Effect of miR-34a in regulating steatosis by targeting PPARα expression in nonalcoholic fatty liver disease.
MicroRNA-34a (miR-34a) is thought to be involved in nonalcoholic fatty liver disease (NAFLD). However, the association between altered expression of miR-34a and the pathophysiological features of NAFLD remains unclear. Here, we investigated the mechanisms by which miR-34a influences NAFLD through the PPARα-related pathway. Real-time quantitative PCR, western blotting and other assays kit were used to investigate the expression and function of miR-34a in an NAFLD model. Cultured cells transfected with miR-34a inhibitor and C57BL/6 mice injected with the miR-34a inhibitor through vein tail were conducted for the effects of miR-34a on its target. MiR-34a levels were significantly upregulated in steatosis-induced hepatocytes and in liver tissues of high-fat diet-fed mice. The upregulation of miR-34a resulted in the downregulation of hepatic PPARα and SIRT1 that are the direct targets of miR-34a. Silencing miR-34a led to an initially increased expression of PPARα, SIRT1 and PPARα's downstream genes. Activation of the central metabolic sensor AMPK was also increased. The miR-34a inhibitor suppressed lipid accumulation and improved the degree of steatosis. Taken together, our data indicated that decreased expression of miR-34a potentially contributes to altered lipid metabolism in NAFLD. Downregulation of miR-34a may be a therapeutic strategy against NAFLD by regulating its target PPARα and SIRT1.
Department of Infectious Diseases, Hangzhou First People's Hospital, No. 261 Huansha Road, Hangzhou 310006, Zhejiang Province, China.
Jiexia
J
Ding
Department of Gastroenterology, The First Affiliated Hospital, Medical School, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China.
Meng
M
Li
Department of Gastroenterology, The First Affiliated Hospital, Medical School, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China.
Xingyong
X
Wan
Department of Gastroenterology, The First Affiliated Hospital, Medical School, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China.
Xi
X
Jin
Department of Gastroenterology, The First Affiliated Hospital, Medical School, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China.
Shaohua
S
Chen
Department of Gastroenterology, The First Affiliated Hospital, Medical School, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China.
Chaohui
C
Yu
Department of Gastroenterology, The First Affiliated Hospital, Medical School, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China.
Youming
Y
Li
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001483:Base Sequence; D002460:Cell Line; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000235:genetics*; D047493:PPAR alpha / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D005227:Fatty Acids; C522425:MIRN34 microRNA, human; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D047493:PPAR alpha; D001219:Aspartate Aminotransferases; D000263:Adenylate Kinase; D056564:Sirtuin 1