Essential roles of bile acids and their nuclear receptors, FXR and PXR, in the cholestatic liver disease

Abstract

Bile acids (BAs) are steroid acids found predominantly in the bile of mammals and other vertebrates. Though BAs have been known as digestive juice, recent studies have revealed that BAs act as signaling molecules to control metabolism and inflammation. Today, BAs are considered as potential therapeutic molecules for treatment of complex metabolic liver disease. However, the detergent properties of BAs lead to hepatic injury and intrahepatic cholestasis when BAs are accumulated in the liver with impaired bile flow into gall bladder. Cholestasis is a pathological condition of hepatic retention of cytotoxic bile acids. To date, hydrophilic ursodeoxycholic acid has been currently used to treat cholestasis, but the efficacy of UDCA for cholestasis is still limited. Given that BAs are endogenous ligands of several nuclear receptors, including Farnesoid X receptor and Pregnane X receptor, novel synthetic ligands for those nuclear receptors are promising for the treatment of cholestatic liver diseases. ARTICLE HISTORY

Pregnane X receptor exacerbates nonalcoholic fatty liver disease accompanied by obesity- and inflammation-prone gut microbiome signature

“…LCA at high concentrations also activate the PXR-target gene Cyp3a11 to protect liver injury in mice, highlighting the importance of gut microbiome in modulating the hepatic PXR-signaling (25). When BAs are toxic at high concentrations such as during cholestasis, PXR acts in concert with the major BA receptor farnesoid X receptor (FXR) to modulate BA detoxi cation and elimination (26). BAs also serve as an important host factor shaping the gut microbiome in diet-induced obese mice, and this effect was more pronounced in PXR-KO mice, suggesting that PXR contributes to the weakening of the effect of BAs on lipoprotein metabolism (27).…”

Ursodeoxycholic acid ameliorates hepatic lipid metabolism in LO2 cells by regulating the AKT/mTOR/SREBP-1 signaling pathway

“…BAs can maintain triglyceride (TG) homeostasis and act as a metabolic regulator of glucose uptake and lipid metabolism[9]. It is confirmed that BAs binding to activated farnesoid X receptor (FXR) in the liver inhibit sterol regulatory element-binding protein 1c (SREBP1c)-mediated lipogenesis[10,11]. Conversely, activation of FXR also suppresses synthesis of BAs when BAs are excessive[12].…”