IL-6 Deficiency Attenuates Murine Diet-Induced Non-Alcoholic Steatohepatitis

Emmanuel Mas,Bruno Ségui,Thierry Levade,Marie Danjoux,Virginie Garcia,Stéphane Carpentier,Irene Oi-Lin Ng

doi:10.1371/journal.pone.0007929

Abstract

BackgroundThe role of inflammation in the pathogenesis of non-alcoholic steatohepatitis (NASH), a common cause of liver disease, is still poorly understood. This study aimed at assessing the involvement of a major inflammatory cytokine, IL-6, in NASH.Materials and MethodsSteatohepatitis was induced by feeding wild-type or IL-6−/− mice for 5 weeks with a methionine and choline-deficient (MCD) diet.ResultsWhereas MCD diet-induced weight loss and decreases in serum glucose, cholesterol and triglyceride levels were similar in both genotypes, serum alanine aminotransferase was less elevated in IL-6−/− mice than in wild-type animals. Despite having a comparable liver steatosis score, IL-6-deficient mice exhibited less lobular inflammation than their wild-type littermates. Liver gene expression of TGF-β and MCP-1 was also strongly attenuated in mutant mice; a more modest reduction was observed for PPAR-γ and F4/80 transcripts as well as proteins. Chromatographic analysis of liver lipids demonstrated that MCD diet induced in normal and mutant mice a similar decrease in the ratio of phosphatidylcholine to phosphatidylethanolamine. However, the diet-induced increase in the levels of sphingomyelin and ceramide was less important in IL-6−/− mice.ConclusionAltogether, these results indicate that IL-6 deficiency does not block the development of NASH; yet, IL-6 plays a critical role in the accompanying liver inflammation.

Highlights

The term non-alcoholic steatohepatitis (NASH) was first used in 1980 by Ludwig et al [1] to describe a histological pattern that mimicked alcoholic hepatitis but occurred in patients without history of alcohol abuse
NASH belongs to the spectrum of nonalcoholic fatty liver disease (NAFLD) and is becoming a major public health problem because it is associated with obesity, insulin resistance and the metabolic syndrome
WT mice were slightly heavier than IL-62/2 mice but both control and mutant mice lost about one third of their initial body weight after 5 weeks of methionine and choline-deficient (MCD) diet (Fig. 1A)

Summary

Introduction

The term non-alcoholic steatohepatitis (NASH) was first used in 1980 by Ludwig et al [1] to describe a histological pattern that mimicked alcoholic hepatitis but occurred in patients without history of alcohol abuse. A ‘two-hit process’ has been proposed to underlie the pathophysiology of NASH [3] According to this concept, in the first hit, there is an increase of circulating free fatty acids resulting in liver steatosis. In the first hit, there is an increase of circulating free fatty acids resulting in liver steatosis This step is enhanced by insulin resistance, which appears to play a prominent role. Secondary insults (‘the second hit’) include oxidative stress, whereby production of radical oxygen species and lipid peroxidation occur, recruitment of inflammatory cells and dysregulated cytokine/adipokine production. This induces hepatocyte cell death, by apoptosis or necrosis, and subsequent liver inflammation and fibrosis. This study aimed at assessing the involvement of a major inflammatory cytokine, IL-6, in NASH

Objectives

Methods

Results

Conclusion