<br>DNA 甲基化对肝脏脂质代谢的表观遗传调控,Advanced Science

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DNA 甲基化对肝脏脂质代谢的表观遗传调控
Advanced Science ( IF 14.3 ) Pub Date : 2023-06-06 , DOI: 10.1002/advs.202206068
Shirong Wang ₁ , Lin Zha _{1,

2} , Xin Cui ₁ , Yu-Te Yeh ₃ , Ruochuan Liu ₄ , Jia Jing ₁ , Huidong Shi ₅ , Weiping Chen ₆ , John Hanover ₆ , Jun Yin ₄ , Liqing Yu ₃ , Bingzhong Xue ₁ , Hang Shi ₁

Affiliation

尽管人们对脂肪肝疾病相关的遗传途径进行了广泛的研究，但人们对这些疾病背后的表观遗传机制知之甚少。 DNA甲基化是环境因素（例如饮食）和复杂疾病（例如非酒精性脂肪肝）之间的表观遗传联系。在此，旨在研究DNA甲基化在肝脏脂质代谢调节中的作用。发现高脂饮食 (HFD) 喂养的小鼠肝脏中 DNA 甲基化组发生动态变化，包括生物功能共受体 Beta-klotho ( Klb)启动子处 DNA 甲基化显着增加成纤维细胞生长因子 (FGF)15/19 和 FGF21。 DNA 甲基转移酶 (DNMT) 1 和 3A 介导 HFD 诱导的Klb启动子甲基化。值得注意的是，HFD 通过泛素化介导的机制增强 DNMT1 蛋白的稳定性。肝脏特异性删除Dnmt1或3a会增加Klb表达并改善 HFD 诱导的肝脂肪变性。单核 RNA 测序分析揭示了Dnmt1缺陷肝细胞中参与脂肪酸氧化的途径。 Klb启动子的靶向去甲基化会增加Klb表达和脂肪酸氧化，从而减少肝脏脂质积累。 HFD 上调甲基转移酶可能会诱导Klb启动子过度甲基化，并随后下调Klb表达，导致肝脂肪变性的发生。

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Epigenetic Regulation of Hepatic Lipid Metabolism by DNA Methylation

While extensive investigations have been devoted to the study of genetic pathways related to fatty liver diseases, much less is known about epigenetic mechanisms underlying these disorders. DNA methylation is an epigenetic link between environmental factors (e.g., diets) and complex diseases (e.g., non-alcoholic fatty liver disease). Here, it is aimed to study the role of DNA methylation in the regulation of hepatic lipid metabolism. A dynamic change in the DNA methylome in the liver of high-fat diet (HFD)-fed mice is discovered, including a marked increase in DNA methylation at the promoter of Beta-klotho (Klb), a co-receptor for the biological functions of fibroblast growth factor (FGF)15/19 and FGF21. DNA methyltransferases (DNMT) 1 and 3A mediate HFD-induced methylation at the Klb promoter. Notably, HFD enhances DNMT1 protein stability via a ubiquitination-mediated mechanism. Liver-specific deletion of Dnmt1 or 3a increases Klb expression and ameliorates HFD-induced hepatic steatosis. Single-nucleus RNA sequencing analysis reveals pathways involved in fatty acid oxidation in Dnmt1-deficient hepatocytes. Targeted demethylation at the Klb promoter increases Klb expression and fatty acid oxidation, resulting in decreased hepatic lipid accumulation. Up-regulation of methyltransferases by HFD may induce hypermethylation of the Klb promoter and subsequent down-regulation of Klb expression, resulting in the development of hepatic steatosis.

更新日期：2023-06-06

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