title: Activation of Peroxisome Proliferator-activated Receptor γ (PPARγ) and CD36 Protein Expression: THE DUAL PATHOPHYSIOLOGICAL ROLES OF PROGESTERONE.
abstract: Progesterone or its analog, one of components of hormone replacement therapy, may attenuate the cardioprotective effects of estrogen. However, the underlying mechanisms have not been fully elucidated. Expression of CD36, a receptor for oxidized LDL (oxLDL) that enhances macrophage/foam cell formation, is activated by the transcription factor peroxisome proliferator-activated receptor γ (PPARγ). CD36 also functions as a fatty acid transporter to influence fatty acid metabolism and the pathophysiological status of several diseases. In this study, we determined that progesterone induced macrophage CD36 expression, which is related to progesterone receptor (PR) activity. Progesterone enhanced cellular oxLDL uptake in a CD36-dependent manner. Mechanistically, progesterone increased PPARγ expression and PPARγ promoter activity in a PR-dependent manner and the binding of PR with the progesterone response element in the PPARγ promoter. Specific deletion of macrophage PPARγ (MφPPARγ KO) expression in mice abolished progesterone-induced macrophage CD36 expression and cellular oxLDL accumulation. We also determined that, associated with gestation and increased serum progesterone levels, CD36 and PPARγ expression in mouse adipose tissue, skeletal muscle, and peritoneal macrophages were substantially activated. Taken together, our study demonstrates that progesterone can play dual pathophysiological roles by activating PPARγ expression, in which progesterone increases macrophage CD36 expression and oxLDL accumulation, a negative effect on atherosclerosis, and enhances the PPARγ-CD36 pathway in adipose tissue and skeletal muscle, a protective effect on pregnancy.
authors.affiliation: From the College of Life Sciences.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the College of Life Sciences.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: the College of Biomedical Engineering, Hefei University of Technology, Hefei 230000, China School of Medicine, and.
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the College of Life Sciences.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the College of Life Sciences.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: From the College of Life Sciences.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the College of Life Sciences.
authors.forename: Mengyang
authors.initials: M
authors.lastname: Liu
authors.affiliation: From the College of Life Sciences.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: From the College of Life Sciences.
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Li
authors.affiliation: the College of Biomedical Engineering, Hefei University of Technology, Hefei 230000, China College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin 300071, China and jihonghan2008@nankai.edu.cn hanjihong2015@hfut.edu.cn.
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
authors.affiliation: the College of Biomedical Engineering, Hefei University of Technology, Hefei 230000, China College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin 300071, China and yduan@hfut.edu.cn.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Duan
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology*; D020218:Response Elements; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D047495:PPAR gamma; C099252:oxidized low density lipoprotein; D011374:Progesterone
keywords: CD36; HRT; atherosclerosis; fatty acid; macrophage; peroxisome proliferator-activated receptor (PPAR); progesterone