Bile acids are end product of cholesterol metabolism generated in the liver and released in the intestine. In addition to their role in nutrient absorption, bile acids are increasingly recognized as regulatory signals which exert their function beyond the intestine by activating a network of membrane and nuclear receptors. The best characterized of these bile acid activated receptors, GPBAR1 (also known as TGR5) and the Farnesosid-x-receptor (FXR) have also been detected in the vascular system and their activation mediate the vasodilatory effects of bile acids in the systemic and splanchnic circulation. GPBAR1, is a G protein coupled receptor, that is preferentially activated by lithocholic acid (LCA) a secondary bile acid. GPBAR1 is expressed in endothelial cells and liver sinusoidal cells (LSEC), and respond to LCA by regulating the expression of both endothelial nitric oxide synthase (eNOS) and cystathionine-γ-liase (CSE), an enzyme involved in generation of hydrogen sulfide (H2S). Activation of CSE by GPBAR1 ligands in LSEC is due to genomic and non-genomic effects, involves protein phosphorylation, and leads to release of H2S. Despite specie-specific effects have been described, vasodilation caused by GPBAR1 ligands in the liver microcirculation and aortic rings is abrogated by inhibition of CSE but not by eNOS inhibitor. Vasodilation caused by GPBAR1 (and FXR) ligands also involves large conductance calcium activated potassium channels likely acting downstream to H2S. The identification of GPBAR1 as a vasodilatory receptor is of relevance in the treatment of complex disorders including metabolic syndrome-associated diseases, liver steatohepatitis and portal hypertension.
- Nitric oxide
- Hydrogen sulfide
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology