miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR

Abstract

Non-alcoholic fatty liver disease (NAFLD) has emerged as a public health issue with a prevalence of 15-30% in Western populations and 6-25% in Asian populations. Certain studies have revealed the alteration of microRNA (miRNA or miR) profiles in NAFLD and it has been suggested that miR-21 is associated with NAFLD. In the present study, we measured the serum levels of miR-21 in patients with NAFLD and also performed in vitro experiments using a cellular model of NAFLD to further investigate the effects of miR-21 on triglyceride and cholesterol metabolism. Furthermore, a novel target through which miR-21 exerts its effects on NAFLD was identified. The results revealed that the serum levels of miR-21 were lower in patients with NAFLD compared with the healthy controls. In addition, 3-hydroxy-3-methylglutaryl-co-enzyme A reductase (HMGCR) expression was increased in the serum of patients with NAFLD both at the mRNA and protein level. To mimic the NAFLD condition in vitro, HepG2 cells were treated with palmitic acid (PA) and oleic acid (OA). Consistent with the results obtained in the in vivo experiments, the expression levels of miR-21 were decreased and those of HMGCR were increased in the in vitro model of NAFLD. Luciferase reporter assay revealed that HMGCR was a direct target of miR-21 and that miR-21 exerted an effect on both HMGCR transcript degradation and protein translation. Furthermore, the results from the in vitro experiments revealed that miR-21 decreased the levels of triglycerides (TG), free cholesterol (FC) and total cholesterol (TC) in the PA/OA-treated HepG2 cells and that this effect was attenuated by HMGCR overexpression. Taken together, to the best of our knowledge, the present study is the first to report that miR-21 regulates triglyceride and cholesterol metabolism in an in vitro model of NAFLD, and that this effect is achieved by the inhibition of HMGCR expression. We speculate that miR-21 may be a useful biomarker for the diagnosis and treatment of NAFLD.

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

“…Thus, one possible explanation for the increased HMGCR expression in Dicer1-KO mouse livers may be due to some miRNAs deficiency, which prevented the targeting of HMGCR. Recent studies have shown that some miRNAs can downregulate the expression of HMGCR directly or indirectly [24,26,[46][47][48] . For example, miR-21 can regulate cholesterol metabolism by targeting HMGCR directly in vitro [46] .…”

Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity

“…Alternatively, ChREBP might activate the expression of miR species that specifically target cholesterol metabolism. Several liver-rich miRs, including miR-21 (42,43), miR-33 (44), and miR34a (16), have been shown to suppress HMGCR expression. Our microarray data showed that several miR species were selectively downregulated in HFrD-fed Chrebp -/-mouse livers.…”

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

“…Specifically, up-regulation of miR-125b by estrogen protects against NAFLD in female mice [13]. MiR-21 decreases the levels of triglyceride and cholesterol by targeting HMGCR [14]. Thus, these studies have raised the enthusiasm to explore the roles of miRNAs in NAFLD.…”