FXR signaling in the enterohepatic system

Abstract

Enterohepatic circulation serves to capture bile acids and other steroid metabolites produced in the liver and secreted to the intestine, for reabsorption back into the circulation and reuptake to the liver. This process is under tight regulation by nuclear receptor signaling. Bile acids, produced from cholesterol, can alter gene expression in the liver and small intestine via activating the nuclear receptors farnesoid X receptor (FXR; NR1H4), pregnane X receptor (PXR; NR1I2), vitamin D receptor (VDR; NR1I1), G protein coupled receptor TGR5, and other cell signaling pathways (JNK1/2, AKT and ERK1/2). Among these controls, FXR is known to be a major bile acid-responsive ligand-activated transcription factor and a crucial control element for maintaining bile acid homeostasis. FXR has a high affinity for several major endogenous bile acids, notably cholic acid, deoxycholic acid, chenodeoxycholic acid, and lithocholic acid. By responding to excess bile acids, FXR is a bridge between the liver and small intestine to control bile acid levels and regulate bile acid synthesis and enterohepatic flow. FXR is highly expressed in the liver and gut, relative to other tissues, and contributes to the maintenance of cholesterol/bile acid homeostasis by regulating a variety of metabolic enzymes and transporters. FXR activation also affects lipid and glucose metabolism, and can influence drug metabolism.

Introduction

In 1995, the farnesoid X receptor (FXR; NR1H4) was identified as an orphan nuclear receptor from mouse (Seol et al., 1995) and rat (Forman et al., 1995). In the early studies, farnesol and related metabolites were proposed as possible ligands for the rat homolog, thus accounting for the original name (Forman et al., 1995). However, subsequently, bile acids were found to be the true endogenous ligands for FXR (Wang et al., 1999, Makishima et al., 1999, Parks et al., 1999), so more accurately, this receptor should have been designated the bile acid receptor. To date, more than 80 compounds have been identified as potential FXR ligands with varying degrees of affinity; these include the endogenous bile acids, and synthetic ligands (Table 1). Several structural structurally diverse compounds show high-affinity binding and agonist activity toward FXR, including steroids, aromatics, terpenoids, alkaloids, and fatty acids (Fig. 1).

Steroids are the major and most important ligands for FXR. Numerous endogenous compounds and their metabolites with important physiological functions encompass bile acids, cholesterol and hormones. Endogenous bile acids, including the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA), and the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), can activate FXR in vivo and in cultured cells, and bind the receptor in vitro. Bile acids have the general properties of a concave hydrophilic face and a convex hydrophobic face. They combine with the hydrophobic pocket of the FXR ligand-binding domain mainly through the hydrophobic face, while the hydroxyl groups in the hydrophilic phase also can greatly affect the affinity of bile acids with FXR. The potency of bile acids to activate FXR is CDCA > DCA > LCA > CA (Parks et al., 1999). Many compounds unrelated to bile acids, can also act as FXR ligands, such as androsterone (Wang et al., 2006), and the exogenous natural product plant sterolsforskolin (Howard et al., 2000), stigmasterol (Carter et al., 2007), and guggulsterone (Urizar et al., 2002). In addition, a series of synthetic bile acid derivatives have been developed as FXR ligands, such as 6α-ethyl-chenodeoxycholic acid (6-ECDCA) and bile alcohols, showing an even higher affinity with FXR than bile acids (Pellicciari et al., 2002).

FXR is the chief sensor of intracellular levels of bile acids, controlling their synthesis and transport. Along with the regulation of bile acid metabolism, FXR is also involved, directly and indirectly, in several important metabolic pathways in vivo, such as modulation of glucose and lipid metabolism. Thus, activation or repression of FXR can have major influences on metabolic homeostasis. In addition, FXR genetic variants are associated with metabolic diseases, including intrahepatic cholestasis of pregnancy (Van Mil et al., 2007), and cholesterol cholelithiasis (Kovacs et al., 2008). FXR ligands have been proposed for possible treatment of metabolic diseases, such as cholestasis (Liu et al., 2003), liver fibrosis (Fiorucci et al., 2004), inflammatory bowel disease (Gadaleta et al., 2011), type 2 diabetes (Zhang et al., 2006), atherosclerosis (Mencarelli and Fiorucci, 2010), and erectile dysfunction (Morelli et al., 2011). Ursodeoxycholic acid (UDCA), an FXR agonist (Campana et al., 2005), was approved by the FDA as a drug for the treatment of primary biliary cirrhosis (PBC), and is widely used for the treatment of a variety of chronic cholestatic diseases. Thus, FXR provides a framework for developing novel therapies for several liver diseases that are due to altered bile acid homeostasis. There are more than 40 target genes for FXR, most of which are positively regulated, although some genes are indirectly down-regulated by FXR (Mencarelli and Fiorucci, 2010). Some of the FXR target genes are involved in hepatic-intestinal bile acid synthesis, transport and homeostasis, while others are functional in other metabolic pathways.