Dietary Copper Plays an Important Role in Maintaining Intestinal Barrier Integrity During Alcohol-Induced Liver Disease Through Regulation of the Intestinal HIF-1α Signaling Pathway and Oxidative Stress.

Hongwei Lin,Ji Li,Yong-Ping Chen,Qianjing Du,Jingjing Tu,Yuedong Xu,Teng Teng,Hanxiao Tu,Lanman Xu,Dazhi Chen,Tongtong Pan,Xiaodong Wang,Zhuo Lin

doi:10.3389/fphys.2020.00369

Abstract

Impaired intestinal barrier function and oxidative stress injury play critical roles in the pathogenesis of alcoholic liver disease (ALD), and recent investigations have revealed a role for dietary copper in the liver and intestinal barrier function. Therefore, the current study investigates the mechanisms and role of dietary copper in alcohol induced liver diseases. C57BL/6 mice were used to create an alcoholic liver disease model with a Lieber-DeCarli diet containing 5% alcohol and were fed with different concentrations of dietary copper of adequate (6 ppm, CuA), marginal (1.5 ppm, CuM), or supplemental (20 ppm, CuS) amounts. Caco-2 cells were also exposed to ethanol and different concentrations of copper. Damages of the liver and intestine were evaluated by transaminases, histology staining, and protein and mRNA level, as well as cell proliferation, oxidative stress, and mitochondrial membrane potential. In animal experiments, the results indicate that an alcohol diet causes liver injury and disruption of intestinal barrier function as well as decreasing the expression of genes such as HIF-1α, occludin, SOD1, and GPX1. Supplemental dietary copper can revert these changes except for SOD1, but marginal dietary copper can worsen these changes. The in vitro cell experiments showed that proper copper supplementation can promote cell growth and reduce reactive oxygen species (ROS) production. In conclusion, supplemental dietary copper has beneficial effects on alcohol-induced intestine and liver injury, and marginal dietary copper shows detrimental effects on these parameters.

Highlights

Alcoholic liver disease (ALD) arises due to excess use of alcohol for a long period of time and ranges from hepatic steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma (Seitz et al, 2018)
Since hypoxia-inducible factor-1α (HIF-1α) is a regulatory subunit of the hypoxia-inducible factor (HIF), which regulates a wide range of genes involved in cellular responses to hypoxia and other tissue environmental cues (Prabhakar and Semenza, 2012), HIF-1α should play an important role in maintaining barrier functions of intestinal epithelial cells
HIF-1α was significantly increased in hepatic fibrotic tissues and activated hepatic stellate cells (HSCs) (Moon et al, 2009), which are the consequences of alcoholic diseases

Summary

Introduction

Alcoholic liver disease (ALD) arises due to excess use of alcohol for a long period of time and ranges from hepatic steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma (Seitz et al, 2018). The pathogenesis of ALD may involve many aspects (Rao, 2009; Gao and Bataller, 2011; Orman et al, 2013; Chen et al, 2016), recent studies have suggested that gut barrier dysfunction induced by alcohol, such as increased intestinal permeability, bacterial translocation, and release of bacteria-derived endotoxin into circulation, may play an important role in ALD development. The barrier function of intestinal epithelial cells is regulated by a variety of factors, including oxygen (Rath et al, 2018). Since hypoxia-inducible factor-1α (HIF-1α) is a regulatory subunit of the hypoxia-inducible factor (HIF), which regulates a wide range of genes involved in cellular responses to hypoxia and other tissue environmental cues (Prabhakar and Semenza, 2012), HIF-1α should play an important role in maintaining barrier functions of intestinal epithelial cells. The role of HIF-1α in alcoholic diseases still remains to be investigated

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Results

Conclusion