Alcoholism is a major cause of liver disease and death in the U.S. Among adults, 52% are “regular drinkers”. Alcoholic liver disease (ALD) includes fatty liver, alcoholic hepatitis and alcoholic cirrhosis. Epigenetic* mechanisms have been shown to play a role in ALD, and this review focuses on abnormal nutrient availability causing histone modifications which may result in ALD. The major nutrients involved are S-adenosylmethionine (SAM), nicotinamide adenine dinucleotide (NAD+), and zinc.
Alcohol is converted to acetaldehyde by liver enzymes (alcohol dehydrogenase). In the process, NAD+ is reduced to NADH. Then, acetaldehyde is changed to acetate by acetaldehyde dehydrogenase. Increased acetate blood levels have been demonstrated in alcoholics, especially among chronic alcoholics. Acetate levels can be increased by 20 times after the use of alcohol. Addition of acetate (methyl units) is the best known way that activity of DNA is altered. The formation of acetate from alcohol may be the key factor in the development of alcoholic hepatitis.
Alcohol depletes NAD, which is used up in an attempt to metabolize the alcohol. NAD is important in DNA functioning and is involved in the processes of aging and metabolism. It is important in longevity and some age-associated diseases, such as diabetes, cancer, and Alzheimer’s disease.
SAM is an important chemical produced by the liver and is a major methyl donor for maintaining normal health. It is metabolized to SAH (S-adenosylhomocysteine) in the liver, which prevents the transference of methyl units. It should be eliminated by the body rapidly. The ratio of SAM to SAH is a measure of the methylation of DNA.
Alcohol is a major cause of SAM deficiency, which may lead to ALD. The conversion of the amino acid methionine to SAM is blocked in alcoholism, resulting in high blood levels of methionine (hypermethioninemia). Glutathione levels are low in alcoholics because the production of glutathione requires the presence of SAM, which is blocked by alcohol. SAM is also deficient in humans with hepatitis, and production of SAM is reduced by a deficiency of methionine. Significantly, when animals were fed alcohol and treated with SAM at the same time, liver damage was markedly reduced. SAM also prevented the changes of gene expression usually seen with alcohol-feeding experiments in animals.
Zinc absorption is reduced and zinc excretion is increased with alcohol use, resulting in zinc depletion. Zinc is needed for the normal function of over 300 enzymes. “Indeed, zinc insufficiency is one of the most commonly observed nutritional manifestations of alcoholic liver disease.” This can result in altered gene expression.
CONCLUSION: SAM deficiency may be the cause of the reduced DNA methylation seen in alcohol-induced liver disease. Alteration of gene expression could be the cause of alcoholic liver disease. A deficiency of NAD or of zinc can play a role also.
NOTE: *Epigenetic refers to ways that DNA function can be altered to change the production of proteins. The changes are chemical and can be the result of environmental and nutritional impacts. As well, the changes are reversible, but can be inherited. The changes include histone modification and abnormal degrees of methylation.
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Summary #966. nutrientmedicine