Figure 3.
Role of m6A modifications in lipid metabolism. The liver expression of m6A RWE is perturbed by physiological and disease processes, resulting in changes in m6A levels and subsequently, transcript processing and protein translation regulated in part by m6A readers. Experimental hepatocyte-specific knockout of Mettl3 in mice increased fibrosis and steatosis and downregulated the indicated transcripts [192]. In T2DM patients, glucose increases FTO expression [188]. Overexpression of FTO in HepG2 cells altered the expression of the indicated transcripts which resulted in increased lipid accumulation [190]. Circadian gene disruption in mice increased Mettl3 and Ythdf2 expression which mediated Ppara mRNA decay [184]. CCl4-induced liver fibrosis in HSCs increased ZC2H13 and decreased FTO increasing m6A levels. YTHDC1 bound to m6A on the NR1D1 transcript, decreasing NR1D1 expression which resulted in disrupted fatty acid regulation, lipid accumulation and liver inflammation [49]. Abbreviations: Enoyl-CoA Hydratase And 3-Hydroxyacyl CoA Dehydrogenase (EHHADH), PPARG Coactivator 1 α (PPARGC1A), Sirtuin 1 (SIRT1), Fatty Acid Synthase (FASN), α-1,3-Mannosyl-Glycoprotein 2-β-N-Acetylglucosaminyltransferase (MGAT1), Stearoyl-CoA Desaturase (SCD1), Microsomal Triglyceride Transfer Protein (MTTP), Apolipoprotein B (APOB), Lipase C, Hepatic Type (LIPC), Peroxisome Proliferator Activated Receptor α (PPARα), Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1). Further details from these studies are provided in the text.