title: Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse non-alcoholic steatohepatitis.
abstract: 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.
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Ming-Xia
authors.initials: MX
authors.lastname: Liu
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Man
authors.initials: M
authors.lastname: Gao
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Chun-Zhu
authors.initials: CZ
authors.lastname: Li
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Cun-Zhi
authors.initials: CZ
authors.lastname: Yu
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Peng
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Cheng-Gang
authors.initials: CG
authors.lastname: Li
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Ze-Long
authors.initials: ZL
authors.lastname: Ma
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Meng-Fan
authors.initials: MF
authors.lastname: Pu
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Miao
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Qi
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000172:deficiency* / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D055786:Gene Knockout Techniques; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D043244:Ribonuclease III / Q000172:deficiency* / Q000378:metabolism
chemical_list: C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D002784:Cholesterol; D008715:Methionine; D006903:Hydroxymethylglutaryl CoA Reductases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases