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

Mingguo Xu,Huanhuan Wang,Yinzhen Zeng,Dongmei Zou,Dongling Dai,Liang Liu

doi:10.1038/s41420-022-00889-7

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.

Highlights

Chronic liver diseases from a range of causes other than alcohol consumption are collectively called nonalcoholic fatty liver disease (NAFLD)
Consistent with in vitro findings, we found that enhancer of zeste homolog 2 (EZH2) level was significantly upregulated while sirtuin 6 (SIRT6) downregulated in liver tissues from high-fat diet (HFD) and HFD + NC mice, but these changes were markedly dampened in liver tissues from HFD + maternally expressed gene 3 (MEG3) mice (Fig. 5K)
Dysregulated lipid metabolism leading to lipotoxicity significantly contributes to the development of NAFLD [24]

Summary

Introduction

Chronic liver diseases from a range of causes other than alcohol consumption are collectively called nonalcoholic fatty liver disease (NAFLD). To understand the pathogenic mechanisms underlying NAFLD, many in vitro and in vivo NAFLD models have been developed, such as challenging hepatocytes with free fatty acids (FFA), the key player for NAFLD, or feeding experimental animals with high-fat diet (HFD) [5]. These models have significantly contributed to the research on NAFLD, our understanding on NAFLD is still rudimentary and effective therapeutic targets remain to be identified

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