport, and detoxification; regulation of glucose utilization; regulation of fatty acid synthesis and oxidation; regulation of immune cell function; regulation of energy expenditure; and regulation of neural processes such as gastric motility. Through these many functions, bile acids regulate many aspects of digestion ranging from uptake of essential vitamins to proper utilization of nutrients. Accordingly, within a short time period, bile acids moved beyond simple detergents and into the realm of complex signaling molecules. Because of the important processes that bile acids regulate through activation of receptors, drugs that target these receptors are under development for the treatment of several diseases, including cholestatic liver disease and metabolic syndrome. In this review, we will describe the various bile acid receptors, the signal transduction pathways activated by these receptors, and briefly discuss the physiological processes that these receptors regulate.

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

“…This suggest that activation of FXR could ameliorate these symptoms, notably liver cholestasis, because FXR is responsible for regulating bile acid synthesis and transport 49 . A highly potent FXR agonist, 6α-ethyl-chenodeoxycholic acid (6-ECDCA, obetacholic acid), a derivative of the FXR agonist CDCA 112 , was recently approved for the treatment of primary biliary cirrhosis (PBC) and is in late clinical trials for NASH 113–115 . PBC is currently treated with UDCA 116 .…”

Roles of Ileal ASBT and OSTα-OSTβ in Regulating Bile Acid Signaling

“…Bile acids also function as ligands for nuclear and G protein-coupled receptors and have important roles as signaling molecules. The best-studied bile acid receptors are the farnesoid X receptor (FXR) and G protein-coupled receptor 1 (GPBAR1; also called TGR5 or membrane-type receptor for bile acids, M-BAR), but the list of bile acid receptors also includes other nuclear receptors, such as the pregnane X receptor (PXR) and vitamin D receptor (VDR), and other G protein-coupled receptors, such as the sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic receptors M2 and M3 [1,2]. It is important to note that bile acids also signal through α5,β1-integrin [3], and can induce membrane perturbations that activate pathways involving membrane-associated proteins such as NAD(P)H oxidases and Phospholipase A2 [4,5].…”

Targeting Bile Acid Receptors: Discovery of a Potent and Selective Farnesoid X Receptor Agonist as a New Lead in the Pharmacological Approach to Liver Diseases

“…The signaling pathways involve the interaction with several nuclear receptors (NRs) and cell surface G-protein-coupled receptors (G-PCRs), including the G protein-coupled bile acid receptor GPBAR1 (also known as TGR5 or M-BAR) (Maruyama et al, 2002; Kawamata et al, 2003; Fiorucci and Distrutti, 2015; Copple and Li, 2016). Among NRs, the farnesoid X receptor (FXR) (Makishima et al, 1999; Parks et al, 1999; Wang et al, 1999) is the master gene that orchestrates BA homeostasis.…”