Aberrant elevation of FTO levels promotes liver steatosis by decreasing the m6A methylation and increasing the stability of SREBF1 and ChREBP mRNAs.
Aberrant elevation of FTO levels promotes liver steatosis by decreasing the m6A methylation and increasing the stability of SREBF1 and ChREBP mRNAs.
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DOI：
10.1093/jmcb/mjac061
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发表时间：
2023-02-07
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
先前的研究表明，脂肪量和肥胖相关（FTO）与非酒精性脂肪性肝病（NAFLD）有关，NAFLD是世界上最常见的慢性肝病。本研究旨在揭示FTO在肝脏脂质代谢中的复杂作用。我们发现，喂食高脂肪饮食（HFD）的小鼠肝脏中n6 -甲基腺苷（m6A） RNA甲基化的降低伴随着FTO表达的增加。肝脏中FTO的过度表达通过上调脂肪生成基因的表达来促进甘油三酯的积累。机制研究表明，FTO可以通过m6A位点的去甲基化来稳定甾醇调节元件结合转录因子1 （SREBF1）和碳水化合物反应元件结合蛋白（ChREBP）这两个主要的脂肪生成转录因子的mrna。敲低SREBF1或ChREBP均可减弱FTO的致脂作用，表明它们是FTO调节脂肪生成的真正效应因子。胰岛素可以通过核内胰岛素受体β的作用来刺激FTO的转录，而FTO的下调则消除了胰岛素的增脂作用。恩他卡朋抑制FTO可降低SREBF1、ChREBP和下游脂肪生成基因的表达，改善hfd喂养小鼠的肝脏脂肪变性。因此，我们的研究确定了FTO在胰岛素调节的肝脏脂肪生成和NAFLD发病机制中的关键作用，并为治疗NAFLD提供了潜在的策略。
Previous studies have indicated an association of fat mass and obesity-associated (FTO) with nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide. This study aimed to decipher the complex role of FTO in hepatic lipid metabolism. We found that a decrease in N6-methyladenosine (m6A) RNA methylation in the liver of mice fed with a high-fat diet (HFD) was accompanied by an increase in FTO expression. Overexpression of FTO in the liver promoted triglyceride accumulation by upregulating the expression of lipogenic genes. Mechanistical studies revealed that FTO could stabilize the mRNAs of sterol regulatory element binding transcription factor 1 (SREBF1) and carbohydrate responsive element binding protein (ChREBP), two master lipogenic transcription factors, by demethylating m6A sites. Knockdown of either SREBF1 or ChREBP attenuated the lipogenic effect of FTO, suggesting that they are bona fide effectors for FTO in regulating lipogenesis. Insulin could stimulate FTO transcription through a mechanism involving the action of intranuclear insulin receptor beta, while knockdown of FTO abrogated the lipogenic effect of insulin. Inhibition of FTO by entacapone decreased the expression of SREBF1, ChREBP, and downstream lipogenic genes, ameliorating liver steatosis in HFD-fed mice. Thus, our study established a critical role of FTO in both the insulin-regulated hepatic lipogenesis and the pathogenesis of NAFLD and provided a potential strategy for treating NAFLD.
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影响因子：
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