Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410078, China.
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
Oxid Med Cell Longev. 2021 Jan 16;2021:3756925. doi: 10.1155/2021/3756925. eCollection 2021.
Fas-associated factor 1 (FAF1), a member of the Fas death-inducing signaling complex, is reported to interact potentially with diverse proteins and function in diverse cellular possesses. It remains unclear, however, whether FAF1 is involved in hepatic metabolic disorder and insulin resistance. This study is aimed at elucidating the role and the molecular mechanism of FAF1 in hepatic insulin resistance. Rats treated with high-fat diets are used as hepatic insulin resistance animal models. Quantitative real-time PCR, immunohistochemistry, and immunofluorescence assay are utilized to detect the FAF1 expression. The expression of relevant proteins is detected by Western blotting. We determine ROS production, lipid accumulation, and glucose uptake by using flow cytometry. Immunoprecipitation is employed to investigate protein-protein interaction. We find that increased expression of FAF1 occurred in the livers of insulin-resistant rats. Using gain-of-function and loss-of-function approaches, we observe dramatic exacerbation of insulin resistance, upregulated gluconeogenesis genes, downregulated glucose transport genes, and enhanced ROS production by FAF1 overexpression, whereas downregulation of FAF1 leads to a completely opposite phenotype. Mechanistically, FAF1 interacts directly with c-Jun N-terminal kinase (JNK) and activates its phosphorylation, thereby blocking the downstream insulin signaling pathway and leading to insulin resistance. Our data indicate that FAF1 is a potent regulator in hepatic metabolic disorder and insulin resistance.
Fas 相关死亡结构域蛋白 1（FAF1）是 Fas 死亡诱导信号复合物的成员，据报道它可以与多种蛋白质相互作用，并在多种细胞中发挥作用。然而，FAF1 是否参与肝脏代谢紊乱和胰岛素抵抗尚不清楚。本研究旨在阐明 FAF1 在肝脏胰岛素抵抗中的作用及其分子机制。我们使用高脂肪饮食处理的大鼠作为肝脏胰岛素抵抗动物模型。采用实时定量 PCR、免疫组织化学和免疫荧光检测 FAF1 的表达。通过 Western blot 检测相关蛋白的表达。我们通过流式细胞术测定 ROS 产生、脂质积累和葡萄糖摄取。采用免疫沉淀法研究蛋白质-蛋白质相互作用。结果发现，胰岛素抵抗大鼠肝脏中 FAF1 的表达增加。通过功能获得和功能丧失方法，我们观察到 FAF1 过表达导致胰岛素抵抗显著恶化，糖异生基因上调，葡萄糖转运基因下调，ROS 产生增强，而 FAF1 下调则导致完全相反的表型。机制上，FAF1 与 c-Jun N 端激酶（JNK）直接相互作用并激活其磷酸化，从而阻断下游胰岛素信号通路，导致胰岛素抵抗。我们的数据表明，FAF1 是肝脏代谢紊乱和胰岛素抵抗的一个强有力的调节因子。
