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Department of Internal Medicine, University of California, Davis, CA 95616
3To whom correspondence should be addressed. E-mail: chhalsted{at}ucdavis.edu.
The goals and objectives of these studies, conducted over the past 30 y, were to determine: a) how chronic alcoholism leads to folate deficiency and b) how folate deficiency contributes to the pathogenesis of alcoholic liver disease (ALD). The intestinal absorption of folic acid was decreased in binge drinking alcoholics and, prospectively, in volunteers fed alcohol with low folate diets. Monkeys fed alcohol for 2 y developed decreased hepatic folate stores, folic acid malabsorption and decreased hepatic uptake but increased urinary excretion of labeled folic acid. Micropigs fed alcohol for 1 y developed features of ALD in association with decreased translation and activity of intestinal reduced folate carrier. Another study in ethanol-fed micropigs demonstrated abnormal hepatic methionine and DNA nucleotide imbalance and increased hepatocellular apoptosis. When alcohol feeding was combined with folate deficiency, micropigs developed typical histological features of ALD in 14 wk, together with elevated plasma homocysteine levels, reduced liver S-adenosylmethionine and glutathione and increased markers for DNA and lipid oxidation. In summary, chronic alcohol exposure impairs folate absorption by inhibiting expression of the reduced folate carrier and decreasing the hepatic uptake and renal conservation of circulating folate. At the same time, folate deficiency accelerates alcohol-induced changes in hepatic methionine metabolism while promoting enhanced oxidative liver injury and the histopathology of ALD.
KEY WORDS: • folate • alcohol • methionine • alcoholic liver disease
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