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.

Keywords: Bile acids; Farnesoid X receptor; Pregnane X receptor; Sphingosine-1-phosphate receptor 2; TGR5; Vitamin D receptor.

Figure 1

Summary of the physiological functions of FXR. In the intestine, bile acids (BAs) are transported into ileal epithelial cells by ASBT. Activation of FXR in ileal epithelial cells suppresses ASBT, upregulates FGF15/19, and upregulates Ost α/β. BAs are transported into hepatocytes by NTCP. Activation of FXR in hepatocytes upregulates SHP which suppresses CYP7A1, NTCP, gluconeogenesis, and lipogenesis. FXR upregulates BSEP which transports BAs into the bile canaliculus. FXR also increases glycogen synthesis and increases lipid oxidation. FGF15/19 activates FGFR4 on hepatocytes which suppresses CYP7A1.

Figure 2

Summary of the physiological functions of TGR5. See text for complete details.

Figure 3

Mechanism by which TUDCA stimulates choleresis. See text for details

Figure 4

Summary of the effects of S1PR2 activation in hepatocytes by bile acids. Conjugated bile acids activate sphingosine-1-phosphate receptor 2 (S1PR2), which transactivates the epidermal growth factor receptor (EGFR) and the insulin receptor (IR). EGFR and/or IR activate Akt, which increases glycogen synthesis and decreases gluconeogenesis; activate Erk1/2, which increases expression of proinflammatory genes; and activates Jnk1/2, which suppresses CYP7A1. DCA stimulates mitochondrial production of ROS (reactive oxygen species) which inhibit phosphatases (PTPase) leading to the activation of EGFR. DCA also activates sphingomyelinase which generates ceramide. This activates FAS receptors, which activates JNK1/2 leading to upregulation of SHP and suppression of CYP7A1.