MicroRNA-421 induces hepatic mitochondrial dysfunction in non-alcoholic fatty liver disease mice by inhibiting sirtuin 3.
Mitochondrial dysfunction plays a major role in critical initiating or propagating events in nonalcoholic fatty liver disease (NAFLD), but its pathogenesis remains obscure. Recently, microRNAs have been found to affect oxidant stress and lipid metabolism. In this study, we elucidated the functions of microRNA-421 in the development of NAFLD and identified its potential targets.



An experimental model for the study of NAFLD was constructed by feeding a high fat diet to C57BL/6J mice. Differentially expressed miRNA in livers of NAFLD mice compared with controls were identified by high-throughput sequencing. Relative repression of luciferase expression standardized to a transfection control was analyzed by luciferase reporter assays.



The microRNA profiling presented that microRNA-421 expression was significantly upregulated in hepatic tissues of NAFLD model mouse. The sirtuin 3 was identified as a functionally relevant target of microRNA-421. The microRNA-421 acts upstream of SIRT3/FOXO3 pathway in modulation the oxidant stress and lipid metabolism. Overexpression of microRNA-421 decreased SIRT3 and FOXO3 protein levels, and then led to MnSOD and CAT decrease, the downstream targets of SIRT3/FOXO3 pathway. On the contrary, suppression of microRNA-421 had adverse effects on performance of celluar oxidative damage.



Regulating or inhibiting hepatic microRNA-421 could decrease celluar oxidative damage and contribute to therapeutic potential in NAFLD.
Institute of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: drchengyang@163.com.
Yang
Y
Cheng
Department of Internal Medicine, Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 201299, China.
Jingyin
J
Mai
Institute of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Tianlu
T
Hou
Institute of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Jian
J
Ping
D000818:Animals; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology*; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; C000606652:MIRN421 microRNA, mouse; D035683:MicroRNAs; C525046:Sirt3 protein, mouse; D056566:Sirtuin 3
Celluar oxidative damage; SIRT3/FOXO3 pathway; Steatosis; microRNA