Shan Lei, Guo Pengzhan, Wen Mumeike, Sun Yue, Gao Fei, Zhang Kai, Zhang Ning, Yang Baoshan
Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, People's Republic of China.
Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, People's Republic of China.
Toxicol Appl Pharmacol. 2025 Feb;495:117210. doi: 10.1016/j.taap.2024.117210. Epub 2024 Dec 20.
Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. The present work aimed to explore the function of regulator of Calcineurin 2 (RCAN2) in NAFLD and its related mechanisms. Mice were fed with high-fat diet (HFD) to construct NAFLD model. Adeno-associated virus injection was performed to interference with RCAN2 in mice. RCAN2 knockdown meliorated HFD-induced NAFLD and impaired glucose metabolism. Abnormal lipid metabolism and inflammation in HFD-fed mice were relieved when RCAN2 was downregulated. Besides, hepatocyte Huh-7 cells, treated with free fatty acids (oleic acid and palmitic acid), were used as NAFLD models in vitro. We found that knockdown of RCAN2 inhibited the accumulation of lipid droplets and inflammation induced by free fatty acids. RCAN2 interference increased the activity of calcineurin (CaN), which enhanced the nuclear translocation of Transcription factor EB (TFEB). Autophagosome and lysosome biogenesis was augmented, and autophagy-dependent lipid degradation (lipophagy) was promoted. Collectively, we demonstrate that RCAN2 insufficiency protects against NAFLD by promoting TFEB-mediated lipophagy.
非酒精性脂肪性肝病（NAFLD）是慢性肝病的主要病因。本研究旨在探讨钙调神经磷酸酶调节蛋白2（RCAN2）在NAFLD中的作用及其相关机制。通过给小鼠喂食高脂饮食（HFD）构建NAFLD模型。采用腺相关病毒注射法干扰小鼠体内的RCAN2。敲低RCAN2可改善HFD诱导的NAFLD并损害葡萄糖代谢。当RCAN2下调时，HFD喂养小鼠的脂质代谢异常和炎症反应得到缓解。此外，用游离脂肪酸（油酸和棕榈酸）处理的肝细胞Huh-7细胞被用作体外NAFLD模型。我们发现敲低RCAN2可抑制游离脂肪酸诱导的脂滴积累和炎症反应。干扰RCAN2可增加钙调神经磷酸酶（CaN）的活性，从而增强转录因子EB（TFEB）的核转位。自噬体和溶酶体生物合成增加，自噬依赖性脂质降解（脂质自噬）被促进。总的来说，我们证明RCAN2功能不足通过促进TFEB介导的脂质自噬来预防NAFLD。
