Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Diabetes. 2024 Jun 1;73(6):909-925. doi: 10.2337/db23-0688.
HSP20 emerges as a novel regulator of autophagy in the heart. Nonetheless, the detailed function of HSP20 in the liver and its effect on autophagy remain unknown. Here, we observed that HSP20 expression is increased in liver tissues from mice and patients with metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease. Liver-specific downregulation of HSP20 mitigates hepatic steatosis and insulin resistance in obese mice, while upregulating HSP20 promotes lipid deposition and hepatocyte cell death. Mechanistically, liquid chromatography-tandem mass spectrometry revealed that HSP20 interacts with phosphorylated extracellular regulated protein kinase 2 (ERK2) and prevents its dephosphorylation by dual specificity phosphatase 6, leading to ERK2-mediated repression of autophagy and resulting in aggravated saturated fatty acid (SFA)-triggered hepatocyte death. Importantly, such adverse effects could be ameliorated by ERK inhibitor. Our data reveal a framework of how HSP20 increases susceptibility of SFA-induced liver injury through enhancing ERK2 phosphorylation, which represents a plausible therapeutic intervention to combat MASLD.
HSP20 作为心脏自噬的新型调节因子出现。然而，HSP20 在肝脏中的详细功能及其对自噬的影响仍不清楚。在这里，我们观察到 HSP20 的表达在代谢功能障碍相关脂肪性肝病（MASLD）（以前称为非酒精性脂肪性肝病）患者和小鼠的肝组织中增加。HSP20 在肥胖小鼠中的肝脏特异性下调减轻了肝脂肪变性和胰岛素抵抗，而上调 HSP20 则促进脂质沉积和肝细胞死亡。在机制上，液质联用技术揭示 HSP20 与磷酸化细胞外调节蛋白激酶 2（ERK2）相互作用，并阻止双特异性磷酸酶 6 使其去磷酸化，导致 ERK2 介导的自噬抑制，从而导致饱和脂肪酸（SFA）触发的肝细胞死亡加重。重要的是，ERK 抑制剂可以改善这种不利影响。我们的数据揭示了 HSP20 通过增强 ERK2 磷酸化增加 SFA 诱导的肝损伤易感性的框架，这代表了对抗 MASLD 的一种合理的治疗干预措施。
