Dietary Zinc Deficiency Exaggerates Ethanol-Induced Liver Injury in Mice: Involvement of Intrahepatic and Extrahepatic Factors

Wei Zhong,Zhanxiang Zhou,Craig J Mcclain,Xinguo Sun,Yantao Zhao,Zhenyuan Song,Marcia B Aguila

doi:10.1371/journal.pone.0076522

Abstract

Clinical studies have demonstrated that alcoholics have a lower dietary zinc intake compared to health controls. The present study was undertaken to determine the interaction between dietary zinc deficiency and ethanol consumption in the pathogenesis of alcoholic liver disease. C57BL/6N mice were subjected to 8-week feeding of 4 experimental liquid diets: (1) zinc adequate diet, (2) zinc adequate diet plus ethanol, (3) zinc deficient diet, and (4) zinc deficient diet plus ethanol. Ethanol exposure with adequate dietary zinc resulted in liver damage as indicated by elevated plasma alanine aminotransferase level and increased hepatic lipid accumulation and inflammatory cell infiltration. Dietary zinc deficiency alone increased hepatic lipid contents, but did not induce hepatic inflammation. Dietary zinc deficiency showed synergistic effects on ethanol-induced liver damage. Dietary zinc deficiency exaggerated ethanol effects on hepatic genes related to lipid metabolism and inflammatory response. Dietary zinc deficiency worsened ethanol-induced imbalance between hepatic pro-oxidant and antioxidant enzymes and hepatic expression of cell death receptors. Dietary zinc deficiency exaggerated ethanol-induced reduction of plasma leptin, although it did not affect ethanol-induced reduction of white adipose tissue mass. Dietary zinc deficiency also deteriorated ethanol-induced gut permeability increase and plasma endotoxin elevation. These results demonstrate, for the first time, that dietary zinc deficiency is a risk factor in alcoholic liver disease, and multiple intrahepatic and extrahepatic factors may mediate the detrimental effects of zinc deficiency.

Highlights

Chronic alcohol consumption leads to alcoholic liver disease, which may evolve through three progressive stages: steatosis, hepatitis, and cirrhosis
zinc deficient diet (ZnD) group showed an increased liver weight compared to zinc adequate diet (ZnA), while the liver weight of zinc deficient diet plus ethanol (ZnD/E) group was greater than both ZnA and zinc adequate diet plus ethanol (ZnA/E) groups
The liver/body weight ratio was increased in ZnA/E group compared to ZnA group, while ZnD/E group showed a further increase with a value which was higher than all the other 3 groups

Summary

Introduction

Chronic alcohol consumption leads to alcoholic liver disease, which may evolve through three progressive stages: steatosis, hepatitis, and cirrhosis. Mechanistic studies have suggested that oxidative stress is a basic cellular disorder in the pathogenesis of alcoholic liver disease [1,2]. Liver is the major organ responsible for ethanol metabolism. Chronic alcohol consumption has been shown to induce hepatic expression of CYP2E1 rather than ADH [3,4]. CYP2E1 induction has been suggested to be a major mechanism of ethanol-induced oxidative stress in the liver [5]. Chronic ethanol consumption reduces hepatic antioxidant enzymes such as superoxide dismutase 1 (SOD-1, called copper zinc SOD) [4]. Modification and inactivation of cellular proteins under oxidative stress account for ethanolinduced metabolic disorders in the liver [1]

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Results

Conclusion