Phenylmethimazole abrogates diet-induced inflammation, glucose intolerance and NAFLD.

Ashley Patton,Tyler Church,Douglas J Goetz,Caroline Wilson,Edward O List,Jean Thuma,Kelly D Mccall,Frank Schwartz,Darlene E Berryman

doi:10.1530/joe-18-0078

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases and has become the leading chronic liver disease worldwide. High-fat (HF) diets promote an increased uptake and storage of free fatty acids (FFAs) and triglycerides (TGs) in hepatocytes, which initiates steatosis and induces lipotoxicity, inflammation and insulin resistance. Activation and signaling of Toll-like receptor 4 (TLR4) by FFAs induces inflammation evident in NAFLD and insulin resistance. Currently, there are no effective treatments to specifically target inflammation associated with this disease. We have established the efficacy of phenylmethimazole (C10) to prevent lipopolysaccharide and palmitate-induced TLR4 signaling. Because TLR4 is a key mediator in pro-inflammatory responses, it is a potential therapeutic target for NAFLD. Here, we show that treatment with C10 inhibits HF diet-induced inflammation in both liver and mesenteric adipose tissue measured by a decrease in mRNA levels of pro-inflammatory cytokines. Additionally, C10 treatment improves glucose tolerance and hepatic steatosis despite the development of obesity due to HF diet feeding. Administration of C10 after 16 weeks of HF diet feeding reversed glucose intolerance, hepatic inflammation, and improved hepatic steatosis. Thus, our findings establish C10 as a potential therapeutic for the treatment of NAFLD.

Highlights

Obesity is the single most important risk factor for the development of nonalcoholic fatty liver disease (NAFLD), which is the most prevalent liver disease in the western hemisphere (Lazo & Clark 2008, Bellentani et al 2010)
Toll-like receptor 4 (TLR4) is abundantly expressed in insulin target tissues such as adipose tissue, liver and skeletal muscle and is accepted as a key player in obesity-induced insulin resistance and type 2 diabetes mellitus (T2DM) (Jialal et al 2014)
Earlier studies suggested that the stimulation of TLR4 seen in obesity/ insulin resistance/T2DM results from gut-derived LPS (Lassenius et al 2011, Jayashree et al 2014, Velloso et al 2015); it is evident that free fatty acids (FFAs) derived from HF diets can trigger TLR4 signaling in these target tissues (Reyna et al 2008, Kim et al 2012) leading to Nonalcoholic fatty liver disease (NAFLD) and insulin resistance

Summary

Introduction

Obesity is the single most important risk factor for the development of nonalcoholic fatty liver disease (NAFLD), which is the most prevalent liver disease in the western hemisphere (Lazo & Clark 2008, Bellentani et al 2010). High-fat (HF) diets promote weight gain leading to an increase in adipose tissue mass (i.e. obesity). These HF diets cause an increase in levels of circulating free fatty acids (FFAs) and triglycerides (TGs) that deposit in adipose tissue as well as in the liver and skeletal muscle (i.e. ectopic fat deposition) (Day 2002, Dowman et al 2010). Ectopic fat deposition in the liver is the hallmark of hepatic steatosis, which is the earliest stage of NAFLD and is associated with the development of insulin resistance (Day & James 1998, Surwit et al 1988, Xu et al 2003, Cani et al 2007). Steatosis often leads to the development of NASH, which is characterized by immune cell infiltrate, hepatocyte injury and/or fibrosis

Methods

Results

Conclusion