Zinc Supplementation Reverses Alcohol-Induced Steatosis in Mice Through Reactivating Hepatocyte Nuclear Factor-4α and Peroxisome Proliferator-Activated Receptor-α†

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Abstract
Alcoholic steatosis is a fundamental metabolic disorder in the progression of alcoholic liver disease. Zinc deficiency is one of the most consistently observed biochemical/nutritional manifestations of alcoholic liver disease. The purpose of this study is to determine whether dietary zinc supplementation to mice previously exposed to alcohol could reverse alcoholic steatosis. Male 129S mice were pair-fed an alcohol or isocaloric maltose dextrin liquid diet for 16 weeks with or without dietary zinc supplementation for the last 4 weeks. Zinc supplementation significantly attenuated alcohol-mediated increases in hepatic triglyceride, cholesterol, and free fatty acids in association with accelerated hepatic fatty acid oxidation and very low density lipoproteins (VLDL) secretion. Hepatic genes related to fatty acid oxidation and VLDL secretion were up-regulated by zinc supplementation, which was accompanied by restoring activity of hepatocyte nuclear factor-4α (HNF-4α) and peroxisome proliferators activated receptor-α (PPAR-α). Zinc supplementation enhanced alcohol metabolism and attenuated oxidative stress and liver injury. Zinc supplementation also normalized alcohol-mediated increases in plasma triglycerides and partially reversed decrease in gonadal adipose depot mass. Studies in HepG2 cells showed that zinc deprivation significantly suppressed the DNA-binding activities of HNF-4α and PPAR-α, and reduced HNF-4α and PPAR-α target proteins. Consequently, zinc deprivation caused cellular accumulation of lipid droplets, triglycerides and free fatty acids in the HepG2 cells. Conclusion: Zinc supplementation reverses alcoholic steatosis, and reactivation of HNF-4α and PPAR-α by increasing zinc availability and inhibiting oxidative stress are potential mechanisms underlying these beneficial effects of zinc on hepatic lipid homeostasis. (Hepatology 2009.)