Methylation and Gene Expression Responses to Ethanol Feeding and Betaine Supplementation in the Cystathionine Beta Synthase‐Deficient Mouse. (14th April 2014)

• Record Type: Journal Article
• Authors: Medici, Valentina; Schroeder, Diane I.; Woods, Rima; LaSalle, Janine M.; Geng, Yongzhi; Shibata, Noreene M.; Peerson, Janet; Hodzic, Emir; Dayal, Sanjana; Tsukamoto, Hidekazu; Kharbanda, Kusum K.; Tillman, Brittany; French, Samuel W.; Halsted, Charles H.
• Is Part Of: Alcoholism. Volume 38:Number 6(2014:Jun.)
• Page Start: 1540
• Page End: 1549
• Publication Date: 2014-04-14
• Subjects: Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.12405
• Languages: English
• ISSNs: 0145-6008

Abstract

<abstract abstract-type="main" id="acer12405-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="acer12405-sec-0001" sec-type="section"> <title>Background</title> <p>Alcoholic steatohepatitis (ASH) is caused in part by the effects of ethanol (EtOH) on hepatic methionine metabolism.</p> </sec> <sec id="acer12405-sec-0002" sec-type="section"> <title>Methods</title> <p>To investigate the phenotypic and epigenetic consequences of altered methionine metabolism in this disease, we studied the effects of 4‐week intragastric EtOH feeding with and without the methyl donor betaine in cystathionine beta synthase (CβS) heterozygous C57BL/6J mice.</p> </sec> <sec id="acer12405-sec-0003" sec-type="section"> <title>Results</title> <p>The histopathology of early ASH was induced by EtOH feeding and prevented by betaine supplementation, while EtOH feeding reduced and betaine supplementation maintained the hepatic methylation ratio of the universal methyl donor S‐adenosylmethionine (SAM) to the methyltransferase inhibitor S‐adenosylhomocysteine (SAH). MethylC‐seq genomic sequencing of heterozygous liver samples from each diet group found 2 to 4% reduced methylation in gene bodies, but not promoter regions of all autosomes of EtOH‐fed mice, each of which were normalized in samples from mice fed the betaine‐supplemented diet. The transcript levels of nitric oxide synthase (<italic>Nos2</italic>) and DNA methyltransferase 1 (<italic>Dnmt1</italic>) were increased, while those of peroxisome proliferator receptor‐<italic>α</italic> (<italic>Pparα</italic>) were reduced in EtOH‐fed mice, and each was normalized in mice fed the betaine‐supplemented diet. DNA pyrosequencing of CβS heterozygous samples found reduced methylation in a gene body of <italic>Nos2</italic> by EtOH feeding that was restored by betaine supplementation and was correlated inversely with its expression and positively with SAM/SAH ratios.</p> </sec> <sec id="acer12405-sec-0004" sec-type="section"> <title>Conclusions</title> <p>The present study has demonstrated relationships among EtOH induction of ASH with aberrant methionine metabolism that was associated with gene body DNA hypomethylation in all autosomes and was prevented by betaine supplementation. The data imply that EtOH‐induced changes in selected gene transcript levels and hypomethylation in gene bodies during the induction of ASH are a result of altered methionine metabolism that can be reversed through dietary supplementation of methyl donors.</p> </sec> </abstract>