Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China.
Gannan Innovation and Translational Medicine Research Institute, State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Medical University, Ganzhou, China.
J Lipid Res. 2024 Mar;65(3):100513. doi: 10.1016/j.jlr.2024.100513. Epub 2024 Jan 29.
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease without specific Food and Drug Administration-approved drugs. Recent advances suggest that chromatin remodeling and epigenetic alteration contribute to the development of NAFLD. The functions of the corresponding molecular modulator in NAFLD, however, are still elusive. KDM1A, commonly known as lysine-specific histone demethylase 1, has been reported to increase glucose uptake in hepatocellular carcinoma. In addition, a recent study suggests that inhibition of KDM1A reduces lipid accumulation in primary brown adipocytes. We here investigated the role of KDM1A, one of the most important histone demethylases, in NAFLD. In this study, we observed a significant upregulation of KDM1A in NAFLD mice, monkeys, and humans compared to the control group. Based on these results, we further found that the KDM1A can exacerbate lipid accumulation and inflammation in hepatocytes and mice. Mechanistically, KDM1A exerted its effects by elevating chromatin accessibility, subsequently promoting the development of NAFLD. Furthermore, the mutation of KDM1A blunted its capability to promote the development of NAFLD. In summary, our study discovered that KDM1A exacerbates hepatic steatosis and inflammation in NAFLD via increasing chromatin accessibility, further indicating the importance of harnessing chromatin remodeling and epigenetic alteration in combating NAFLD. KDM1A might be considered as a potential therapeutic target in this regard.
非酒精性脂肪性肝病 (NAFLD) 是最常见的慢性肝病，没有获得美国食品和药物管理局批准的特定药物。最近的研究进展表明，染色质重塑和表观遗传改变有助于 NAFLD 的发展。然而，相应分子调节剂在 NAFLD 中的功能仍不清楚。KDM1A，通常称为赖氨酸特异性组蛋白去甲基酶 1，据报道可增加肝癌细胞中的葡萄糖摄取。此外，最近的一项研究表明，抑制 KDM1A 可减少原代棕色脂肪细胞中的脂质积累。我们在此研究了 KDM1A 在 NAFLD 中的作用，KDM1A 是最重要的组蛋白去甲基酶之一。在这项研究中，我们观察到与对照组相比，NAFLD 小鼠、猴子和人类的 KDM1A 显著上调。基于这些结果，我们进一步发现 KDM1A 可加剧肝细胞和小鼠中的脂质积累和炎症。从机制上讲，KDM1A 通过提高染色质可及性来发挥作用，随后促进了 NAFLD 的发展。此外，KDM1A 的突变削弱了其促进 NAFLD 发展的能力。总之，我们的研究发现，KDM1A 通过增加染色质可及性加剧了 NAFLD 中的肝脂肪变性和炎症，进一步表明了利用染色质重塑和表观遗传改变来对抗 NAFLD 的重要性。KDM1A 可能被认为是这方面的一个潜在治疗靶点。
