FTO reduces mitochondria and promotes hepatic fat accumulation through RNA demethylation

Abstract

Fat mass and obesity-associated protein (FTO) is a RNA demethylase, whether FTO regulates fat metabolism through its demethylation is unclear. The results of this study confirmed that N6-methyladenosine (m A) is associated with fat accumulation both in vivo and in vitro. The data showed that FTO down-regulated m A levels, decreased mitochondrial content, and increased triglyceride (TG) deposition. However, an FTO (R316A) mutant lacking demethylation activity could not regulate mitochondria and TG content, indicating that FTO affects mitochondrial content and fat metabolism by modulating m A levels in hepatocytes. In addition, the regulatory roles of cycloleucine (methylation inhibitor) and betaine (methyl donor) could regulate m A levels and fat deposition. This work clarified that the demethylation function of FTO plays an essential role in the fat metabolism of hepatocytes and links the epigenetic modification of RNA with fat deposition, thereby providing a new target (m A) for regulation of hepatic fat metabolism.

N6‐methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO‐PGC‐1α signalling axis

“…41 Recent studies have demonstrated that meclofenamic acid, a highly selective inhibitor of FTO, reduce ROS accumulation and apoptosis, 42 and that FTO regulates mitochondrial function. 35,36 We have been suggested that (Figure 4A,B).…”

“…However, the impact of FTO, especially as an RNA demethylase, in mitochondrial biogenesis, oxidative stress and ccRCC progression remain elusive. Importantly, recent reports suggest that FTO regulate mitochondria content through mediating mitochondrial fusion, fission and biogenesis‐associated genes expression as a N6‐methyladenosine RNA demethylase . To the point, we aim to explore the biological function of FTO in the post‐transcriptional modification of mitochondrial biogenesis and its subsequent influence in ccRCC and also explore the underlying molecular mechanism through identifying its key mRNA targets.…”

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

“…Suppressing adipogenesis by promoting cell cycle transition in mitotic clonal expansion [89] YTHDF2 Inhibiting autophagy and adipogenesis by decreasing protein expression of ATG5 and ATG7 and shortening the lifespan of their m 6 A-modified mRNAs [87] Suppressing adipogenesis by increasing m 6 A methylation of CCNA2 and CDK2 and reversing the methylation effect of FTO on CCNA2 and CDK2 [90,91] Inhibiting adipogenesis via the downregulation of CCND1 [92] NAFLD FTO Down-regulating mitochondrial content and up-regulating TG deposition [101] Promoting hepatic fat accumulation by increasing the expression of lipogenic genes, including FASN, SCD and MOGAT1, and intracellular TG level in HepG2 cells [101] Increasing oxidative stress and lipid deposition [99] YTHDF2 Increasing lipid accumulation by decreasing both PPARα mRNA lifetime and expression [105] METTL3 Increasing lipid accumulation by decreasing both PPARα mRNA lifetime and expression [105] Hypertension m 6 A-SNPs EncodIing β1-adrenoreceptor, a hypertension-susceptibility candidate gene [108,109] Altering BP-related gene expression, mRNA stability and homeostasis [110] Cardiovascular diseases FTO Decreasing fibrosis and enhancing angiogenesis in mouse models of myocardial infarction [111] METTL3 Driving cardiomyocyte hypertrophy by catalyzing methylation of m 6 A on certain subsets of mRNAs [112] Decreasing eccentric cardiomyocyte remodeling and dysfunction [112] Inhibiting cellular autophagic flux and promoting apoptosis in hypoxia/reoxygenation-treated cardiomyocytes [113] Osteoporosis METTL3 Inhibiting adipogenesis and adipogenic differentiation via JAK1/STAT5/C/EBPβ pathway in bone marrow stem cells [119] Inhibiting osteoporosis pathological phenotypes, consisting of decreased bone mass and increased marrow adiposity via PTH/PTH1R signaling axis [118] FTO Promoting the differentiation of adipocyte and osteoblast by upregulating GDF11-FTO-PPARγ signalling way [116] Enhancing the stability of mRNA of proteins which function to protect osteoblasts from genotoxic damage through Hspa1a-NF-κB signaling way [120] Immune-related MDs ALKBH5 Expressing highly in organs enriched in immune cells with frequent immune reactions [10,123] METTL3 Stimulating T cell activation and the development of T lymphocytes in the thymus by regulating the translation of CD40, CD80 and TLR4 signaling adaptor TIRAP transcripts in den...…”

Determination of five nucleosides by LC‐MS/MS and the application of the method to quantify N6‐methyladenosine level in liver messenger ribonucleic acid of an acetaminophen‐induced hepatotoxicity mouse model

“…RNA m 6 A methylation has been explored from many perspectives in the past few years. Researchers have suggested that m 6 A plays an important role in a variety of biological mechanisms and related diseases, including metabolism, circadian rhythm, immune response, gametogenesis, neurologic development, and cancer . Chen et al.…”

“…RNA m 6 A methylation has been explored from many perspectives in the past few years. Researchers have suggested that m 6 A plays an important role in a variety of biological mechanisms and related diseases, including metabolism, circadian rhythm, immune response, gametogenesis, neurologic development, and cancer [6][7][8][9][10][11][12][13]. Chen et al and Ma et al demonstrated that m 6 A modification is associated with the progression and metastasis of hepatocellular carcinoma [14,15].…”