Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China.
The Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
Metabolism. 2021 Apr;117:154725. doi: 10.1016/j.metabol.2021.154725. Epub 2021 Feb 9.
Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, has become an increasingly severe public health problem. However, the underlying mechanism for the occurrence and development of NAFLD remains largely unknown. S100 calcium-binding protein A11 (S100A11) is a multifunctional protein previously reported to be a poor prognostic indicator of hepatocellular carcinoma, while the role of S100A11 affects NAFLD is still not clear.
Immunohistochemical staining was performed using human NAFLD and control biopsy specimens. Serum level of S100A11 were analyzed by Elisa assays. The S100A11 over-expressed/ knocked-down model was established in vitro or in vivo. The expression levels of genes related to lipid metabolism in liver tissue were performed by quantitative PCR and western blotting. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry.
We showed that the concentration of serum S100A11 was significantly elevated in NAFLD patients, and expression of S100A11 was remarkedly increased in the livers of NAFLD patients and mouse models. Overexpression of S100A11 in vivo markedly increased liver steatosis, body weight, and serum aspartate aminotransaminase (AST) levels. Mechanistically, our results demonstrated that S100A11 acted as a positive regulator of AKT/mTOR signaling to induce lipid synthesis and aggravate lipid deposition.
These results provide evidence for a novel role of S100A11 that contributes to hepatic steatosis, suggesting that targeting S100A11 may be an alternative approach for the treatment of NAFLD.
非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病病因，已成为日益严重的公共卫生问题。然而，NAFLD 发生和发展的潜在机制在很大程度上仍不清楚。S100 钙结合蛋白 A11（S100A11）是一种多功能蛋白，先前有报道称其是肝细胞癌预后不良的指标，而 S100A11 的作用影响 NAFLD 尚不清楚。
用人 NAFLD 和对照活检标本进行免疫组织化学染色。通过 Elisa 测定血清 S100A11 水平。在体外或体内建立 S100A11 过表达/敲低模型。通过定量 PCR 和 Western blot 检测肝组织中与脂质代谢相关基因的表达水平。通过生化测量和组织化学检测确定肝内脂质积聚。
我们发现，NAFLD 患者血清 S100A11 浓度明显升高，NAFLD 患者和小鼠模型肝脏中 S100A11 的表达显著增加。体内过表达 S100A11 明显增加肝脏脂肪变性、体重和血清天冬氨酸氨基转移酶（AST）水平。机制上，我们的结果表明 S100A11 作为 AKT/mTOR 信号的正调节剂，促进脂质合成并加重脂质沉积。
这些结果为 S100A11 的新作用提供了证据，该作用有助于肝脂肪变性，表明靶向 S100A11 可能是治疗 NAFLD 的一种替代方法。
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