title: Aberrant miR199a-5p/caveolin1/PPARα axis in hepatic steatosis.
abstract: The prevalence of non-alcoholic fatty liver disease (NAFLD), a condition characterized by an excessive accumulation of triglycerides (TGs) in hepatocytes, has dramatically increased globally during recent decades. MicroRNAs (miRs) have been suggested to play crucial roles in many complex diseases and lipid metabolism. Our results indicated that miR199a-5p was remarkably upregulated in free fatty acid (FA)-treated hepatocytes. To investigate the role of miR199a-5p in the pathogenesis of fatty liver and the potential mechanism by which miR199a-5p regulates NAFLD, we first transfected two hepatocyte cell lines, HepG2 and AML12 cells, with agomiR199a-5p or antagomiR199a-5p. Our results indicated that miR199a-5p overexpression exacerbated deposition of FA and inhibited ATP levels and mitochondrial DNA (mtDNA) contents. Consistently, suppression of miR199a-5p partially alleviated deposition of FA and increased ATP levels and mtDNA contents. Moreover, miR199a-5p suppressed the expression of mitochondrial FA β-oxidation-related genes through inhibition of caveolin1 (CAV1) and the related peroxisome proliferator-activated receptor alpha (PPARα) pathway. Furthermore, suppression of CAV1 gene expression by CAV1 siRNA inhibited the PPARα signalling pathway. Finally, we examined the expression of miR199a-5p in liver samples derived from mice fed a high-fat diet, db/db mice, ob/ob mice and NAFLD patients, and found that miR199a-5p was upregulated while CAV1 and PPARA were downregulated in these systems, which was strongly indicative of the essential role of miR199a-5p in NAFLD. In summary, miR199a-5p plays a vital role in lipid metabolism, mitochondrial activity and mitochondrial β-oxidation in liver. Upregulated miR199a-5p in hepatocytes may contribute to impaired FA β-oxidation in mitochondria and aberrant lipid deposits, probably via CAV1 and the PPARα pathway.
authors.affiliation: Shanghai Institute of Endocrine and Metabolic DiseasesShanghai Clinical Center for Endocrine and Metabolic Diseases, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, ChinaDepartment of NeurosurgeryHuashan Hospital of Fudan University, Shanghai 200040, ChinaDepartment of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Shanghai Institute of Endocrine and Metabolic DiseasesShanghai Clinical Center for Endocrine and Metabolic Diseases, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, ChinaDepartment of NeurosurgeryHuashan Hospital of Fudan University, Shanghai 200040, ChinaDepartment of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Endocrine and Metabolic DiseasesShanghai Clinical Center for Endocrine and Metabolic Diseases, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, ChinaDepartment of NeurosurgeryHuashan Hospital of Fudan University, Shanghai 200040, ChinaDepartment of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Huizhi
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Endocrine and Metabolic DiseasesShanghai Clinical Center for Endocrine and Metabolic Diseases, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, ChinaDepartment of NeurosurgeryHuashan Hospital of Fudan University, Shanghai 200040, ChinaDepartment of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Quan
authors.affiliation: Shanghai Institute of Endocrine and Metabolic DiseasesShanghai Clinical Center for Endocrine and Metabolic Diseases, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, ChinaDepartment of NeurosurgeryHuashan Hospital of Fudan University, Shanghai 200040, ChinaDepartment of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Shanghai Institute of Endocrine and Metabolic DiseasesShanghai Clinical Center for Endocrine and Metabolic Diseases, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, ChinaDepartment of NeurosurgeryHuashan Hospital of Fudan University, Shanghai 200040, ChinaDepartment of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
authors.affiliation: Shanghai Institute of Endocrine and Metabolic DiseasesShanghai Clinical Center for Endocrine and Metabolic Diseases, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, ChinaDepartment of NeurosurgeryHuashan Hospital of Fudan University, Shanghai 200040, ChinaDepartment of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York 10461, USA guangning@medmail.com.cn.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051242:Caveolin 1; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; D047493:PPAR alpha
keywords: PPARα; caveolin1; fatty acid β-oxidation; miR199a-5p; non-alcoholic fatty liver disease