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

Farah Esfandiari, Valentina Medici, Donna H. Wong, Soumia Jose, Maryam Dolatshahi, Eoin Quinlivan, Sanjana Dayal, Steven R. Lentz, Hidekazu Tsukamoto, Yue Hua Zhang, Samuel W. French, Charles H. Halsted

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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.

Original languageEnglish (US)
Pages (from-to)932-941
Number of pages10
JournalHepatology
Volume51
Issue number3
DOIs
StatePublished - Mar 2010

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Cystathionine beta-Synthase
Endoplasmic Reticulum Stress
Epigenomics
Ethanol
Liver
S-Adenosylhomocysteine
S-Adenosylmethionine
Alcoholic Fatty Liver
Response Elements
Sterols
Methionine
Histones
Lysine
DNA Damage
Carrier Proteins
Activating Transcription Factor 4
Caspase 12
Genotype
Lipogenesis
Chromatin Immunoprecipitation

ASJC Scopus subject areas

  • Hepatology

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Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse. / Esfandiari, Farah; Medici, Valentina; Wong, Donna H.; Jose, Soumia; Dolatshahi, Maryam; Quinlivan, Eoin; Dayal, Sanjana; Lentz, Steven R.; Tsukamoto, Hidekazu; Zhang, Yue Hua; French, Samuel W.; Halsted, Charles H.

In: Hepatology, Vol. 51, No. 3, 03.2010, p. 932-941.

Research output: Contribution to journalArticle

Esfandiari, F, Medici, V, Wong, DH, Jose, S, Dolatshahi, M, Quinlivan, E, Dayal, S, Lentz, SR, Tsukamoto, H, Zhang, YH, French, SW & Halsted, CH 2010, 'Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse', Hepatology, vol. 51, no. 3, pp. 932-941. https://doi.org/10.1002/hep.23382
Esfandiari, Farah ; Medici, Valentina ; Wong, Donna H. ; Jose, Soumia ; Dolatshahi, Maryam ; Quinlivan, Eoin ; Dayal, Sanjana ; Lentz, Steven R. ; Tsukamoto, Hidekazu ; Zhang, Yue Hua ; French, Samuel W. ; Halsted, Charles H. / Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse. In: Hepatology. 2010 ; Vol. 51, No. 3. pp. 932-941.
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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.",
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AU - Quinlivan, Eoin

AU - Dayal, Sanjana

AU - Lentz, Steven R.

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AU - French, Samuel W.

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