title: Modulation of FABP4 hypomethylation by DNMT1 and its inverse interaction with miR-148a/152 in the placenta of preeclamptic rats and HTR-8 cells.
abstract: Inflammation and dysregulated lipid metabolism are involved in the pathogenesis of preeclampsia, and fatty acid binding protein 4 (FABP4) is known to regulate both inflammation and lipid metabolism. In the present study, we elucidated the role of FABP4 using in vitro and in vivo models of preclampsia. We found increased expression of FABP4 in the placenta of preeclamptic rats, which was further confirmed in HTR-8 cells, an extravillous trophoblast cell line, treated with L-NAME. Overexpression of FABP4 in HTR-8 cells resulted in upregulated expression of pro-inflammatory cytokines IL-6 and TNF-α, and increased lipid accumulation, suggesting that FABP4 plays a role in preeclampsia. Furthermore, downregulation of methylation in the promotor resulted in increased FABP4 expression, which was mediated by downregulated DNA methyltransferase 1 (DNMT1). Bioinformatics analysis showed that miR-148a/152 regulated the expression of DNMT1, and additional in vitro studies revealed that miR-148a/152 inhibited DNMT1 expression by directly binding to its 3'-UTR. Interestingly, DNMT1 enhanced the expression of miR-148a/152 by downregulation of methylation in its promotor. Taken together, our results showed that FABP4 may be involved in the pathogenesis of preeclampsia, and the expression of FABP4 is enhanced by miR-148a/152 mediated inhibition of DNMT1 expression.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China; West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
authors.forename: Anning
authors.initials: A
authors.lastname: Yang
authors.affiliation: Prenatal Diagnosis Center of Ningxia Medical University General Hospital, Yinchuan, China; Ningxia Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Yinchuan, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China; State Key Laboratory of Biotherapy, Chengdu, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Prenatal Diagnosis Center of Ningxia Medical University General Hospital, Yinchuan, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China; Ningxia Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Yinchuan, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China; Ningxia Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Yinchuan, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
authors.forename: Guangrong
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China; Ningxia Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Yinchuan, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China; Ningxia Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Yinchuan, China.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China; Ningxia Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Yinchuan, China. Electronic address: nyxxgjyd@163.com.
authors.forename: Yideng
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005260:Female; D050356:Lipid Metabolism; D008745:Methylation; D035683:MicroRNAs / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000209:etiology* / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D016207:Cytokines; C524662:FABP4 protein, rat; D050556:Fatty Acid-Binding Proteins; C554180:MIRN146 microRNA, rat; C000623169:MIRN148a microRNA, rat; C578788:MIRN152 microRNA, rat; D035683:MicroRNAs; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619382:Dnmt1 protein, rat; D019331:NG-Nitroarginine Methyl Ester
keywords: DNA methylation; DNMT1; FABP4; Preeclampsia; miR-148a/152