Bile acid receptors in non-alcoholic fatty liver disease

Abstract

Accumulating data have shown that bile acids are important cell signaling molecules, which may activate several signaling pathways to regulate biological processes. Bile acids are endogenous ligands for the farnesoid X receptor (FXR) and TGR5, a G-protein coupled receptor. Gain- and loss-of-function studies have demonstrated that both FXR and TGR5 play important roles in regulating lipid and carbohydrate metabolism and inflammatory responses. Importantly, activation of FXR or TGR5 lowers hepatic triglyceride levels and inhibits inflammation. Such properties of FXR or TGR5 have indicated that these two bile acid receptors are ideal targets for treatment of non-alcoholic fatty liver disease, one of the major health concerns worldwide. In this article, we will focus on recent advances on the role of both FXR and TGR5 in regulating hepatic triglyceride metabolism and inflammatory responses under normal and disease conditions.

Keywords: Cholesterol; FXR; Inflammation; TGR5; Triglyceride.

Figure 1

Chemical structures of BAs, FXR agonists, TGR5 agonists and FXR/TGR5 dual agonists.

Figure 2. Role of FXR in lipid metabolism

Bile acids (CA and CDCA), synthetic FXR agonists (GW4064, INT-747 and WAY-362450) and a dual FXR/TGR5 agonist (INT-767) activate hepatic FXR, resulting in modulation of hepatic and plasma lipid homeostasis. FXR lowers hepatic triglyceride levels likely through multiple mechanisms. The FXR-SHP-SREBP-1c pathway does not appear to play a role in this process [, –32]. Instead, other genes/pathways, including FGF21 [43], ChREBP [33], PPARα [36, 41], and AKR1B7 [34] may play a role in FXR-mediated reduction in hepatic triglyceride levels. Activation of FXR regulates plasma cholesterol and triglyceride levels through modulating several genes, including SR-BI [19], LDLR [16], Syndecan-1[39], VLDLR [38], ApoCII, ApoCIII [37] and ANGPTL3 [25].

Figure 3. Role of TGR5 in lipid metabolism, inflammation and energy homeostasis

In the absence of a ligand, TGR5 is tightly bound to a G protein complex consisting of α, β and γ subunits. Upon binding to a ligand (bile acids, synthetic TGR5 agonist (INT-777), synthetic dual FXR/TGR5 agonist (INT-767)), the G protein complex dissociates to form α and βγ protein subunits. The α protein subunit then activates adenylate cyclase which in turn converts ATP to cAMP. The resultant cAMP accumulation activates protein kinase A, which exerts downstream effects [11]. In macrophages and hepatic Kupffer cells, TGR5 attenuates inflammatory cytokine production through antagonizing the activity of NF-κB [69]. In intestinal L cells, TGR5 induces GLP1 secretion, which subsequently stimulates insulin secretion from pancreatic β cells to regulate glucose homeostasis [62]. In skeletal muscle and brown adipose tissue (BAT), TGR5 increases energy expenditure through inducing mitochondrial thermogenesis via PGC1α and T3 [61]. In the liver, TGR5 attenuated triglyceride accumulation through a yet-to-be-determined mechanism [62].

Figure 4. Major pathways regulated by FXR and TGR5

Activation of either FXR or TGR5 lowers hepatic TG levels and inhibits inflammation, thus protecting against the development of NAFLD. Activation of either receptor also lowers plasma lipids and improves glucose homeostasis. Activation of FXR reduces energy expenditure. In contrast, activation of TGR5 increases energy expenditure. The mechanism by which TGR5 lowers hepatic TG levels or plasma lipids remains to be determined.