Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver

Jong Eun Yeon, Sophia Califano, Julia Xu, Jack R. Wands, Suzanne M. De La Monte

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95 Citations (Scopus)


Chronic ethanol consumption can cause sustained hepatocellular injury and inhibit the subsequent regenerative response. These effects of ethanol may be mediated by impaired hepatocyte survival mechanisms. The present study examines the effects of ethanol on survival signaling in the intact liver. Adult Long Evans rats were maintained on ethanol-containing or isocaloric control liquid diets for 8 weeks, after which the livers were harvested to measure mRNA levels, protein expression, and kinase or phosphatase activity related to survival or proapoptosis mechanisms. Chronic ethanol exposure resulted in increased hepatocellular labeling for activated caspase 3 and nuclear DNA damage as demonstrated using the TUNEL assay. These effects of ethanol were associated with reduced levels of tyrosyl phosphorylated (PY) IRS-1 and PI3 kinase, Akt kinase, and Erk MAPK activities and increased levels of phosphatase tensin homologue deleted on chromosome 10 (PTEN) mRNA, protein, and phosphatase activity in liver tissue. In vitro experiments demonstrated that ethanol increases PTEN expression and function in hepatocytes. However, analysis of signaling cascade pertinent to PTEN function revealed increased levels of nuclear p53 and Fas receptor mRNA but without corresponding increases in GSK-3 activity or activated BAD. Although fork-head transcription factor levels were increased in ethanol-exposed livers, virtually all of the fork-head protein detected by Western blot analysis was localized within the cytosolic fraction. In conclusion, chronic ethanol exposure impairs survival mechanisms in the liver because of inhibition of signaling through PI3 kinase and Akt and increased levels of PTEN. However, uncoupling of the signaling cascade downstream of PTEN that mediates apoptosis may account for the relatively modest degrees of ongoing cell loss observed in livers of chronic ethanol-fed rats.

Original languageEnglish
Pages (from-to)703-714
Number of pages12
Issue number3
Publication statusPublished - 2003 Sept 1
Externally publishedYes

Bibliographical note

Funding Information:
Supported by COBRE Grant P20RR15578 from the NIH; AA02666, AA02169, AA11431, and AA12908 from the NIAAA; and the Korean Association Study of Liver Disease Glaxo Wellcome Hepatologist Hepatitis Fellowship Fund (to J.E.Y.) Address reprint requests to: Suzanne M. de la Monte, M.D., M.P.H. Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903. E-mail: Suzanne_DeLaMonte_MD@Brown.edu; fax: 401-444-2939. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3803-0021$30.00/0 doi:10.1053/jhep.2003.50368

ASJC Scopus subject areas

  • Hepatology


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