Dietary iron restriction leads to a reduction in hepatic fibrosis in a rat model of non-alcoholic steatohepatitis.

Naomichi Abe,Kozo Oka,Takuma Tsuchida,Shin-Ichiro Yasuda

doi:10.1242/bio.040519

Abstract

ABSTRACTIron overload in the liver causes oxidative stress and inflammation, which result in organ dysfunction, making it a risk factor for non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. We aimed to evaluate the effect of dietary iron restriction on disease progression in rats fed a choline-deficient L-amino acid-defined (CDAA) diet. Male F344 rats were fed a choline-sufficient amino acid-defined (control) diet, a CDAA diet or an iron-restricted CDAA diet for 4, 8 and 12 weeks. At each time point, hepatic iron levels, oxidative stress, inflammation and fibrosis were evaluated by immunohistochemistry. The iron-restricted CDAA diet significantly decreased serum iron levels for 12 weeks compared with the CDAA diet. Histological analysis confirmed that feeding with the CDAA diet induced hepatic iron overload and that this was associated with oxidative stress (number of 8-hydroxydeoxyguanosine-positive cells), inflammation (CD68 positive area) and fibrosis (Sirius Red positive area). Iron restriction with the CDAA diet significantly led to a reduction in the hepatic iron levels, oxidative stress, inflammation and fibrosis. Therefore, dietary iron restriction could be a useful therapeutic approach for NASH patients with hepatic iron overload.

Highlights

Iron facilitates the formation of reactive oxygen species (ROS), and these increase cytotoxicity through lipid peroxidation, protein denaturation and DNA damage (Bacon and Britton, 1990; Olynyk et al, 2005; Pietrangelo, 2016)
We aimed to evaluate the therapeutic effect of dietary iron restriction on hepatic iron, oxidative stress, inflammation and fibrosis in a rat model of nonalcoholic steatohepatitis (NASH) induced by a choline-deficient L-amino acid-defined (CDAA) diet
There was no significant difference in food intake among the three dietary groups (CSAA, CDAA and iron-restricted CDAA diets; Fig. 1B)

Summary

Introduction

Iron facilitates the formation of reactive oxygen species (ROS), and these increase cytotoxicity through lipid peroxidation, protein denaturation and DNA damage (Bacon and Britton, 1990; Olynyk et al, 2005; Pietrangelo, 2016). In patients with hereditary hemochromatosis, where iron overload is caused by a deficiency of the Hfe gene, iron absorption in the duodenum is increased, resulting in excessive iron accumulation in the liver and tissue damage and fibrosis (Andrews, 1999). Iron overload is associated with an increased risk of hepatocellular carcinoma (HCC) (Kowdley, 2004; Pietrangelo, 2009). Iron reduction therapies, such as phlebotomy and iron chelation, are widely used for patients with disorders of iron overload (Bacon et al, 2011; European Association for the Study of the Liver, 2010; Musallam et al, 2013). Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 22-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan

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