PMID- 34758326 OWN - NLM STAT- MEDLINE DCOM- 20220217 LR - 20220506 IS - 2211-1247 (Electronic) VI - 37 IP - 6 DP - 2021 Nov 9 TI - m(6)A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity. PG - 109968 LID - S2211-1247(21)01447-9 [pii] LID - 10.1016/j.celrep.2021.109968 [doi] AB - N(6)-methyladenosine (m(6)A) 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 m(6)A "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 m(6)A, 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 kappaB (NF-kappaB) 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 m(6)A modification of Ddit4 mRNA to macrophage metabolic reprogramming in NAFLD and obesity. CI - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Qin, Yanqin AU - Qin Y AD - Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA; Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China. FAU - Li, Binghua AU - Li B AD - Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China. FAU - Arumugam, Suyavaran AU - Arumugam S AD - Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA. FAU - Lu, Qiuxia AU - Lu Q AD - Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA. FAU - Mankash, Salah M AU - Mankash SM AD - Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA. FAU - Li, Junzi AU - Li J AD - Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA; Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China. FAU - Sun, Beicheng AU - Sun B AD - Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China. FAU - Li, Jiansheng AU - Li J AD - Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China. FAU - Flavell, Richard A AU - Flavell RA AD - Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: richard.flavell@yale.edu. FAU - Li, Hua-Bing AU - Li HB AD - Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: huabing.li@shsmu.edu.cn. FAU - Ouyang, Xinshou AU - Ouyang X AD - Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: xinshou.ouyang@yale.edu. LA - eng GR - P30 DK034989/DK/NIDDK NIH HHS/United States GR - R01 CA224023/CA/NCI NIH HHS/United States GR - U01 AA026962/AA/NIAAA NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (NF-kappa B) RN - 0 (RNA, Messenger) RN - CLE6G00625 (N-methyladenosine) RN - EC 2.1.1.- (Methyltransferases) RN - EC 2.1.1.- (Mettl3 protein, mouse) RN - K72T3FS567 (Adenosine) SB - IM CIN - Nat Rev Endocrinol. 2022 Feb;18(2):69. PMID: 34848874 MH - Adenosine/*analogs & derivatives/chemistry MH - Animals MH - DNA Methylation MH - Female MH - Immunity, Innate MH - Macrophages/*immunology MH - Male MH - Methyltransferases/*physiology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Myeloid Cells/*immunology MH - NF-kappa B/genetics/metabolism MH - Non-alcoholic Fatty Liver Disease/etiology/metabolism/*pathology MH - Obesity/etiology/metabolism/*pathology MH - RNA, Messenger/*chemistry/genetics PMC - PMC8667589 MID - NIHMS1759113 OTO - NOTNLM OT - DDIT4 OT - NAFLD OT - liver inflammation OT - mRNA m(6)A methylation OT - myeloid cells OT - non-alcoholic fatty liver disease COIS- Declaration of interests The authors declare no competing interests. EDAT- 2021/11/11 06:00 MHDA- 2022/02/19 06:00 PMCR- 2021/12/13 CRDT- 2021/11/10 20:06 PHST- 2021/01/14 00:00 [received] PHST- 2021/08/02 00:00 [revised] PHST- 2021/10/19 00:00 [accepted] PHST- 2021/11/10 20:06 [entrez] PHST- 2021/11/11 06:00 [pubmed] PHST- 2022/02/19 06:00 [medline] PHST- 2021/12/13 00:00 [pmc-release] AID - S2211-1247(21)01447-9 [pii] AID - 10.1016/j.celrep.2021.109968 [doi] PST - ppublish SO - Cell Rep. 2021 Nov 9;37(6):109968. doi: 10.1016/j.celrep.2021.109968.