Journal article
Methylation and Gene Expression Responses to Ethanol Feeding and Betaine Supplementation in the Cystathionine Beta Synthase-Deficient Mouse
Alcoholism, clinical and experimental research, Vol.38(6), pp.1540-1549
06/2014
DOI: 10.1111/acer.12405
PMCID: PMC4047166
PMID: 24730561
Abstract
Background
Alcoholic steatohepatitis (ASH) is caused in part by the effects of ethanol (EtOH) on hepatic methionine metabolism.
Methods
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.
Results
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 (Nos2) and DNA methyltransferase 1 (Dnmt1) were increased, while those of peroxisome proliferator receptor-α (Pparα) 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 Nos2 by EtOH feeding that was restored by betaine supplementation and was correlated inversely with its expression and positively with SAM/SAH ratios.
Conclusions
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.
Details
- Title: Subtitle
- Methylation and Gene Expression Responses to Ethanol Feeding and Betaine Supplementation in the Cystathionine Beta Synthase-Deficient Mouse
- Creators
- Valentina Medici - University of California DavisDiane I Schroeder - University of California DavisRima Woods - University of California DavisJanine M LaSalle - University of California DavisYongzhi Geng - University of California DavisNoreene M Shibata - University of California DavisJanet Peerson - University of California DavisEmir Hodzic - University of California DavisSanjana Dayal - University of IowaHidekazu Tsukamoto - Greater Los Angeles VA Healthcare SystemKusum K Kharbanda - Veterans Affairs Nebraska‐Western Iowa Health Care SystemBrittany Tillman - UCLA/Harbor Medical CenterSamuel W French - UCLA/Harbor Medical CenterCharles H Halsted - University of California Davis
- Resource Type
- Journal article
- Publication Details
- Alcoholism, clinical and experimental research, Vol.38(6), pp.1540-1549
- DOI
- 10.1111/acer.12405
- PMID
- 24730561
- PMCID
- PMC4047166
- NLM abbreviation
- Alcohol Clin Exp Res
- ISSN
- 0145-6008
- eISSN
- 1530-0277
- Publisher
- Wiley
- Number of pages
- 10
- Grant note
- Division of Gastroenterology and Hepatology at UC Davis P50AA11991 Morphology Core (R01ES021707) P50AA11991 Southern California Research Center Department of Veterans Affairs, Office of Research and Development Biomedical Laboratory Research and Development National Merit Review (BX001155) National Institutes of Health (K08DK084111; R03AA020577‐01) University of California San Francisco Liver Center (P30 DK026743)
- Language
- English
- Date published
- 06/2014
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984065487202771
Metrics
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