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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 aims to elucidate 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-Associated Factor 1 Promotes Hepatic Insulin Resistance via JNK Signaling Pathway