American journal of physiology. Heart and circulatory physiologyMay 3, 2015

An enzyme that produces hydrogen sulfide is controlled by a bile acid receptor and helps widen blood vessels in response to secondary bile acids

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Updated Mar 31, 2026

Abstract

GPBAR1 null mice exhibited increased levels of primary and secondary bile acids and impaired vasoconstriction to phenylephrine.

Vasodilation induced by lithocholic acid (LCA) is dependent on GPBAR1 and inhibited by specific blockers.
Chenodeoxycholic acid (CDCA) causes vasodilation that is independent of GPBAR1 but involves large-conductance calcium-activated potassium channels.
Activation of GPBAR1 in endothelial cells enhances the expression and activity of cystathionine-γ-lyase, leading to increased hydrogen sulfide production.
Two specific binding sites on the cystathionine-γ-lyase promoter are linked to activation by GPBAR1.
The GPBAR1/CSE pathway may be associated with endothelial dysfunction and hyperdynamic circulation in liver cirrhosis.

Simplified

GPBAR1 is a bile acid-activated receptor (BAR) for secondary bile acids, lithocholic (LCA) and deoxycholic acid (DCA), expressed in the enterohepatic tissues and in the vasculature by endothelial and smooth muscle cells. Despite that bile acids cause vasodilation, it is unclear why these effects involve GPBAR1, and the vascular phenotype of GPBAR1 deficient mice remains poorly defined. Previous studies have suggested a role for nitric oxide (NO) in regulatory activity exerted by GPBAR1 in liver endothelial cells. Hydrogen sulfide (H2S) is a vasodilatory agent generated in endothelial cells by cystathionine-γ-lyase (CSE). Here we demonstrate that GPBAR1 null mice had increased levels of primary and secondary bile acids and impaired vasoconstriction to phenylephrine. In aortic ring preparations, vasodilation caused by chenodeoxycholic acid (CDCA), a weak GPBAR1 ligand and farnesoid-x-receptor agonist (FXR), was iberiotoxin-dependent and GPBAR1-independent. In contrast, vasodilation caused by LCA was GPBAR1 dependent and abrogated by propargyl-glycine, a CSE inhibitor, and by 5β-cholanic acid, a GPBAR1 antagonist, but not by N(5)-(1-iminoethyl)-l-ornithine (l-NIO), an endothelial NO synthase inhibitor, or iberiotoxin, a large-conductance calcium-activated potassium (BKCa) channels antagonist. In venular and aortic endothelial (HUVEC and HAEC) cells GPBAR1 activation increases CSE expression/activity and H2S production. Two cAMP response element binding protein (CREB) sites (CREs) were identified in the CSE promoter. In addition, TLCA stimulates CSE phosphorylation on serine residues. In conclusion we demonstrate that GPBAR1 mediates the vasodilatory activity of LCA and regulates the expression/activity of CSE. Vasodilation caused by CDCA involves BKCa channels. The GPBAR1/CSE pathway might contribute to endothelial dysfunction and hyperdynamic circulation in liver cirrhosis.

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An enzyme that produces hydrogen sulfide is controlled by a bile acid receptor and helps widen blood vessels in response to secondary bile acids

Abstract

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