dicer1mir29hmgcr axis contributes to hepatic free cholesterol accumulation in mouse nonalcoholic steatohepatitis 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 nonalcoholic steatohepatitis nash remains elusive in this study we used the liverspecific dicer1knockout mice to identify the mirnas involved in hepatic fc accumulation in a widely used dietary nash model mice were fed a methioninecholinedeficient 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 liverspecific dicer1knockout induced hepatic fc accumulation at 56 weeks accompanied by increased mrna and protein levels of 3hydroxy3methylglutaryl coenzyme a reductase hmgcr a ratelimiting enzyme of cholesterol synthesis in livers eleven predicted mirnas were screened revealing that mir29abc significantly suppressed hmgcr expression by targeting the hmgcr mrna 3utr overexpression of mir29a in smmc7721 cells a steatosis hepatic cell model significantly decreased hmgcr expression and the fc level furthermore the expression levels of mir29a were inversely correlated with hmgcr expression levels in the mcd diet mouse model in vivo and in 2 steatosis hepatic cell models smmc7721 and hl7702 cells in vitro our results show that dicer1mir29hmgcr axis contributes to hepatic free cholesterol accumulation in mouse nash and mir29 may serve as an important regulator of hepatic cholesterol homeostasis thus mir29a could be utilized as a potential therapeutic target for the treatment of nonalcoholic fatty liver disease as well as for other liver diseases associated with fc accumulation