Zinc deficiency is one of the most consistent nutritional/biochemical observations in alcoholic liver disease (ALD). The objectives of our research are to determine how alcohol interferes with cellular zinc homeostasis and if zinc deficiency is a causal factor in the development of ALD. Metallothionein (MT) is a major protein responsible for cellular zinc homeostasis. MT-transgenic (MT-TG) mice with hepatic overexpression of MT and elevation of zinc level were resistant to ethanol-induced liver injury. MT-knockout (MT-KO) mice with a reduction of hepatic zinc were more susceptible to alcohol toxicity. However, zinc treatment also provided beneficial effects on alcohol hepatoxicity in MT-KO mice, suggesting a MT-independent action. Dietary zinc supplementation normalized hepatic zinc level and attenuated the pathological changes in the liver of mice chronically fed alcohol. Several mechanisms were involved in zinc action against alcoholic cytotoxicity. Zinc enhanced cellular antioxidant capacity and corrected alcohol metabolic switch from alcohol dehydrogenase to cytochrome P4502E1. Zinc attenuated cytokine production and TNF-α receptor- and Fas-mediated cell death pathways. Zinc restored activities of hepatocyte nuclear factor-4α (HNF-4α) and peroxisome proliferation activator-α (PPAR-α), and enhanced hepatic fatty acid β-oxidation and lipid secretion. Hepatoma cell cultures showed that zinc deprivation induces lipid accumulation via inactivating HNF-4α and PPAR-α. These results suggest that alcohol exposure interferes with hepatic zinc homeostasis, leading to cellular zinc deprivation. Inactivation of zinc proteins due to zinc release is likely an important molecular mechanism in the pathogenesis of ALD.

McClain CJ, Antonow DR, Cohen DA, Shedlofsky S: Zinc metabolism in alcoholic liver disease. Alcohol Clin Exp Res 1986;10:582–589.
Dinsmore W, Callender ME, McMaster D, Todd SJ, Love AH: Zinc absorption in alcoholics using zinc-65. Digestion 1985;32:238–342.
Kägi JH: Overview of metallothionein. Methods Enzymol 1991;205:613–626.
Davis SR, Cousind RJ: Metallothionein expression in animals: a physiological perspective on function. J Nutr 2000;130:1085–1088.
Thornalley PJ, Vasak M: Possible role for metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim Biophys Acta 1985;827:36–44.
Iszard MB, Liu J, Liu Y, Dalton T, Andrews GK, Palmiter RD, Klaassen CD: Characterization of metallothionein-I-transgenic mice. Toxicol Appl Pharmacol 1995;133:305–312.
Masters BA, Kelly EJ, Quaife CJ, Brinster RL, Palmiter RD: Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium. Proc Natl Acad Sci USA 1994;91:584–588.
Kang YJ: The antioxidant function of metallothionein in the heart. Proc Soc Exp Biol Med 1999;222:263–273.
Zhou Z, Sun X, James Kang Y: Metallothionein protection against alcoholic liver injury through inhibition of oxidative stress. Exp Biol Med 2002;227:214–222.
Zhou Z, Sun X, Lambert JC, Saari JT, Kang YJ: Metallothionein-independent zinc protection from alcoholic liver injury. Am J Pathol 2002;160:2267–2274.
Lieber CS: Alcohol metabolism, cirrhosis and alcoholism. Clin Chim Acta 1997;257:59–84.
McClearn GE, Bernett EL, Hebert M, Kakehana R, Schlesinger K: Alcohol dehydrogenase activity and previous ethanol consumption in mice. Nature 1964;203:793–794.
Cederbaum AI, Lu Y, Wu D: Role of oxidative stress in alcohol-induced liver injury. Arch Toxicol 2009;83:519–548.
Parat MO, Richard MJ, Beani JC, Favier A: Involvement of zinc in intracellular oxidant/antioxidant balance. Biol Trace Elem Res 1997;60:187–204.
Zhou Z, Wang L, Song Z, Saari JT, McClain CJ, Kang YJ: Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress. Am J Pathol 2005;166:1681–1690.
Natori S, Rust C, Stadheim LM, Srinivasan A, Burgart LJ, Gores GJ: Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis. J Hepatol 2001;34:248–253.
Ziol M, Tepper M, Lohez M, Arcangeli G, Ganne N, Christidis C, Trinchet JC, Beaugrand M, Guillet JG, Guettier C: Clinical and biological relevance of hepatocyte apoptosis in alcoholic hepatitis. J Hepatol 2001;34:254–260.
Meerarani P, Ramadass P, Toborek M, Bauer HC, Bauer H, Hennig B: Zinc protects against apoptosis of endothelial cells induced by linoleic acid and tumor necrosis factor-α. Am J Clin Nutr 2000;71:81–87.
