Abstract
TGR5 is a G protein-coupled bile acid receptor that is increasingly recognized as a key regulator of glucose homeostasis. While the role of TGR5 signaling in immune cells, adipocytes and enteroendocrine L cells in metabolic regulation has been well described and extensively reviewed, the impact of TGR5-mediated effects on hepatic physiology and pathophysiology in metabolic regulation has received less attention. Recent studies suggest that TGR5 signaling contributes to improvements in hepatic insulin signaling and decreased hepatic inflammation, as well as metabolically beneficial improvements in bile acid profile. Additionally, TGR5 signaling has been associated with reduced hepatic steatosis and liver fibrosis, and improved liver function. Despite the beneficial effects of TGR5 signaling on metabolic health, TGR5-mediated gallstone formation and gallbladder filling complicate therapeutic targeting of TGR5 signaling. To this end, there is a growing need to identify cell type-specific effects of hepatic TGR5 signaling to begin to identify and target the downstream effectors of TGR5 signaling. Herein, we describe and integrate recent advances in our understanding of the impact of TGR5 signaling on liver physiology and how its effects on the liver integrate more broadly with whole body glucose regulation.
Highlights
TGR5 is a transmembrane G-protein coupled receptor (GPCR) for bile acids that is ubiquitously expressed in mouse and human tissues [1,2,3,4,5,6]
Kawamata et al, reported that treatment of a TGR5-expressing human monocytic cell line (THP-1) with taurolithocholic acid (TLCA), LCA, and deoxycholic acid (DCA), dramatically increased cAMP production and suppressed cytokine production [1]. These studies identified that, in most cell types, TGR5 is coupled to a stimulatory G-alpha-protein (Gαs ), whereby ligand binding to TGR5 results in the activation of adenylyl cyclase-cAMP-PKA signaling and the associated downstream effects, including the recruitment of cAMP response element-binding protein (CREB) to target genes [1,2]
These findings suggest that TGR5 signaling may upregulate the alternative pathway of bile acid synthesis, which reduces taurocholic acid (TCA) and CA and increases tauromuricholic acid (TMCA), thereby decreasing the hydrophobicity of the bile acid pool (Figure 2B)
Summary
TGR5 is a transmembrane G-protein coupled receptor (GPCR) for bile acids that is ubiquitously expressed in mouse and human tissues [1,2,3,4,5,6]. Initial studies revealed that TGR5 signaling regulates glucose tolerance, inflammation, and energy expenditure [9,13,14,15], such that TGR5 is recognized as a potential target for the treatment of metabolic disorders. To this end, much metabolic research regarding. This review will summarize the currently available knowledge on the impact of TGR5 on hepatic physiology, its influences on metabolic regulation, and the knowledge gaps that need to be addressed to enable effective therapeutic targeting of the TGR5 signaling for the treatment of metabolic disease
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