title: Prostaglandin E2promotes hepatic bile acid synthesis by an E prostanoid receptor 3-mediated hepatocyte nuclear receptor 4α/cholesterol 7α-hydroxylase pathway in mice.
abstract: Prostaglandin E2(PGE2) is an important lipid mediator of inflammation. However, whether and how PGE2regulates hepatic cholesterol metabolism remains unknown. We found that expression of the PGE2receptor, 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 PGE2in 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).
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Yan
authors.affiliation: Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.affiliation: Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yuyao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Yuanyang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Shengkai
authors.initials: S
authors.lastname: Zuo
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yu
authors.affiliation: School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China.|Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Sheng-Zhong
authors.initials: SZ
authors.lastname: Duan
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D066273:Diet, Western; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000235:genetics; D011897:Random Allocation; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism*; D012680:Sensitivity and Specificity
chemical_list: D051557:Hepatocyte Nuclear Factor 4; D008077:Lipoproteins, LDL; C545648:Ptger3 protein, mouse; D058308:Receptors, Prostaglandin E, EP3 Subtype; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D015232:Dinoprostone