Etifoxine, a TSPO Ligand, Worsens Hepatitis C-Related Insulin Resistance but Relieves Lipid Accumulation.

Yu-Min Lin,Kung-Chia Young,Wen-Tai Chiu,Yu-Chieh Chien,Lee-Won Chong,Hui-Chen Su,Hung-Chuen Chang,Heng-Ai Chang,Hung-Yu Sun,Chiung-Wen Tsao,Chyi-Huey Bai

doi:10.1155/2019/3102414

Abstract

Etifoxine, an 18 kDa translocator protein (TSPO) agonist for the treatment of anxiety disorders in clinic, may be able to cause acute liver injury or cytolytic hepatitis. TSPO has been demonstrated to participate in inflammatory responses in infective diseases as well as to modulate glucose and lipid homeostasis. Hepatitis C virus (HCV) infection disrupts glucose and lipid homoeostasis, leading to insulin resistance (IR). Whether TSPO affects the HCV-induced IR remains unclear. Here, we found that the administration of etifoxine increased the TSPO protein expression and recovered the HCV-mediated lower mitochondrial membrane potential (MMP) without affecting HCV infection. Moreover, etifoxine reversed the HCV-induced lipid accumulation by modulating the expressions of sterol regulatory element-binding protein-1 and apolipoprotein J. On the other hand, in infected cells pretreated with etifoxine, the insulin-mediated insulin receptor substrate-1/Akt signals, forkhead box protein O1 translocation, and glucose uptake were blocked. Taken together, our results pointed out that etifoxine relieved the HCV-retarded MMP and reduced the lipid accumulation but deteriorated the HCV-induced IR by interfering with insulin signal molecules.

Highlights

Hepatitis C virus (HCV) is the cause of a global health problem with approximately 3% of the world’s population being chronically infected
The Huh7.5-secreted alkaline phosphatase (SEAP) cells were infected with HCV at a multiplicity of infection (MOI) of 0.01 in the presence of etifoxine (0.01-25 μM)
The SEAP activity as a reflection of the quantitative evaluation of HCV infection in culture media was determined at 6-day post-infection

Summary

Introduction

Hepatitis C virus (HCV) is the cause of a global health problem with approximately 3% of the world’s population being chronically infected. HCV infection is a major risk factor that can cause hepatic insulin resistance (IR), steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma. The frequency of diabetes is approximately 20% in patients with HCV [1]. HCV induces IR in a genotypedependent fashion, contributing to steatosis, the progression of fibrosis, apoptosis, and resistance to interferon-α therapy [2]. The intricately pathological IR mechanisms in HCV core protein-infected hepatocytes are associated with an impaired activation of insulin receptor substrate (IRS)-1 and Akt and a blockade of insulin-stimulated glucose uptake [3]. Upregulation of sterol regulatory element-binding protein-1 (SREBP-1) and the interference with forkhead box protein O1 (FoxO1) transcriptional activity contribute to HCV core

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Conclusion