Review
Zinc in gastrointestinal and liver disease

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Abstract

Zinc is an essential trace element with important biological functions, depending on the structural and/or catalytic role played by zinc ions in a large variety of enzymes. Zinc plays a critical role in cellular integrity, protein synthesis, nucleic acid metabolism, contributing to cell growth, proliferation, differentiation and death. The present review reports data on zinc homeostasis and metabolism, zinc absorption, intercellular trafficking, intracellular transport inside enterocytes and hepatocytes. Particular emphasis is given to data regarding the role of zinc carriers ZnTs and Zips, and to their expression in liver and gut in experimental and in human studies. The role of zinc in the gastrointestinal tract and in the liver as a powerful antioxidant and its relationship with apoptosis is discussed. Possible implications of zinc status in different disorders of the gastrointestinal tract are presented, focusing on its possible introduction in the therapy of inflammatory bowel diseases. Data on the role of zinc and zinc carriers in the evolution of liver fibrosis towards cirrhosis are also discussed. Finally, data on the ability of zinc therapy to obtain regression of liver cirrhosis in patients affected by Wilson's disease are reported, and the hypothesis that zinc could protect against liver fibrosis in chronic liver disease of different origin is presented.

Introduction

Recent years have registered an explosion of interest by the scientific community regarding the role of zinc, the second most prevalent trace element in the human body, in human and animal diseases, together with the understanding of the large spectrum of functions of zinc at the subcellular level [1]. The relevance of zinc in metabolic processes of living cells has been underlined by the discovery of a large number of molecules involved in the uptake and in the excretion of zinc, which regulate the intracellular molecular pathways of this trace element in mammals [2].

The number of metalloproteins which need zinc ions to stabilize their structure and to allow their function is increasing: members of oxidoreductase, hydrolase–ligase, lyase family [3] and Cu/Zn superoxide dismutase [4] are among the several hundred zinc–proteins present in our body. Zinc is so ubiquitous in cell metabolism that even minor changes in its availability may have relevant biological and, eventually, clinical consequences.

The central role played by zinc in cell growth and differentiation may easily explain the dramatic effects of its deficiency in tissues with rapid cell turnover, especially the skin, the gastrointestinal tract mucosa and the immune system. With respect to fetal development, the consequences of zinc deficiency on the outcome of pregnancy can be severe, like fetal abnormalities, growth retardation, and eventually fetal death [5]. In order to protect fetal growth and development, and maintain fetal zinc homeostasis, a complex regulatory mechanism of zinc transporters has been developed in the human placenta. This mechanism mediates zinc transfer between mother and fetus, assuring a coordinated regulatory response to changes in dietary zinc intake [6].

The encouraging recent progress in the field of molecular biology, regarding absorption, tissue distribution, intracellular transport and excretion of zinc in mammals, may be identified as the future area of research, focusing on the role of this trace element in human health and disease.

Recent evidence of a putative efficacy of zinc supplementation in the cure of liver disease and, in particular, in halting liver fibrosis, could recommend the field of zinc and liver as an important future area of research, with a possible relevance of zinc towards a clinical application.

The antioxidant role of zinc, together with its ability to protect human cells from apoptosis, the mechanism of cell death involved in acute and chronic inflammatory diseases of the liver and of the gastrointestinal tract, may suggest the field of zinc and gut relationship as an interesting field of research. The aim of this paper is to give a general view on the current status of the scientific basis for the role of zinc in human health and disease, with particular attention towards the interaction of zinc status and liver function in health, in acute and in chronic liver disease of different aetiology and in inflammatory bowel disease. Data on other trace elements–zinc interactions from the level of enterocyte to other systems in the body are presented. Possible implications of zinc in apoptosis and in the pathogenesis of different liver diseases are also prospected. Finally, the putative role for zinc in prevention and therapy of liver fibrosis is discussed.

Section snippets

Zinc homeostasis and functions

Zinc is an essential trace element for normal cell function and metabolism, i.e. for life [7]. It participates in all aspects of metabolism, in the regulation of gene expression, in the structural maintenance of chromatin and biomembranes, in immunity and in protection against free radicals [8]. Zinc ions are key structural components of a large number of proteins with highly specific functions: the matrix metalloproteinases, responsible for cartilage destruction seen in rheumatoid arthritis [9]

Conclusions

Zinc research may be considered still at an early stage of its evolution. There is a need for accelerate its progress, which could be relevant in human health and disease and, in particular, to better understand the pathogenesis and progression of liver and gastrointestinal disease. The correlation of zinc status in liver and gut in patients affected by chronic hepatitis or inflammatory bowel disease respectively could help to better analyze the role played by pro-inflammatory factors and by

Acknowledgements

We are grateful to Prof. Guido Crisponi for revising the manuscript and to Prof. Vassilios Fanos for his critical suggestions. We are also indebted to Mrs. Laura Di Pietro for the typing of the paper.

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