title: Decoding the vasoregulatory activities of bile acid-activated receptors in systemic and portal circulation: role of gaseous mediators.
abstract: Bile acids are end products of cholesterol metabolism generated in the liver and released in the intestine. Primary and secondary bile acids are the result of the symbiotic relation between the host and intestinal microbiota. In addition to their role in nutrient absorption, bile acids are increasingly recognized as regulatory signals that 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 mediates 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 (LSECs) and responds to LCA by regulating the expression of both endothelial nitric oxide synthase (eNOS) and cystathionine-γ-lyase (CSE), an enzyme involved in generation of hydrogen sulfide (H2S). Activation of CSE by GPBAR1 ligands in LSECs is due to genomic and nongenomic effects, involves protein phosphorylation, and leads to release of H2S. Despite that species-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.
authors.affiliation: Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy; stefano.fiorucci@unipg.it.
authors.forename: Stefano
authors.identifier: http://orcid.org/0000-0003-3816-4222
authors.initials: S
authors.lastname: Fiorucci
authors.affiliation: Department of Pharmacy, University of Naples "Federico II," Naples, Italy; and.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.affiliation: Department of Pharmacy, University of Naples "Federico II," Naples, Italy; and.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.affiliation: Department of Pharmacy, University of Naples "Federico II," Naples, Italy; and.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.affiliation: Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
mesh_terms: D001011:Aorta; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D064426:Gasotransmitters / Q000378:metabolism*; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008095:Lithocholic Acid / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008102:Liver Circulation; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011168:Portal System; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D003542:Cystathionine gamma-Lyase; D064426:Gasotransmitters; D006862:Hydrogen Sulfide; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008095:Lithocholic Acid; D052250:Nitric Oxide Synthase Type III; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human
keywords: FXR; GPBAR1; TGR5; hydrogen sulfide; nitric oxide