Prostaglandin E2 promotes hepatic bile acid synthesis by an e prostanoid receptor 3-mediated hepatocyte nuclear receptor 4α/cholesterol 7α-hydroxylase pathway in mice

Yan, S.; Tang, J.; Zhang, Y.; Wang, Y.; Zuo, S.; Shen, Y.; Zhang, Q.; Chen, D.; Yu, Y.; Wang, K.; Duan, S.-Z.; Yu, Y.

Hepatology 65(3): 999-1014


ISSN/ISBN: 1527-3350
PMID: 28039934
DOI: 10.1002/hep.28928
Accession: 060144777

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Prostaglandin E2 (PGE2 ) is an important lipid mediator of inflammation. However, whether and how PGE2 regulates hepatic cholesterol metabolism remains unknown. We found that expression of the PGE2 receptor, E prostanoid receptor 3 (EP3) expression is remarkably increased in hepatocytes in response to hyperlipidemic stress. Hepatocyte-specific deletion of EP3 receptor (EP3hep-/- ) results in hypercholesterolemia and augments diet-induced atherosclerosis in low-density lipoprotein receptor knockout (Ldlr-/- ) mice. Cholesterol 7α-hydroxylase (CYP7A1) is down-regulated in livers of EP3hep-/- Ldlr-/- mice, leading to suppressed hepatic bile acid (BA) biosynthesis. Mechanistically, hepatic-EP3 deficiency suppresses CYP7A1 expression by elevating protein kinase A (PKA)-dependent Ser143 phosphorylation of hepatocyte nuclear receptor 4α (HNF4α). Disruption of the PKA-HNF4α interaction and BA sequestration rescue impaired BA excretion and ameliorated atherosclerosis in EP3hep-/- Ldlr-/- mice. Our results demonstrated an unexpected role of proinflammatory mediator PGE2 in improving hepatic cholesterol metabolism through activation of the EP3-mediated PKA/HNF4α/CYP7A1 pathway, indicating that inhibition of this pathway may be a novel therapeutic strategy for dyslipidemia and atherosclerosis. (Hepatology 2017;65:999-1014).