Roles of the microRNAs in fatty liver lipid accumulation

Abstract

Nonalcoholic fatty liver disease (NAFLD) includes common liver disorder ranging from hepatic steatosis to steatohepatitis, all of which are the result of accumulation of hepatic fat. MicroRNAs (miRNAs) are endogenous non-coding RNAs involved in the process of silencing gene expression. In this study, we sought to understand the role of miRNAs in hepatic lipid metabolism and liver steatosis.

An in vitro model that mimics the benign steatosis was established by inducing lipid accumulation in two human hepatoma cell lines, HepG2 and HuH7. With regards to the in vivo model, C57BL mice were given fatty chow for 16 weeks while control animals were given normal rodent chow. The changes of selected miRNA expressions in fatty mice liver and fatty acid (FA)- treated cells compared to their respective controls were determined by reverse transcription-real-time PCR. Targets of the differentially expressed miRNAs were examined with western blots.

miR-21, miR-34a, miR-132, miR-221/222 and miR-203 were among the up-regulated miRNAs in the livers of fatty mice and FA-treated cells, and there were corresponding down-regulations of their targets PPARalpha, SIRT1 and IRS-2. miR-130a, miR-27a and miR-27b were down-regulated, with a corresponding up-regulation of the target PPARgamma. Furthermore, over- expression of miR-203 resulted in the reduction of IRS-2 protein levels in HepG2 and HuH7 cells. Protein expression of SIRT1 was up- or down- regulated mainly by knockdown or over-expression of miR-34a.

Taken together, these results suggest that the accumulation of fats in the liver over time caused the differential expression of miRNAs that contributed to the regulation of the expression of key metabolic regulators IRS-2, SIRT1, PPARalpha and PPARgamma and these in turn further affect lipid metabolism and promote lipid accumulation.