Development of a mouse iron overload-induced liver injury model and evaluation of the beneficial effects of placenta extract on iron metabolism

Akihiro Yamauchi,Akiko Kamiyoshi,Takayuki Sakurai,Hiroyuki Miyazaki,Eiichi Hirano,Hong-Seok Lim,Taiichi Kaku,Takayuki Shindo

doi:10.1016/j.heliyon.2019.e01637

Akihiro Yamauchi, Akiko Kamiyoshi + Show 6 more

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https://doi.org/10.1016/j.heliyon.2019.e01637

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Journal: Heliyon	Publication Date: May 1, 2019
Citations: 7	License type: cc-by

Affiliation: Ōtani University, Japan Bio Products (Japan)

Abstract

Hepatic iron deposition is seen in cases of chronic hepatitis and cirrhosis, and is a hallmark of a poorer prognosis. Iron deposition is also found in non-alcoholic steatohepatitis (NASH) patients. We have now developed a mouse model of NASH with hepatic iron deposition by combining a methione- and choline-deficient (MCD) diet with an iron-overload diet. Using this model, we evaluated the effects of human placenta extract (HPE), which has been shown to ameliorate the pathology of NASH. Four-week-old male C57BL/6 mice were fed the MCD diet with 2% iron for 12 weeks. In liver sections, iron deposition was first detected around the portal vein after 1 week. From there it spread throughout the parenchyma. Biliary iron concentrations were continuously elevated throughout the entire 12-week diet. As a compensatory response, the diet caused elevation of serum hepcidin, which accelerates excretion of iron from the body. Accumulation of F4/80-positive macrophages was detected within the sinusoids from the first week onward, and real-time PCR analysis revealed elevated hepatic expression of genes related inflammation and oxidative stress. In the model mice, HPE treatment led to a marked reduction of hepatic iron deposition with a corresponding increase in biliary iron excretion. Macrophage accumulation was much reduced by HPE treatment, as was the serum oxidation-reduction potential, an index of oxidative stress. These data indicate that by suppressing inflammation, oxidative stress and iron deposition, and enhancing iron excretion, HPE effectively ameliorates iron overload-induced liver injury. HPE administration may thus be an effective strategy for treating NASH.

Highlights

Iron is an essential element in virtually all organisms, playing key roles in a variety of integrative metabolic pathways, including DNAsynthesis, hematopoiesis, mitochondrial biogenesis, energy metabolism and oxygen transport [1]
We found that mice in the methione- and choline-deficient (MCD)-Fe group lost a substantial amount of weight during the first week of the diet (Fig. 1B)
There are currently no standard animal models that correctly reproduce the pathogenesis of non-alcoholic steatohepatitis” (NASH) in humans, though several have been proposed [16]

Summary

Introduction

Iron is an essential element in virtually all organisms, playing key roles in a variety of integrative metabolic pathways, including DNAsynthesis, hematopoiesis, mitochondrial biogenesis, energy metabolism and oxygen transport [1]. In the latter case, iron atoms cause Fenton reactions and promote production of toxic reactive oxygen species (ROS) [1, 2]. The liver, in particular, is susceptible to damage caused by ROS, and iron deposition in the liver is an exacerbating factor in cases of chronic hepatitis and cirrhosis [3]. The spectrum of NAFLD includes the relatively benign “simple steatosis” and the more severe “non-alcoholic steatohepatitis” (NASH). Hepatic iron deposition has been confirmed in about one-third of adult NAFLD patients and is a hallmark of a poorer prognosis [11]

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Conclusion