Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse nonalcoholic steatohepatitis

doi:10.1038/aps.2016.158

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	Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse nonalcoholic steatohepatitis
	Liu, Ming-xia 1,2; Gao, Man 1,2; Li, Chun-zhu 1,2; Yu, Cun-zhi 1,2; Yan, Hong 1,2; Peng, Chun 1,2; Li, Yu 1,2; Li, Cheng-gang 1,2; Ma, Ze-long 1,2; Zhao, Yang 1,2
刊名	ACTA PHARMACOLOGICA SINICA
	2017-05
卷号	38 期号:5 页码:660-671
关键词	non-alcoholic steatohepatitis cholesterol accumulation Dicer1 HMGCR microRNA-29 MCD diet-treated mice
ISSN号	1671-4083
DOI	10.1038/aps.2016.158
文献子类	Article
英文摘要	Dicer1 is an enzyme essential for microRNA (miRNA) maturation. The loss of miRNAs resulted from Dicer1 deficiency greatly contributes to the progression of many diseases, including lipid dysregulation, but its role in hepatic accumulation of free cholesterol (FC) that is critical in the development of non-alcoholic steatohepatitis (NASH) remains elusive. In this study, we used the liver-specific Dicer1-knockout mice to identify the miRNAs involved in hepatic FC accumulation. In a widely used dietary NASH model, mice were fed a methionine-choline-deficient (MCD) diet for 3 weeks, which resulted in significant increase in hepatic FC levels as well as decrease of Dicer1 mRNA levels in livers. The liver-specific Dicer1-knockout induced hepatic FC accumulation at 5-6 weeks, accompanied by increased mRNA and protein levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting enzyme of cholesterol synthesis in livers. Eleven predicted miRNAs were screened, revealing that miR-29a/b/c significantly suppressed HMGCR expression by targeting the HMGCR mRNA 3'-UTR. Overexpression of miR-29a in SMMC-7721 cells, a steatosis hepatic cell model, significantly decreased HMGCR expression and the FC level. Furthermore, the expression levels of miR-29a were inversely correlated with HMGCR expression levels in the MCD diet mouse model in vivo and in 2 steatosis hepatic cell models (SMMC-7721 and HL-7702 cells) in vitro. Our results show that Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse NASH, and miR-29 may serve as an important regulator of hepatic cholesterol homeostasis. Thus, miR-29a could be utilized as a potential therapeutic target for the treatment of non-alcoholic fatty liver disease as well as for other liver diseases associated with FC accumulation.
资助项目	National Science and Technology Major Project[2015ZX09102005]
WOS关键词	FATTY LIVER-DISEASE ; HMG-COA REDUCTASE ; EMBRYONIC STEM-CELLS ; DISEASE/NONALCOHOLIC STEATOHEPATITIS ; MICRORNA EXPRESSION ; MATURE MICRORNAS ; GENE-EXPRESSION ; IN-VIVO ; MICE ; PATHOGENESIS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5980183
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000400566600006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272685]
专题	药物安全性评价中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Qi, Xin-ming; Ren, Jin
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Ctr Drug Safety Evaluat & Res, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Liu, Ming-xia,Gao, Man,Li, Chun-zhu,et al. Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse nonalcoholic steatohepatitis[J]. ACTA PHARMACOLOGICA SINICA,2017,38(5):660-671.
APA	Liu, Ming-xia.,Gao, Man.,Li, Chun-zhu.,Yu, Cun-zhi.,Yan, Hong.,...&Ren, Jin.(2017).Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse nonalcoholic steatohepatitis.ACTA PHARMACOLOGICA SINICA,38(5),660-671.
MLA	Liu, Ming-xia,et al."Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse nonalcoholic steatohepatitis".ACTA PHARMACOLOGICA SINICA 38.5(2017):660-671.