A Low Iron Diet Protects from Steatohepatitis in a Mouse Model.

Lipika Salaye,Kylie Kavanagh,Robert Cooksey,Alexandria V Harrison,Ashley T Davis,Sandy Sink,Donald A Mcclain,George L Donati,Nuwan T Meegalla,Shalini Jain,Ielizaveta Bychkova,Felipe Lorenzo,Herbert L Bonkovsky,Soh-Hyun Lee,Katherine Turnbull,Manish S Bharadwaj,Alexander J Kovalic

doi:10.3390/nu11092172

Abstract

High tissue iron levels are a risk factor for multiple chronic diseases including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). To investigate causal relationships and underlying mechanisms, we used an established NAFLD model—mice fed a high fat diet with supplemental fructose in the water (“fast food”, FF). Iron did not affect excess hepatic triglyceride accumulation in the mice on FF, and FF did not affect iron accumulation compared to normal chow. Mice on low iron are protected from worsening of markers for non-alcoholic steatohepatitis (NASH), including serum transaminases and fibrotic gene transcript levels. These occurred prior to the onset of significant insulin resistance or changes in adipokines. Transcriptome sequencing revealed the major effects of iron to be on signaling by the transforming growth factor beta (TGF-β) pathway, a known mechanistic factor in NASH. High iron increased fibrotic gene expression in vitro, demonstrating that the effect of dietary iron on NASH is direct. Conclusion: A lower tissue iron level prevents accelerated progression of NAFLD to NASH, suggesting a possible therapeutic strategy in humans with the disease.

Highlights

The prevalence of nonalcoholic fatty liver disease (NAFLD) is steadily increasing worldwide, mirroring increased rates of obesity and type 2 diabetes mellitus (T2DM) [1]
Nutrients 2019, 11, 2172 patients with non-alcoholic fatty liver disease (NAFLD) exhibit the “dysmetabolic iron overload syndrome,” as manifested by elevated serum ferritin with normal or mildly elevated transferrin saturation [6]. This suggests that in addition to pathologic iron overload, even the upper range of normal levels of iron, as might be seen in people with higher dietary intake, could pose a danger to liver health as it does for T2DM risk [7,8,9]
Fasting glucose values did not differ (Figure 1B), the area under the glucose curve (AUC) during intraperitoneal glucose tolerance testing was higher in the FF group overall, though only the high iron (HI) FF group differed significantly from the corresponding normal chow (NC) group (Figure 1C)

Summary

Introduction

The prevalence of nonalcoholic fatty liver disease (NAFLD) is steadily increasing worldwide, mirroring increased rates of obesity and type 2 diabetes mellitus (T2DM) [1]. Pathologic iron overload, as seen in hereditary hemochromatosis, is associated with hepatic fibrosis, and hepatic iron levels correlate with the severity of NASH [4,5]. Nutrients 2019, 11, 2172 patients with NAFLD exhibit the “dysmetabolic iron overload syndrome,” as manifested by elevated serum ferritin with normal or mildly elevated transferrin saturation [6]. This suggests that in addition to pathologic iron overload, even the upper range of normal levels of iron, as might be seen in people with higher dietary intake, could pose a danger to liver health as it does for T2DM risk [7,8,9]

Methods

Results

Discussion

Conclusion