Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse.
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.


CONCLUSIONS
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.
Esfandiari
Farah
F
Department of Internal Medicine, 5303 Genome and Biomedical Science Facility, 451 E Health Sciences Drive, University of California, Davis, Davis, CA 95616, USA. fesfandiari@ucdavis.edu
Medici
Valentina
V
Wong
Donna H
DH
Jose
Soumia
S
Dolatshahi
Maryam
M
Quinlivan
Eoin
E
Dayal
Sanjana
S
Lentz
Steven R
SR
Tsukamoto
Hidekazu
H
Zhang
Yue Hua
YH
French
Samuel W
SW
Halsted
Charles H
CH
D000818:Animals; D004721:Endoplasmic Reticulum / Q000235:genetics*; D000091342:Endoplasmic Reticulum Chaperone BiP; D044127:Epigenesis, Genetic; D000431:Ethanol / Q000008:administration & dosage; D005235:Fatty Liver, Alcoholic / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D006712:Homocystinuria / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000648:ultrastructure*; D051379:Mice; D013312:Stress, Physiological / Q000235:genetics*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D000431:Ethanol