Department of Environmental and Occupational Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China.
Cell Biol Int. 2021 Feb;45(2):334-344. doi: 10.1002/cbin.11490. Epub 2020 Nov 8.
As the first identified N -methyladenosine (m A) demethylase, fat mass and obesity-associated (FTO) protein is associated with fatty acid synthase (FASN) and lipid accumulation. However, little is known about the regulatory role of FTO in the expression of FASN and de novo lipogenesis through m A modification. In this study, we used FTO small interfering RNA to explore the effects of FTO knockdown on hepatic lipogenesis and its underlying epigenetic mechanism in HepG2 cells. We found that knockdown of FTO increased m A levels in total RNA and enhanced the expression of YTH domain family member 2 which serves as the m A-binding protein. The de novo lipogenic enzymes and intracellular lipid content were significantly decreased under FTO knockdown. Mechanistically, knockdown of FTO dramatically enhanced m A levels in FASN messenger RNA (mRNA), leading to the reduced expression of FASN mRNA through m A-mediated mRNA decay. The protein expressions of FASN along with acetyl CoA carboxylase and ATP-citrate lyase were further decreased, which inhibited de novo lipogenesis, thereby resulting in the deficiency of lipid accumulation in HepG2 cells and the induction of cellular apoptosis. The results reveal that FTO regulates hepatic lipogenesis via FTO-dependent m A demethylation in FASN mRNA and indicate the critical role of FTO-mediated lipid metabolism in the survival of HepG2 cells. This study provides novel insights into a unique RNA epigenetic mechanism by which FTO mediates hepatic lipid accumulation through m A modification and indicates that FTO could be a potential target for obesity-related diseases and cancer.
作为首个鉴定的 N-甲基腺苷（m A）去甲基酶，肥胖相关基因（FTO）蛋白与脂肪酸合酶（FASN）和脂质积累有关。然而，关于 FTO 通过 m A 修饰调节 FASN 表达和从头脂肪生成的调控作用知之甚少。在本研究中，我们使用 FTO 小干扰 RNA 来探讨 FTO 敲低对 HepG2 细胞中肝脂肪生成及其潜在表观遗传机制的影响。我们发现，FTO 敲低增加了总 RNA 中的 m A 水平，并增强了 YTH 结构域家族成员 2 的表达，后者作为 m A 结合蛋白。在 FTO 敲低时，新合成的脂肪生成酶和细胞内脂质含量显著降低。从机制上讲，FTO 显著增强了 FASN 信使 RNA（mRNA）中的 m A 水平，导致 FASN mRNA 的表达通过 m A 介导的 mRNA 降解而降低。FASN 及其乙酰辅酶 A 羧化酶和三磷酸柠檬酸裂解酶的蛋白表达进一步降低，抑制了从头脂肪生成，从而导致 HepG2 细胞中脂质积累不足和细胞凋亡诱导。结果表明，FTO 通过 FASN mRNA 中的 FTO 依赖性 m A 去甲基化来调节肝脂肪生成，并表明 FTO 介导的脂质代谢在 HepG2 细胞存活中的关键作用。本研究提供了新的见解，揭示了 FTO 通过 m A 修饰介导肝脂质积累的独特 RNA 表观遗传机制，并表明 FTO 可能成为肥胖相关疾病和癌症的潜在靶点。
