胆固醇7α羟化酶
内科学
内分泌学
低密度脂蛋白受体
肝X受体
G蛋白偶联胆汁酸受体
核受体
肝细胞
肝细胞核因子4
化学
法尼甾体X受体
胆固醇
生物
胆汁酸
脂蛋白
医学
生物化学
转录因子
基因
体外
作者
Shuai Yan,Juan Tang,Yuyao Zhang,Yuanyang Wang,Shengkai Zuo,Yujun Shen,Qianqian Zhang,Di Chen,Yu Yu,Kai Wang,Sheng‐Zhong Duan,Ying Yu
出处
期刊:Hepatology
[Wiley]
日期:2016-12-31
卷期号:65 (3): 999-1014
被引量:14
摘要
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).
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