Journal Article

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

Ming-xia LIU Man GAO Chun-zhu LI Cun-zhi YU Hong YAN Chun PENG Yu LI Cheng-gang LI Ze-long MA Yang ZHAO Meng-fan PU Ling-ling MIAO Xin-ming QI Jin RENI

2017

Overview

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 Dicerl-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 Dicerl-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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Cholesterol - metabolism / DEAD-box RNA Helicases - deficiency / DEAD-box RNA Helicases - metabolism / Diet - adverse effects / Gene Knockout Techniques / Hydroxymethylglutaryl CoA Reductases - metabolism / Immunology / Internal Medicine / Male / Medical Microbiology / Methionine - deficiency / Mice / MicroRNAs - metabolism / Non-alcoholic Fatty Liver Disease - metabolism / Non-alcoholic Fatty Liver Disease - pathology / Original / original-article / Pharmacology/Toxicology / Ribonuclease III - deficiency / Ribonuclease III - metabolism / RNA, Messenger - metabolism / Vaccine