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Prostaglandin E 2 promotes hepatic bile acid synthesis by an E prostanoid receptor 3‐mediated hepatocyte nuclear receptor 4α/cholesterol 7α‐hydroxylase pathway in mice
Author(s) -
Yan Shuai,
Tang Juan,
Zhang Yuyao,
Wang Yuanyang,
Zuo Shengkai,
Shen Yujun,
Zhang Qianqian,
Chen Di,
Yu Yu,
Wang Kai,
Duan ShengZhong,
Yu Ying
Publication year - 2017
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28928
Subject(s) - cholesterol 7 alpha hydroxylase , medicine , endocrinology , liver x receptor , ldl receptor , g protein coupled bile acid receptor , nuclear receptor , hepatocyte , hepatocyte nuclear factor 4 , farnesoid x receptor , cholesterol , chemistry , bile acid , biology , lipoprotein , biochemistry , gene , transcription factor , in vitro
Prostaglandin E 2 (PGE 2 ) is an important lipid mediator of inflammation. However, whether and how PGE 2 regulates hepatic cholesterol metabolism remains unknown. We found that expression of the PGE 2 receptor, E prostanoid receptor 3 (EP3) expression is remarkably increased in hepatocytes in response to hyperlipidemic stress. Hepatocyte‐specific deletion of EP3 receptor ( EP3 hep–/– ) 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 EP3 hep–/– 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 EP3 hep–/– Ldlr −/− mice. Conclusion : Our results demonstrated an unexpected role of proinflammatory mediator PGE 2 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. (H epatology 2017;65:999‐1014)