Journal article
Epigenetic Regulation of Hepatic Endoplasmic Reticulum Stress Pathways in the Ethanol-Fed Cystathionine Beta Synthase-Deficient Mouse
Hepatology (Baltimore, Md.), Vol.51(3), pp.932-941
2010
DOI: 10.1002/hep.23382
PMID: 19957376
Abstract
We tested the hypothesis that the pathogenesis of alcoholic liver injury is mediated by epigenetic changes in regulatory genes that result from the induction of aberrant methionine metabolism by ethanol feeding. Five-month-old cystathionine beta synthase heterozygous and wild-type C57BL/6J littermate mice were fed liquid control or ethanol diets by intragastric infusion for 4 weeks. Both ethanol-fed groups showed typical histopathology of alcoholic steatohepatitis, with reduction in liver S-adenosylmethionine (SAM), elevation in liver S-adenosylhomocysteine (SAH), and reduction in the SAM/SAH ratio with interactions of ethanol and genotype effects. Hepatic endoplasmic reticulum stress signals including glucose-regulated protein-78 (GRP78), activating transcription factor 4, growth arrest and DNA damage-inducible gene 153 (GADD153), caspase 12, and transcription factor sterol response element binding protein-1c (SREBP-1c) were up-regulated in ethanol-fed mice with genotype interactions and negative correlations with the SAM/SAH ratio. Immunohistochemical staining showed reduction in trimethylated histone H3 lysine-9 (3meH3K9) protein levels in centrilobular regions in both ethanol groups, with no changes in trimethylated histone H3 lysine-4 levels. The chromatin immunoprecipitation assay revealed a decrease in levels of suppressor chromatin marker 3meH3K9 in the promoter regions of GRP78, SREBP-1c, and GADD153 in ethanol-treated heterozygous cystathionine beta synthase mice. The messenger RNA expression of the histone H3K9 methyltransferase EHMT2 (G9a) was selectively decreased in ethanol-fed mice. Conclusion: The pathogenesis of alcoholic steatohepatitis is mediated in part through the effects of altered methionine metabolism on epigenetic regulation of pathways of endoplasmic reticulum stress relating to apoptosis and lipogenesis.
Details
- Title: Subtitle
- Epigenetic Regulation of Hepatic Endoplasmic Reticulum Stress Pathways in the Ethanol-Fed Cystathionine Beta Synthase-Deficient Mouse
- Creators
- Farah ESFANDIARI - Department of Internal Medicine, University of California Davis, Davis, CA, United StatesValentina MEDICI - Department of Internal Medicine, University of California Davis, Davis, CA, United StatesSamuel W FRENCH - Department of Pathology, UCLA/Harbor Medical Center, Torrance, CA, United StatesCharles H HALSTED - Department of Internal Medicine, University of California Davis, Davis, CA, United StatesDonna H WONG - Department of Internal Medicine, University of California Davis, Davis, CA, United StatesSoumia JOSE - Department of Internal Medicine, University of California Davis, Davis, CA, United StatesMaryam DOLATSHAHI - Department of Internal Medicine, University of California Davis, Davis, CA, United StatesEoin QUINHVAN - Department of Nutrition, University of Florida, Gainesville, FL, United StatesSanjana DAYAL - Department of Medicine, University of Iowa, Iowa City, IA, United StatesSteven R LENTZ - Department of Medicine, University of Iowa, Iowa City, IA, United StatesHidekazu TSUKAMOTO - Department of Pathology, University of Southern California, Los Angeles, CA, United StatesYue Hua Zhang - Department of Pathology, UCLA/Harbor Medical Center, Torrance, CA, United States
- Resource Type
- Journal article
- Publication Details
- Hepatology (Baltimore, Md.), Vol.51(3), pp.932-941
- Publisher
- Wiley; Hoboken, NJ
- DOI
- 10.1002/hep.23382
- PMID
- 19957376
- ISSN
- 0270-9139
- eISSN
- 1527-3350
- Language
- English
- Date published
- 2010
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984065384802771
Metrics
19 Record Views