Fas-Associated Factor 1 Promotes Hepatic Insulin Resistance via JNK Signaling Pathway.

Bao Sun,Ling Chen,Yongchao Gao,Jiecan Zhou,Heng Xu,Xiaoping Chen,Fazhong He,Wei Zhang,Vladimir Jakovljevic

doi:10.1155/2021/3756925

Abstract

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.

Highlights

Insulin resistance, which is defined as impaired ability of cells, such as hepatocytes, adipocytes, and skeletal muscle cells to respond to the action of insulin, plays an essential role in the development of type 2 diabetes, obesity, and metabolic syndrome [1]
We show that Fas-associated factor 1 (FAF1) overexpression dramatically exacerbates glucose and lipid metabolic disorder, as well as insulin resistance by contributing to Jun N-terminal kinase (JNK) activation in hepatocytes
Considering that FAF1 overexpression impaired glucose and lipid metabolic perturbation, we further explored the effect of FAF1 overexpression on hepatic insulin resistance

Summary

Introduction

Insulin resistance, which is defined as impaired ability of cells, such as hepatocytes, adipocytes, and skeletal muscle cells to respond to the action of insulin, plays an essential role in the development of type 2 diabetes, obesity, and metabolic syndrome [1]. Dysregulation of glucose metabolism is a hallmark of insulin resistance in the hepatocytes, and the potential mechanisms mainly include decreased glycogen synthesis and failure to inhibit glucose production [2]. The elaborated mechanisms, including the complex molecular interactions and relevant cellular behaviors, involved in the process of metabolic disorder and hepatic insulin resistance are not yet fully understood. Literature demonstrated that Fas regulated hepatic mitochondrial function and fatty acid oxidation, promoting the progression of hepatic steatosis and insulin resistance [9]. The relationship between Fas and insulin resistance has been widely studied, it remains unknown whether FAF1, a Fas-binding protein, may be involved in hepatic metabolic disorders and insulin resistance

Objectives

Methods

Results

Conclusion