The role of RNA m6A methylation in lipid metabolism

Abstract

The m6A methylation is the most numerous modification of mRNA in mammals, coordinated by RNA m6A methyltransferases, RNA m6A demethylases, and RNA m6A binding proteins. They change the RNA m6A methylation level in their specific manner. RNA m6A modification has a significant impact on lipid metabolic regulation. The "writer" METTL3/METTL14 and the "eraser" FTO can promote the accumulation of lipids in various cells by affecting the decomposition and synthesis of lipids. The "reader" YTHDF recognizes m6A methylation sites of RNA and regulates the target genes' translation. Due to this function that regulates lipid metabolism, RNA m6A methylation plays a pivotal role in metabolic diseases and makes it a great potential target for therapy.

Keywords: FTO (fat mass and obesity-associated) gene; M6A; METTL3; lipid; obesity.

Figure 1

The main steps of lipogenesis and the regulation of FTO and METTL3/14. SREBP, sterol regulatory element-binding protein; FASN, fatty acid synthase; ACCY, acetyl-CoA carboxylase; SCD, stearoyl-CoA desaturase.

Figure 2

RNA m6A regulators influence lipid cellar accumulation in various ways. TG, triglyceride; ANGPTL4, angiopoietin-like protein 4; IRX3, iroquois homeobox protein 3; MAPK, mitogen-activated protein kinase; FFA, free fatty acid; IL-6, interleukin 6; Plin5, perilipin5; CPT1, carnitine palmitoyltransferase 1; LIPE, hormone-sensitive lipase; ATGL, adipose triglyceride lipase; PPAR, peroxisome proliferator-activated receptor; FASN, fatty acid synthase; LPL, lipoprotein lipase; SREBP1, sterol regulatory element-bindin protein-1; SCD, stearoyl-CoA desaturase; Traf6, TNF receptor associated factor 6; ACCY, acetyl-CoA carboxylase; NF-κb, nuclear factor kappa-B; AMPK, adenosine 5’-monophosphate-activated protein kinase.

Figure 3

RNA m6A regulators are involved in the regulation of lipid metabolic diseases in various ways. NAFLD, non-alcoholic fatty liver disease; CCL, C-C motif chemokine ligand 2; SREBP1c, sterol regulatory element-bindin protein-1; FASN, Fatty acid synthase; SCD1, stearoyl-CoA desaturase; ACCY1, acetyl-CoA carboxylase, CIDEC, cell death-inducing DFF45-like effector C; MAGAT, monoacylglycerol acyltransferases; LIPC, hepatic lipase; APOB, apolipoprotein; ZFAS1/RAB22a, zinc finger antisense 1/ras-related protein rab-22a; DDIT3, DNA damage-inducible transcript 4; T2DM, diabetes mellitus type 2; METTL, methyltransferase-like 3; YTHFD, YT521-B homology domain family; FTO, fat mass and obesity-associated protein; IGFBP, Insulin-like growth factor-binding proteins; MTTP, microsomal triglyceride transfer protein.