TGR5

TGR5, also known as GPBAR1, is a G protein-coupled receptor that binds bile acids. It is activated by endogenous bile acids and is expressed in a variety of tissues, including the intestinal tract, liver ducts, brown adipose tissue, and immune cells. As a GPCR, TGR5 transduces signals through Gs proteins to increase intracellular cyclic AMP (cAMP) levels.

Upon activation, TGR5 stimulates cAMP-dependent pathways. In brown adipose tissue, this signaling can induce the enzyme type 2 iodothyronine deiodinase (DIO2), enhancing local production of thyroid hormone and promoting thermogenesis and energy expenditure. In enteroendocrine L cells of the intestine, TGR5 activation promotes the release of glucagon-like peptide-1 (GLP-1), which can improve glucose homeostasis and insulin secretion. In immune cells such as macrophages, TGR5 signaling generally exerts anti-inflammatory effects by reducing pro-inflammatory cytokine production. Additional physiological effects include regulation of biliary dynamics, such as modulation of bile flow and gallbladder smooth muscle relaxation.

Endogenous bile acids, notably lithocholic acid and chenodeoxycholic acid, act as TGR5 agonists. Synthetic and selective TGR5 agonists have been developed for research and potential therapeutic purposes, particularly for metabolic diseases such as obesity and type 2 diabetes. However, targeting TGR5 can be associated with side effects observed in some studies, including pruritus and effects on gallbladder function, underscoring the need for careful evaluation in clinical contexts.