M⁶A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity.

ABSTRACT: 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.

SUBMITTER: Qin Y 

PROVIDER: S-EPMC8667589 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature