基因敲除
下调和上调
生物
细胞生物学
PI3K/AKT/mTOR通路
信使核糖核酸
重编程
癌症研究
信号转导
细胞
基因
遗传学
作者
Yanqin Qin,Binghua Li,Suyavaran Arumugam,Qiuxia Lu,Salah M. Mankash,Junzi Li,Beicheng Sun,Jiansheng Li,Richard A. Flavell,Huabing Li,Xinshou Ouyang
出处
期刊:Cell Reports
[Elsevier]
日期:2021-11-01
卷期号:37 (6): 109968-109968
被引量:54
标识
DOI:10.1016/j.celrep.2021.109968
摘要
N6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism, but its role in innate immunity-driven non-alcoholic fatty liver disease (NAFLD) and obesity is not known. Here, we show that myeloid lineage-restricted deletion of the m6A "writer" protein Methyltransferase Like 3 (METTL3) prevents age-related and diet-induced development of NAFLD and obesity in mice with improved inflammatory and metabolic phenotypes. Mechanistically, loss of METTL3 results in the differential expression of multiple mRNA transcripts marked with m6A, with a notable increase of DNA Damage Inducible Transcript 4 (DDIT4) mRNA level. In METTL3-deficient macrophages, there is a significant downregulation of mammalian target of rapamycin (mTOR) and nuclear factor κB (NF-κB) pathway activity in response to cellular stress and cytokine stimulation, which can be restored by knockdown of DDIT4. Taken together, our findings identify the contribution of METTL3-mediated m6A modification of Ddit4 mRNA to macrophage metabolic reprogramming in NAFLD and obesity.
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