Nakatani T, Tawaramoto M, Opare Kennedy D, Kojima A, Matsui-Yuasa I: Apoptosis induced by chelation of intracellular zinc is associated with depletion of cellular reduced glutathione level in rat hepatocytes. Chem Biol Interact 2000;125:151–163.
Cao J, Bobo JA, Liuzzi JP, Cousins RJ: Effects of intracellular zinc depletion on metallothionein and ZIP2 transporter expression and apoptosis. J Leukoc Biol 2001;70:559–566.
Bao S, Knoell DL: Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosis. Am J Physiol Lung Cell Mol Physiol 2006;290:L433–L441.
Lambert JC, Zhou Z, Kang YJ: Suppression of Fas-mediated signaling pathway is involved in zinc inhibition of ethanol-induced liver apoptosis. Exp Biol Med 2003;228:406–412.
Zhou Z, Kang X, Jiang Y, Song Z, Feng W, McClain CJ, Kang YJ: Preservation of hepatocyte nuclear factor-4α is associated with zinc protection against TNF-α hepatotoxicity in mice. Exp Biol Med 2007;232:622–628.
Zhou Z, Liu J, Song Z, McClain CJ, Kang YJ: Zinc supplementation inhibits hepatic apoptosis in mice subjected to a long-term ethanol exposure. Exp Biol Med 2008;233:540–548.
Purohit V, Russo D, Coates PM: Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium. Alcohol 2004;34:3–8.
Lakshman MR: Some novel insights into the pathogenesis of alcoholic steatosis. Alcohol 2004;34:45–48.
Nagy LE: Molecular aspects of alcohol metabolism: transcription factors involved in early alcohol-induced liver injury. Annu Rev Nutr 2004;24:55–78.
Crabb DW, Liangpunsakul S: Alcohol and lipid metabolism. J Gastroenterol Hepatol 2006;21:S56–S60.
Tomita K, Azuma T, Kitamura N, Tamiya G, Ando S, Nagata H, Kato S, Inokuchi S, Nishimura T, Ishii H, Hibi T: Leptin deficiency enhances sensitivity of rats to alcoholic steatohepatitis through suppression of metallothionein. Am J Physiol Gastrointest Liver Physiol 2004;287:G1078–G1085.
Tom Dieck H, Döring F, Fuchs D, Roth HP, Daniel H: Changes in rat hepatic gene expression in response to zinc deficiency as assessed by DNA arrays. J Nutr 2003;133:1004–1010.
Tom Dieck H, Döring F, Roth HP, Daniel H: Transcriptome and proteome analysis identifies the pathways that increase hepatic lipid accumulation in zinc-deficient rats. J Nutr 2005;135:199–205
Yousef MI, El-Hendy HA, El-Demerdash FM, Elagamy EI: Dietary zinc deficiency induced-changes in the activity of enzymes and the levels of free radicals, lipids and protein electrophoretic behavior in growing rats. Toxicology 2002;175:223–234.
Kang X, Zhong W, Liu J, Song Z, McClain CJ, Kang YJ, Zhou Z: Zinc supplementation reverses alcohol-induced steatosis in mice through reactivating hepatocyte nuclear factor-4α and peroxisome proliferator-activated receptor-α. Hepatology 2009;50:1241–1250.
Staudinger JL, Lichti K: Cell signaling and nuclear receptors: new opportunities for molecular pharmaceuticals in liver disease. Mol Pharm 2008;5:17–34.
Nagy LE: Molecular aspects of alcohol metabolism: transcription factors involved in early alcohol-induced liver injury. Annu Rev Nutr 2004;24:55–78.
Crabb DW, Galli A, Fischer M, You M: Molecular mechanisms of alcoholic fatty liver: role of peroxisome proliferator-activated receptor-α. Alcohol 2004;34:35–38.
Fischer M, You M, Matsumoto M, Crabb DW: Peroxisome proliferator-activated receptor-α (PPAR-α) agonist treatment reverses PPAR-α dysfunction and abnormalities in hepatic lipid metabolism in alcohol-fed mice. J Biol Chem 2003;278:27997–28004.
Watt AJ, Garrison WD, Duncan SA: HNF4: a central regulator of hepatocyte differentiation and function. Hepatology 2003;37:1249–1253.
Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, Volkert TL, Schreiber J, Rolfe PA, Gifford DK, Fraenkel E, Bell GI, Young RA: Control of pancreas and liver gene expression by HNF transcription factors. Science 2004;303:1378–1381.
Webster KA, Prentice H, Bishopric NH: Oxidation of zinc finger transcription factors: physiological consequences. Antioxid Redox Signal 2001;3:535–548.
Wilcox DE, Schenk AD, Feldman BM, Xu Y: Oxidation of zinc-binding cysteine residues in transcription factor proteins. Antioxid Redox Signal 2001;3:549–564.
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