Fat mass and obesity‐associated protein regulates lipogenesis via m6A modification in fatty acid synthase mRNA
Fat mass and obesity‐associated protein regulates lipogenesis via m6A modification in fatty acid synthase mRNA
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DOI：
10.1002/cbin.11490
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发表时间：
2020-10
影响因子：
3.9
通讯作者：
Donglei Sun;Tianhe Zhao;Qian Zhang;Mei Wu;Zunzhen Zhang
中科院分区：
文献类型：
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作者：
Donglei Sun;Tianhe Zhao;Qian Zhang;Mei Wu;Zunzhen Zhang
作为第一个被鉴定的N6-甲基腺苷（m6 A）脱甲基酶，脂肪质量和肥胖相关（FTO）蛋白与脂肪酸合成酶（FOS）和脂质积累相关。然而，很少有人知道FTO的调节作用，FTO的表达和从头脂肪通过m6 A修饰。在本研究中，我们使用FTO小干扰RNA来探讨FTO敲低对HepG 2细胞中肝脏脂肪生成的影响及其潜在的表观遗传机制。我们发现FTO的敲低增加了总RNA中的m6 A水平，并增强了作为m6 A结合蛋白的YTH结构域家族成员2的表达。在FTO敲低下，从头脂肪生成酶和细胞内脂质含量显著降低。从机制上讲，FTO的敲低显著提高了FIGH信使RNA（mRNA）中的m6 A水平，导致FIGH mRNA通过m6 A介导的mRNA衰减表达减少。进一步降低FXR沿着乙酰辅酶A羧化酶和ATP-柠檬酸裂解酶的蛋白表达，抑制了从头脂肪生成，从而导致HepG 2细胞中脂质积聚不足并诱导细胞凋亡。结果表明，FTO通过FTO依赖性m6 A去甲基化调节肝脏脂肪生成，并表明FTO介导的脂质代谢在HepG 2细胞存活中的关键作用。这项研究为FTO通过m6 A修饰介导肝脏脂质蓄积的独特RNA表观遗传机制提供了新的见解，并表明FTO可能是肥胖相关疾病和癌症的潜在靶点。
As the first identified N6‐methyladenosine (m6A) 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 m6A 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 m6A levels in total RNA and enhanced the expression of YTH domain family member 2 which serves as the m6A‐binding protein. The de novo lipogenic enzymes and intracellular lipid content were significantly decreased under FTO knockdown. Mechanistically, knockdown of FTO dramatically enhanced m6A levels in FASN messenger RNA (mRNA), leading to the reduced expression of FASN mRNA through m6A‐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 m6A 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 m6A modification and indicates that FTO could be a potential target for obesity‐related diseases and cancer.