METTL3 inhibits hepatic insulin sensitivity via N6-methyladenosine modification of Fasn mRNA and promoting fatty acid metabolism

RNA N6-methyladenosine: a promising molecular target in metabolic diseases

“…T2D FTO Promoting the mRNA expression of FOXO1, G6PC, and DGAT2, which are associated with glucose and lipid metabolism [32] METTL3 Inhibiting hepatic insulin sensitivity via N6-methylation of FASN mRNA and promoting fatty acid metabolism [69] Upregulating insulin/IGF1-AKT-PDX1 pathway in human β-cells [71] METTL14 Decreasing cell death and the changes of cell differentiation of β-cells, increasing β-cell mass and insulin secretion [70] Upregulating insulin/IGF1-AKT-PDX1 pathway in human β-cells [71] Obesity FTO Promoting adipogenesis by inhibiting the Wnt/β-catenin signaling pathway [86] Promoting autophagy and adipogenesis via increasing the expression of ATG5 and ATG7 [87] Promoting adipocyte proliferation via enhancing the expression of the pro-adipogenic short isoform of RUNX1 [77] WTAP Suppressing adipogenesis by promoting cell cycle transition in mitotic clonal expansion [89]…”

“…Intriguingly, the levels of m 6 A methyltransferases (METTL3, METTL14, WTAP) mRNA expression are also significantly elevated in patients with T2D, but the expression of METTL3, METTL14, and KIAA1429 are negatively correlated with m 6 A content [32]. In addition, METTL3 inhibits hepatic insulin sensitivity via N6-methylation of FASN (fatty acid synthetase) mRNA and promoting fatty acid metabolism, which eventually results in the development of T2D [69]. In addition, METTL14 is essential for β-survival, differentiation and insulin secretion, the deficiency of METTL14 in β-cells increases cell death, changes cell differentiation and decreases β-cell mass and insulin secretion, leading to glucose intolerance and T2D [70].…”

Mechanisms of RNA N6-Methyladenosine in Hepatocellular Carcinoma: From the Perspectives of Etiology

“…NAFLD is strongly correlated with metabolic syndromes such as diabetes and obesity, and these risk factors interact to increase the risk for HCC occurrence in NAFLD patients. The pathogenesis of HCC in NAFLD patients is a complex process involving multiple mechanisms including lipogenesis, fat accumulation, insulin resistance, oxidative, and endoplasmic reticulum (ER) stress, inflammatory response and DNA damage (83)(84)(85)(86) (Figure 2). Recent studies have indicated that m 6 A modification actively participates in these processes.…”

“…Another major mechanism of NAFLD progression is insulin resistance (Figure 3D) (86). Intracellular METTL3 and m 6 A methylation in type 2 diabetes patients are positively related with insulin resistance (HOMA-β) and negatively related with β-cell function (84). METTL3 knockout in the liver of mice inhibits m 6 A modification and decreases the intracellular level of fatty acid synthase (Fasn).…”

Advances in the role of m6A RNA modification in cancer metabolic reprogramming

“…Mechanically, HK2, and GLUT1 were found to be regulated by m 6 A modification and participate in glycolysis activation in colorectal cancer [17] PKM2 FTO triggered the m 6 A demethylation of PKM2 mRNA and accelerated the translated production, thus promoting hepatocellular carcinoma tumorigenesis [96] PIK3CB A missense variant rs142933486 in PIK3CB reduced the PIK3CB m 6 A level and facilitated its mRNA and protein expression levels mediated by the m 6 A "writers" complex (METTL3/METTL14/WTAP) and YTHDF2 [97] EGFR, MEK/ERK signaling YTHDF2 negatively modulated the EGFR mRNA stability in HCC via its binding the m 6 A site in the EGFR 3′-UTR, which in turn impaired the MEK/ERK pathway and consequently impedes the cell proliferation and growth [102] NF-κB signaling METTL3 positively regulated MYD88 expression through controlling m 6 A methylation status of MYD88-RNA, leading to the activation of NF-κB signaling [103] NF-κB signaling METTL3 activated NF-κB signaling by promoting the expression of IKBKB and RELA through regulating translational efficiency [94] AKT signaling m 6 A methylation normally attenuates AKT activity in the endometrium by promoting the m 6 Adependent translation of PHLPP2 and m 6 A-dependent degradation of transcripts encoding subunits of mTORC2, increasing proliferation and tumorigenicity in endometrial cancer [14] AKT signaling The association between m 6 A and AKT signaling was also confirmed in multiple tumor types including leukemia cells and clear cell renal cell carcinoma [101,117] Lipid metabolism ACC1, ACLY, DGAT2, EHHADH, FASN, FOXO, PGC1A, and SIRT1 ACC1, ACLY, DGAT2, EHHADH, FASN, FOXO, PGC1A, and SIRT1 were dramatically decreased in livers of hepatocyte-specific METTL3 knockout mice. CD36 and LDLR were also downregulated by improving the expression of FASN through its m 6 A demethylase activity [106] SREBP1c, CIDEC FTO increased lipid accumulation by a novel FTO/SREBP1c/CIDEC signaling pathway in an m 6 A-dependent manner in HepG2 cells [108] SREBP1c, FASN, SCD1, ACC1 YTHDF2 could also bind to the mRNA of SREBP1c, FASN, SCD1, and ACC1, to decrease their mRNA stability and inhibit gene expression [109] AMPK m 6 A modification resulted in reduced AMPK activity [110] FAM225A m 6 A was highly enriched within FAM225A and enhanced its RNA stability [111] Glutamine metabolism α-KG FTO and ALKBH5 are α-KG-dependent dioxygenases and competitively inhibited ...…”