MiR-30c-5p ameliorates hepatic steatosis in leptin receptor-deficient (db/db) mice via down-regulating FASN.

Jiahui Fan,Yanru Zhao,Zhongwei Yin,Huaping Li,Xiang Nie,Chen Chen,Dao Wen Wang

doi:10.18632/oncotarget.14561

Abstract

Approximately 15–40% of the general adult population suffers from non-alcoholic fatty liver disease (NAFLD) worldwide. However, no drug is currently licensed for its treatment. In this study, we observed a significant reduction of miR-30c-5p in the liver of leptin receptor-deficient (db/db) mice. Remarkably, recombinant adeno-associated virus (rAAV)-mediated delivery of miR-30c-5p was sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice. Through computational prediction, KEGG analysis and Ago2 co-immunoprecipitation, we identified that miR-30c-5p directly targeted fatty acid synthase, a key enzyme in fatty acid biosynthesis. Moreover, down-regulation of FASN by siRNA attenuated some key features of NAFLD, including decreased triglyceride accumulate and lipid deposition. Our findings reveal a new role of miR-30c-5p in counterbalancing fatty acid biosynthesis, which is sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice.

Highlights

With the obesity pandemic, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease affecting 15–40% of the general adult population and an important cause of cirrhosis and hepatic carcinoma worldwide [1,2,3]
Our findings reveal a new role of miR-30c-5p in counterbalancing fatty acid biosynthesis, which is sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice
We found that miR-30c-5p was able to suppress FASN, the crucial enzyme in fatty acid biosynthesis and delivery of exogenous miR-30c-5p by recombinant adenoassociated virus (rAAV) was sufficient to attenuate triglyceride accumulation and liver steatosis in the db/db mice, suggesting a new therapeutic strategy against NAFLD

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease affecting 15–40% of the general adult population and an important cause of cirrhosis and hepatic carcinoma worldwide [1,2,3]. MiRNAs suppress gene expression through two major mechanisms: translational repression or mRNA cleavage/. Degradation, depending on the ability to bind their mRNA targets [8]. Due to their extraordinary variability of expression patterns and functions across tissues and physiological/pathophysiological states, miRNAs can be powerful diagnostic and therapeutic tools in various disorders, such as cancer, neurological diseases, cardiovascular diseases and metabolism disorders including NAFLD [9,10,11,12]. MiR-21 decreases the levels of triglyceride and cholesterol by targeting HMGCR [14]. These studies have raised the enthusiasm to explore the roles of miRNAs in NAFLD

Methods

Results

Conclusion