Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China.
Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, P.R. China.
Hepatol Commun. 2023 Aug 31;7(9). doi: 10.1097/HC9.0000000000000232. eCollection 2023 Sep 1.
S100 calcium-binding protein A6 (S100A6) is a calcium-binding protein that is involved in a variety of cellular processes, such as proliferation, apoptosis, and the cellular response to various stress stimuli. However, its role in NAFLD and associated metabolic diseases remains uncertain.
In this study, we revealed a new function and mechanism of S100A6 in NAFLD. S100A6 expression was upregulated in human and mouse livers with hepatic steatosis, and the depletion of hepatic S100A6 remarkably inhibited lipid accumulation, insulin resistance, inflammation, and obesity in a high-fat, high-cholesterol (HFHC) diet-induced murine hepatic steatosis model. In vitro mechanistic investigations showed that the depletion of S100A6 in hepatocytes restored lipophagy, suggesting S100A6 inhibition could alleviate HFHC-induced NAFLD. Moreover, S100A6 liver-specific ablation mediated by AAV9 alleviated NAFLD in obese mice.
Our study demonstrates that S100A6 functions as a positive regulator of NAFLD, targeting the S100A6-lipophagy axis may be a promising treatment option for NAFLD and associated metabolic diseases.
S100 钙结合蛋白 A6（S100A6）是一种参与多种细胞过程的钙结合蛋白，如增殖、凋亡和细胞对各种应激刺激的反应。然而，其在非酒精性脂肪性肝病（NAFLD）和相关代谢性疾病中的作用尚不确定。
在本研究中，我们揭示了 S100A6 在 NAFLD 中的一个新功能和机制。S100A6 在人肝和有肝脂肪变性的鼠肝中表达上调，肝 S100A6 的耗竭显著抑制高脂肪、高胆固醇（HFHC）饮食诱导的鼠肝脂肪变性模型中的脂质积累、胰岛素抵抗、炎症和肥胖。体外机制研究表明，肝细胞中 S100A6 的耗竭恢复了脂自噬，提示 S100A6 抑制可能减轻 HFHC 诱导的 NAFLD。此外，AAV9 介导的 S100A6 肝特异性消融减轻了肥胖小鼠的 NAFLD。
我们的研究表明，S100A6 是 NAFLD 的一个正向调节因子，靶向 S100A6-脂自噬轴可能是治疗 NAFLD 和相关代谢性疾病的一种有前途的选择。
