LncRNA MEG3 up-regulates SIRT6 by ubiquitinating EZH2 and alleviates nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a global health threat. Here, we presented the significant role of a novel signaling axis comprising long non-coding RNA maternally expressed gene 3 (MEG3), enhancer of zeste homolog 2 (EZH2), and sirtuin 6 (SIRT6) in controlling lipid accumulation, inflammation, and the progression of NAFLD. Mice fed with high-fat diet (HFD) were established as in vitro and in vivo NAFLD models, respectively. Lipid accumulation was measured by oil red O staining and assays for triglycerides or cholesterol. Inflammation was examined by ELISA for pro-inflammatory cytokines. Gene expressions were examined by RT-qPCR or Western blot. Interactions between key signaling molecules were examined by combining expressional analysis, RNA immunoprecipitation, cycloheximide stability assay, co-immunoprecipitation, and chromatin immunoprecipitation. MEG3 level was reduced in FFA-challenged hepatocytes or liver from HFD-fed mice, and the reduction paralleled the severity of NAFLD in clinic. Overexpressing MEG3 suppressed FFA-induced lipid accumulation or inflammation in hepatocytes. By promoting the ubiquitination and degradation of EZH2, MEG3 upregulated SIRT6, an EZH2 target. SIRT6 essentially mediated the protective effects of MEG3 in hepatocytes. Consistently, overexpressing MEG3 alleviated HFD-induced NAFLD in vivo. By controlling the expressions of genes involved in lipid metabolism and inflammation, the MEG3/EZH2/SIRT6 axis significantly suppressed lipid accumulation and inflammation in vitro, and NAFLD development in vivo. Therefore, boosting MEG3 level may benefit the treatment of NAFLD.

Noncoding RNAs as additional mediators of epigenetic regulation in nonalcoholic fatty liver disease

“…In line with this these studies, Huang et al [ 131 ] showed that the downregulation of MEG3 in in vitro and in vivo models of NAFLD is negatively correlated with lipogenesis-related genes, and that overexpression of MEG3 alleviates lipid overaccumulation in HepG2 cells. The downregulation of MEG3 in two models of NAFLD (free fatty acid-challenged primary hepatocytes and HFD-induced mouse) was also indicated in a more recent study by Zou et al [ 132 ].…”

LncRNA and circRNA in Patients with Non-Alcoholic Fatty Liver Disease: A Systematic Review

“…The authors of another study also observed that MEG3 was markedly increased in NASH cirrhosis specimens [ 39 ]. In contrast, Zou et al showed the opposite finding that MEG3 was downregulated in NAFLD and its reduction paralleled the severity of NAFLD [ 40 ]. A possible explanation for this inconsistency might be that the reactivation and induction of MEG3 in NAFLD and NASH patients is likely a compensatory mechanism.…”

The long noncoding RNA Meg3 mediates TLR4-induced inflammation in experimental obstructive nephropathy

“…Meg3 also promotes oxidative stress and inflammation in non-cancer cells [ 37–39 ]. However, there are other studies showing a protective role of Meg3 against inflammation [ 40 , 41 ]. Here, we showed that up-regulation of Meg3 in UUO kidneys is detrimental as KO of tubular Meg3 suppressed LPS-induced p38 MAPK activation and CCL-2 and CXCL-2 chemokine production.…”