Effects of Indoleamine 2,3-Dioxygenase Deficiency on High-Fat Diet-Induced Hepatic Inflammation

Junji Nagano,Mitsuru Seishima,Takeshi Hara,Kuniaki Saito,Yohei Shirakami,Takahiro Kochi,Nobuhiko Nakamura,Hisataka Moriwaki,Hiroyasu Ito,Hisashi Tsurumi,Masahito Shimizu,Hirofumi Ohtaki,Takuji Tanaka,Rafael Aldabe

doi:10.1371/journal.pone.0073404

Junji Nagano, Mitsuru Seishima + Show 12 more

Open Access

https://doi.org/10.1371/journal.pone.0073404

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Journal: PloS one	Publication Date: Sep 9, 2013
Citations: 48	License type: CC BY 4.0

Affiliation: Gifu University, Kyoto University

Abstract

Hepatic immune regulation is associated with the progression from simple steatosis to non-alcoholic steatohepatitis, a severe condition of inflamed fatty liver. Indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that mediates the catabolism of L-tryptophan to L-kynurenine, plays an important role in hepatic immune regulation. In the present study, we examined the effects of IDO gene silencing on high-fat diet (HFD)-induced liver inflammation and fibrosis in mice. After being fed a HFD for 26 weeks, the IDO-knockout (KO) mice showed a marked infiltration of inflammatory cells, especially macrophages and T lymphocytes, in the liver. The expression levels of F4/80, IFNγ, IL-1β, and IL-6 mRNA in the liver and the expression levels of F4/80 and TNF-α mRNA in the white adipose tissue were significantly increased in IDO-KO mice, although hepatic steatosis, the accumulation of intrahepatic triglycerides, and the amount of oxidative stress were lower than those in IDO-wild-type mice. IDO-KO mice also developed marked pericellular fibrosis in the liver, accumulated hepatic hydroxyproline, and exhibited increased expression levels of hepatic TGF-β1 mRNA. These findings suggest that IDO-KO renders the mice more susceptible to HFD-induced hepatic inflammation and fibrosis. Therefore, IDO may have a protective effect against hepatic fibrosis, at least in this HFD-induced liver injury model.

Highlights

Non-alcoholic fatty liver disease (NAFLD), which is strongly associated with obesity and metabolic syndrome, is one of the most common causes of chronic liver disease worldwide
NAFLD includes a spectrum of disturbances that encompasses various degrees of liver damage ranging from non-alcoholic steatohepatitis (NASH), a severe condition of inflamed fatty liver that can progress to hepatic fibrosis, cirrhosis, or even hepatocellular carcinoma
The results of the present study indicate that high-fat diet (HFD)-induced hepatic inflammation and fibrosis are significantly aggravated in IDO-KO mice, the level of hepatic steatosis and amount of oxidative stress were lower compared to those in IDO-WT mice

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD), which is strongly associated with obesity and metabolic syndrome, is one of the most common causes of chronic liver disease worldwide. NAFLD includes a spectrum of disturbances that encompasses various degrees of liver damage ranging from non-alcoholic steatohepatitis (NASH), a severe condition of inflamed fatty liver that can progress to hepatic fibrosis, cirrhosis, or even hepatocellular carcinoma. Macrophage infiltration into WAT is an early contributing event in the development of systemic inflammation because it is accompanied by tumor necrosis factor (TNF)-α production, a central mediator of the inflammatory response [6]. These reports, indicate that chronic inflammation plays a key role in the pathogenesis of NASH [7]

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