In vivo acute on chronic ethanol effects in liver

A mouse model exhibiting exacerbated injury, altered metabolic and epigenetic responses

Shivendra D. Shukla, Annayya R. Aroor, Ricardo Restrepo, Kusum Kharbanda, Jamal A. Ibdah

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease.

Original languageEnglish (US)
Pages (from-to)3280-3294
Number of pages15
JournalBiomolecules
Volume5
Issue number4
DOIs
StatePublished - Nov 20 2015

Fingerprint

Epigenomics
Liver
Ethanol
Histones
Wounds and Injuries
Lysine
Histone Code
Eating
Fat Necrosis
Cytochrome P-450 CYP2E1
Acetylation
Alcoholic Liver Diseases
Phosphorylation
Histone Deacetylases
Alcoholics
Nutrition
Transferases
Nuclear Proteins
Adenosine
Amplification

Keywords

  • Acute ethanol
  • Acute on chronic ethanol
  • Alcoholic liver disease
  • Binge alcohol
  • Chronic-binge alcohol
  • Epigenetics
  • Histone modifications
  • Mouse liver

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry
  • Molecular Biology

Cite this

In vivo acute on chronic ethanol effects in liver : A mouse model exhibiting exacerbated injury, altered metabolic and epigenetic responses. / Shukla, Shivendra D.; Aroor, Annayya R.; Restrepo, Ricardo; Kharbanda, Kusum; Ibdah, Jamal A.

In: Biomolecules, Vol. 5, No. 4, 20.11.2015, p. 3280-3294.

Research output: Contribution to journalArticle

Shukla, Shivendra D. ; Aroor, Annayya R. ; Restrepo, Ricardo ; Kharbanda, Kusum ; Ibdah, Jamal A. / In vivo acute on chronic ethanol effects in liver : A mouse model exhibiting exacerbated injury, altered metabolic and epigenetic responses. In: Biomolecules. 2015 ; Vol. 5, No. 4. pp. 3280-3294.
@article{2fd7bb7463514f01b8516b146c0b5ce4,
title = "In vivo acute on chronic ethanol effects in liver: A mouse model exhibiting exacerbated injury, altered metabolic and epigenetic responses",
abstract = "Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4{\%}) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease.",
keywords = "Acute ethanol, Acute on chronic ethanol, Alcoholic liver disease, Binge alcohol, Chronic-binge alcohol, Epigenetics, Histone modifications, Mouse liver",
author = "Shukla, {Shivendra D.} and Aroor, {Annayya R.} and Ricardo Restrepo and Kusum Kharbanda and Ibdah, {Jamal A.}",
year = "2015",
month = "11",
day = "20",
doi = "10.3390/biom5043280",
language = "English (US)",
volume = "5",
pages = "3280--3294",
journal = "Biomolecules",
issn = "2218-273X",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "4",

}

TY - JOUR

T1 - In vivo acute on chronic ethanol effects in liver

T2 - A mouse model exhibiting exacerbated injury, altered metabolic and epigenetic responses

AU - Shukla, Shivendra D.

AU - Aroor, Annayya R.

AU - Restrepo, Ricardo

AU - Kharbanda, Kusum

AU - Ibdah, Jamal A.

PY - 2015/11/20

Y1 - 2015/11/20

N2 - Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease.

AB - Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease.

KW - Acute ethanol

KW - Acute on chronic ethanol

KW - Alcoholic liver disease

KW - Binge alcohol

KW - Chronic-binge alcohol

KW - Epigenetics

KW - Histone modifications

KW - Mouse liver

UR - http://www.scopus.com/inward/record.url?scp=84971288815&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84971288815&partnerID=8YFLogxK

U2 - 10.3390/biom5043280

DO - 10.3390/biom5043280

M3 - Article

VL - 5

SP - 3280

EP - 3294

JO - Biomolecules

JF - Biomolecules

SN - 2218-273X

IS - 4

ER -