METTL16-mediated translation of CIDEA promotes non-alcoholic fatty liver disease progression via m6A-dependent manner

PeerJ

article

Jinhong Tang¹  Xiangyun Zhao³  Wei Wei¹  Weiwei Liu¹  Huining Fan¹  Xiu ping Liu⁴  Yungai Li⁵  Long Wang¹  Jinghui Guo¹ 

[1] Department of Gastroenterology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine;Current Affiliation: Endoscopy Center, Minhang Hospital, Fudan University;Digestive Endoscopic Center, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine;Department of Gastroenterology, Shanghai Fudan University Affiliated Fifth People’s Hospital;Department of Clinical Laboratory, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

关键词: Non-alcoholic fatty liver disease;    N6-methyladenosine (m6A);    METTL16;    CIDEA;    m6A sequencing;   

DOI  :  10.7717/peerj.14379

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Background As the most prevalent chemical modifications on eukaryotic mRNAs, N6-methyladenosine (m6A) methylation was reported to participate in the regulation of various metabolic diseases. This study aimed to investigate the roles of m6A methylation and methyltransferase-like16 (METTL16) in non-alcoholic fatty liver disease (NAFLD). Methods In this study, we used a model of diet-induced NAFLD, maintaining six male C57BL/6J mice on high-fat diet (HFD) to generate hepatic steatosis. The high-throughput sequencing and RNA sequencing were performed to identify the m6A methylation patterns and differentially expressed mRNAs in HFD mice livers. Furthermore, we detected the expression levels of m6A modify enzymes by qRT-PCR in liver tissues, and further investigated the potential role of METTL16 in NAFLD through constructing overexpression and a knockdown model of METTL16 in HepG2 cells. Results In total, we confirmed 15,999 m6A recurrent peaks in HFD mice and 12,322 in the control. Genes with differentially methylated m6A peaks were significantly associated with the dysregulated glucolipid metabolism and aggravated hepatic inflammatory response. In addition, we identified five genes (CIDEA, THRSP, OSBPL3, GDF15 and LGALS1) that played important roles in NAFLD progression after analyzing the differentially expressed genes containing differentially methylated m6A peaks. Intriguingly, we found that the expression levels of METTL16 were substantially increased in the NAFLD model in vivo and in vitro, and further confirmed that METTL16 upregulated the expression level of lipogenic genes CIDEA in HepG2 cells. Conclusions These results indicate the critical roles of m6A methylation and METTL16 in HFD-induced mice and cell NAFLD models, which broaden people’s perspectives on potential m6A-related treatments and biomarkers for NAFLD.

【 授权许可】

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