Perspective: TGR5 (Gpbar-1) in liver physiology and disease

Summary

Bile acids are signaling molecules with diverse endocrine functions. Bile acid effects are mediated through the nuclear receptor farnesoid X receptor (FXR), the G-protein coupled receptor TGR5 (Gpbar-1) and various other bile acid sensing molecules. TGR5 is almost ubiquitously expressed and has been detected in different non-parenchymal cells of human and rodent liver. Here, TGR5 has anti-inflammatory, anti-apoptotic and choleretic functions. Mice with targeted deletion of TGR5 are protected from the development of cholesterol gallstones. Administration of specific TGR5 agonists lowers serum and liver triglyceride levels thereby reducing liver steatosis. Furthermore, activation of TGR5 promotes intestinal glucagon-like peptide-1 (GLP-1) release, thereby modulating glucose homeostasis and energy expenditure in brown adipose tissue and skeletal muscle. Additionally, TGR5 exerts anti-inflammatory actions resulting in decreased liver injury in animal models of sepsis. These beneficial effects make TGR5 an attractive therapeutic target for metabolic diseases, such as diabetes, obesity, atherosclerosis and steatohepatitis.

Introduction

Bile acids are signaling molecules with diverse endocrine and paracrine functions [1], [2], [3]. Bile acids have been shown to regulate bile acid, glucose and lipid metabolism and to modulate the immune response. Furthermore, bile acids can induce programmed cell death (apoptosis) but can also trigger cell proliferation, cell differentiation and liver regeneration [2], [4], [5], [6], [7], [8], [9].

In liver several different receptors and molecular structures have been identified as bile acid sensing molecules (Table 1). These comprise nuclear bile acid receptors, such as the farnesoid X receptor (FXR, NR1H4), which are ligand-activated transcription factors [10], [11], [12], [13] as well as plasma membrane-bound, G-protein coupled receptors like TGR5 (Gpbar-1) or the sphingosine-1-phosphate receptor 2 (S1P₂) [14], [15], [16]. However, the role of the S1P₂ receptor for bile acid signaling in the liver remains to be determined. Furthermore, bile acids can bind and modify integrin signaling [17] and have been demonstrated to activate various signaling cascades, such as kinase pathways and ion channels in different liver cells [4], [5], [8], [17], [18], [19], [20], [21], [22].

In liver the nuclear bile acid receptor FXR is highly expressed in hepatocytes [10], [11], [23] and chenodeoxycholic acid (CDCA) and its conjugates constitute the most potent FXR ligands with an EC₅₀ of approximately 5–10 μM [12], [13], [24]. The membrane-bound bile acid receptor TGR5 is expressed in many tissues, including liver, gallbladder, intestine, kidney, spleen and brain [14], [15], [25], [26], [27]. In liver TGR5 has not been detected in hepatocytes but is localized in sinusoidal endothelial cells (SEC), Kupffer cells (KC), cholangiocytes, gallbladder epithelial cells and gallbladder smooth muscle cells [28], [29], [30], [31], [32], [33], [34]. Different unconjugated and conjugated bile acids constitute natural ligands for TGR5 (rank order of potency of unconjugated bile acids: lithocholic acid [LCA] > deoxycholic acid [DCA] > chenodeoxycholic acid [CDCA] > cholic acid [CA]). While conjugation of bile acids with glycine has only negligible impact on their TGR5 agonistic activity, conjugation of bile acids with taurine increases their TGR5 agonistic potency, rendering taurolithocholic acid (TLCA) the most potent agonist with an EC₅₀ of 0.29 μM [35]. In brain TGR5 may function as a neurosteroid receptor, which is activated by nanomolar concentrations of 5ß-pregnan-3α-ol-20-one [25]. Stimulation of TGR5 by bile acids or neurosteroids activates adenylate cyclase thereby elevating intracellular cyclic AMP levels [14], [15], [25].

Bile acid signaling pathways have been linked to the pathogenesis of different liver diseases and bile acid receptors have emerged as potential therapeutic targets for the treatment of metabolic and liver disorders. This review will focus on the role of TGR5 in the liver. For a recent overview on extrahepatic functions of TGR5 refer to [36].