Liver-Specific Deletion of Phosphatase and Tensin Homolog Deleted on Chromosome 10 Significantly Ameliorates Chronic EtOH-Induced Increases in Hepatocellular Damage

PLoS One. 2016 Apr 28;11(4):e0154152. doi: 10.1371/journal.pone.0154152. eCollection 2016.


Alcoholic liver disease is a significant contributor to global liver failure. In murine models, chronic ethanol consumption dysregulates PTEN/Akt signaling. Hepatospecific deletion of phosphatase and tensin homolog deleted on chromosome 10 (PTENLKO) mice possess constitutive activation of Akt(s) and increased de novo lipogenesis resulting in increased hepatocellular steatosis. This makes PTENLKO a viable model to examine the effects of ethanol in an environment of preexisting steatosis. The aim of this study was to determine the impact of chronic ethanol consumption and the absence of PTEN (PTENLKO) compared to Alb-Cre control mice (PTENf/f) on hepatocellular damage as evidenced by changes in lipid accumulation, protein carbonylation and alanine amino transferase (ALT). In the control PTENf/f animals, ethanol significantly increased ALT, liver triglycerides and steatosis. In contrast, chronic ethanol consumption in PTENLKO mice decreased hepatocellular damage when compared to PTENLKO pair-fed controls. Consumption of ethanol elevated protein carbonylation in PTENf/f animals but had no effect in PTENLKO animals. In PTENLKO mice, overall hepatic mRNA expression of genes that contribute to GSH homeostasis as well as reduced glutathione (GSH) and oxidized glutathione (GSSG) concentrations were significantly elevated compared to respective PTENf/f counterparts. These data indicate that during conditions of constitutive Akt activation and steatosis, increased GSH homeostasis assists in mitigation of ethanol-dependent induction of oxidative stress and hepatocellular damage. Furthermore, data herein suggest a divergence in EtOH-induced hepatocellular damage and increases in steatosis due to polyunsaturated fatty acids downstream of PTEN.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alanine Transaminase / genetics
  • Alanine Transaminase / metabolism
  • Alcohol Drinking / genetics
  • Alcohol Drinking / metabolism*
  • Alcohol Drinking / pathology
  • Animals
  • Chemical and Drug Induced Liver Injury, Chronic / genetics
  • Chemical and Drug Induced Liver Injury, Chronic / metabolism*
  • Chemical and Drug Induced Liver Injury, Chronic / pathology
  • Disease Models, Animal
  • Ethanol / adverse effects*
  • Fatty Acids, Unsaturated / metabolism
  • Fatty Liver, Alcoholic / genetics
  • Fatty Liver, Alcoholic / metabolism*
  • Fatty Liver, Alcoholic / pathology
  • Female
  • Gene Expression Regulation
  • Glutathione / metabolism
  • Lipogenesis / genetics
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Oxidative Stress
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics*
  • Protein Carbonylation
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Triglycerides / metabolism


  • Fatty Acids, Unsaturated
  • Triglycerides
  • Ethanol
  • Alanine Transaminase
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Glutathione