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

Research output: Contribution to journalArticle

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Abstract

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
JournalHepatology
Volume38
Issue number3
DOIs
Publication statusPublished - 2003 Sep 1
Externally publishedYes

Fingerprint

PTEN Phosphohydrolase
Ethanol
Liver
Phosphatidylinositol 3-Kinases
Messenger RNA
Hepatocytes
CD95 Antigens
Glycogen Synthase Kinase 3
Chromosomes, Human, Pair 10
Long Evans Rats
Phosphoprotein Phosphatases
Mitogen-Activated Protein Kinase Kinases
In Situ Nick-End Labeling
Cytoplasmic and Nuclear Receptors
Phosphoric Monoester Hydrolases
Caspase 3
Protein Kinases
DNA Damage
Transcription Factors
Western Blotting

ASJC Scopus subject areas

  • Hepatology

Cite this

Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver. / Yeon, Jong Eun; Califano, Sophia; Xu, Julia; Wands, Jack R.; De La Monte, Suzanne M.

In: Hepatology, Vol. 38, No. 3, 01.09.2003, p. 703-714.

Research output: Contribution to journalArticle

Yeon, Jong Eun ; Califano, Sophia ; Xu, Julia ; Wands, Jack R. ; De La Monte, Suzanne M. / Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver. In: Hepatology. 2003 ; Vol. 38, No. 3. pp. 703-714.
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