TGR5 Signaling in Hepatic Metabolic Health

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.