Zhou Bing, Liu Caizhi, Xu Lingyan, Yuan Youwen, Zhao Jiejie, Zhao Wenjun, Chen Yiyan, Qiu Jin, Meng Meiyao, Zheng Ying, Wang Dongmei, Gao Xin, Li Xiaoying, Zhao Qihong, Wei Xiaohui, Wu Duojiao, Zhang Huijie, Hu Cheng, Zhuo Xiaozhen, Zheng Minghua, Wang Hua, Lu Yan, Ma Xinran
The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China.
Hepatology. 2021 Jan;73(1):91-103. doi: 10.1002/hep.31220. Epub 2020 Oct 25.
Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N -methyladenosine (m A) RNA methylation is the most common internal modification in eukaryotic mRNA.
In the present study, by m A sequencing and RNA sequencing, we found that both m A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin-receptor-deficient db/db mice. Importantly, our results showed that YT521-B homology domain-containing 2 (Ythdc2), an m A reader, was markedly down-regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression.
Our findings describe an important role of the m A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD.
非酒精性脂肪性肝病（NAFLD）的特征是肝细胞内甘油三酯（TGs）过度积累。肥胖是脂肪肝发生的主要危险因素，但其细胞内分子机制仍在很大程度上不清楚。N-甲基腺苷（m⁶A）RNA甲基化是真核生物mRNA中最常见的内部修饰。
在本研究中，通过m⁶A测序和RNA测序，我们发现瘦素受体缺陷型db/db小鼠中，生脂基因的m⁶A富集和mRNA表达均显著增加。重要的是，我们的结果表明，一种m⁶A阅读蛋白——含YT521-B同源结构域2（Ythdc2），在肥胖小鼠和NAFLD患者的肝脏中明显下调。在瘦小鼠肝脏中抑制Ythdc2会导致TG积累，而在肥胖小鼠肝脏中异位过表达Ythdc2则改善了肝脏脂肪变性和胰岛素抵抗。机制上，我们发现Ythdc2可以结合生脂基因的mRNA，包括固醇调节元件结合蛋白1c、脂肪酸合酶、硬脂酰辅酶A去饱和酶1和乙酰辅酶A羧化酶1，以降低它们的mRNA稳定性并抑制基因表达。
我们的研究结果描述了m⁶A阅读蛋白Ythdc2在调节肝脏脂肪生成和TG稳态中的重要作用，这可能为治疗肥胖相关的NAFLD提供一个潜在靶点。
