Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease

Zoltan Derdak, Charles H. Lang, Kristine A. Villegas, Ming Tong, Nicholas M. Mark, Suzanne M. De La Monte, Jack R. Wands

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Abstract

Background & Aims: Chronic ethanol consumption in the Long-Evans (LE) rat has been associated with hepatic p53 activation, and inhibition of the insulin/PI3K/AKT signal transduction cascade due to increased expression of PTEN. We hypothesize that p53 activation and altered insulin signaling may influence the susceptibility of rats to ethanol-induced liver damage. Furthermore, p53 not only activates programmed cell death pathways and suppresses hepatocellular survival signals, but also promotes gluconeogenesis to increase systemic insulin resistance due to a novel metabolic function. Methods: Fischer (F), Sprague-Dawley (SD) and LE rats were fed ethanol-containing or control liquid diet for 8 weeks. Histopathological and biochemical changes were assessed. Results: Here, we demonstrate that chronic ethanol feeding in rats promotes p53 activation, hepatic steatosis, oxidative stress, PUMA, and PTEN expression, which contribute to hepatocellular death and diminished insulin signaling in the liver. Such changes are pronounced in the LE, less prominent in SD, and virtually absent in the F rat strain. More importantly, there is activation of Tp53-induced glycolysis and apoptosis regulator (TIGAR) in the ethanol-fed LE rat. This event generates low hepatic fructose-2,6-bisphosphate (Fru-2,6-P2) levels, reduced lactate/pyruvate ratio and may contribute to increased basal glucose turnover and high residual hepatic glucose production during euglycemic hyperinsulinemic clamp. Conclusions: p53 activation correlates with the susceptibility to ethanol-induced liver damage in different rat strains. p53 not only orchestrates apoptosis and suppresses cell survival, but by activating TIGAR and decreasing hepatic Fru-2,6-P2 levels it promotes insulin resistance and therefore, contributes to the metabolic abnormalities associated with hepatic steatosis.

Original languageEnglish (US)
Pages (from-to)164-172
Number of pages9
JournalJournal of Hepatology
Volume54
Issue number1
DOIs
StatePublished - Jan 1 2011

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Alcoholic Liver Diseases
Insulin Resistance
Apoptosis
Liver
Ethanol
Long Evans Rats
Glycolysis
Insulin
Glucose
Glucose Clamp Technique
Gluconeogenesis
Pyruvic Acid
Phosphatidylinositol 3-Kinases
Lactic Acid
Signal Transduction
Cell Survival
Oxidative Stress
Cell Death
Diet

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Derdak, Zoltan ; Lang, Charles H. ; Villegas, Kristine A. ; Tong, Ming ; Mark, Nicholas M. ; De La Monte, Suzanne M. ; Wands, Jack R. / Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease. In: Journal of Hepatology. 2011 ; Vol. 54, No. 1. pp. 164-172.
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abstract = "Background & Aims: Chronic ethanol consumption in the Long-Evans (LE) rat has been associated with hepatic p53 activation, and inhibition of the insulin/PI3K/AKT signal transduction cascade due to increased expression of PTEN. We hypothesize that p53 activation and altered insulin signaling may influence the susceptibility of rats to ethanol-induced liver damage. Furthermore, p53 not only activates programmed cell death pathways and suppresses hepatocellular survival signals, but also promotes gluconeogenesis to increase systemic insulin resistance due to a novel metabolic function. Methods: Fischer (F), Sprague-Dawley (SD) and LE rats were fed ethanol-containing or control liquid diet for 8 weeks. Histopathological and biochemical changes were assessed. Results: Here, we demonstrate that chronic ethanol feeding in rats promotes p53 activation, hepatic steatosis, oxidative stress, PUMA, and PTEN expression, which contribute to hepatocellular death and diminished insulin signaling in the liver. Such changes are pronounced in the LE, less prominent in SD, and virtually absent in the F rat strain. More importantly, there is activation of Tp53-induced glycolysis and apoptosis regulator (TIGAR) in the ethanol-fed LE rat. This event generates low hepatic fructose-2,6-bisphosphate (Fru-2,6-P2) levels, reduced lactate/pyruvate ratio and may contribute to increased basal glucose turnover and high residual hepatic glucose production during euglycemic hyperinsulinemic clamp. Conclusions: p53 activation correlates with the susceptibility to ethanol-induced liver damage in different rat strains. p53 not only orchestrates apoptosis and suppresses cell survival, but by activating TIGAR and decreasing hepatic Fru-2,6-P2 levels it promotes insulin resistance and therefore, contributes to the metabolic abnormalities associated with hepatic steatosis.",
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Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease. / Derdak, Zoltan; Lang, Charles H.; Villegas, Kristine A.; Tong, Ming; Mark, Nicholas M.; De La Monte, Suzanne M.; Wands, Jack R.

In: Journal of Hepatology, Vol. 54, No. 1, 01.01.2011, p. 164-172.

Research output: Contribution to journalArticle

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T1 - Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease

AU - Derdak, Zoltan

AU - Lang, Charles H.

AU - Villegas, Kristine A.

AU - Tong, Ming

AU - Mark, Nicholas M.

AU - De La Monte, Suzanne M.

AU - Wands, Jack R.

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N2 - Background & Aims: Chronic ethanol consumption in the Long-Evans (LE) rat has been associated with hepatic p53 activation, and inhibition of the insulin/PI3K/AKT signal transduction cascade due to increased expression of PTEN. We hypothesize that p53 activation and altered insulin signaling may influence the susceptibility of rats to ethanol-induced liver damage. Furthermore, p53 not only activates programmed cell death pathways and suppresses hepatocellular survival signals, but also promotes gluconeogenesis to increase systemic insulin resistance due to a novel metabolic function. Methods: Fischer (F), Sprague-Dawley (SD) and LE rats were fed ethanol-containing or control liquid diet for 8 weeks. Histopathological and biochemical changes were assessed. Results: Here, we demonstrate that chronic ethanol feeding in rats promotes p53 activation, hepatic steatosis, oxidative stress, PUMA, and PTEN expression, which contribute to hepatocellular death and diminished insulin signaling in the liver. Such changes are pronounced in the LE, less prominent in SD, and virtually absent in the F rat strain. More importantly, there is activation of Tp53-induced glycolysis and apoptosis regulator (TIGAR) in the ethanol-fed LE rat. This event generates low hepatic fructose-2,6-bisphosphate (Fru-2,6-P2) levels, reduced lactate/pyruvate ratio and may contribute to increased basal glucose turnover and high residual hepatic glucose production during euglycemic hyperinsulinemic clamp. Conclusions: p53 activation correlates with the susceptibility to ethanol-induced liver damage in different rat strains. p53 not only orchestrates apoptosis and suppresses cell survival, but by activating TIGAR and decreasing hepatic Fru-2,6-P2 levels it promotes insulin resistance and therefore, contributes to the metabolic abnormalities associated with hepatic steatosis.

AB - Background & Aims: Chronic ethanol consumption in the Long-Evans (LE) rat has been associated with hepatic p53 activation, and inhibition of the insulin/PI3K/AKT signal transduction cascade due to increased expression of PTEN. We hypothesize that p53 activation and altered insulin signaling may influence the susceptibility of rats to ethanol-induced liver damage. Furthermore, p53 not only activates programmed cell death pathways and suppresses hepatocellular survival signals, but also promotes gluconeogenesis to increase systemic insulin resistance due to a novel metabolic function. Methods: Fischer (F), Sprague-Dawley (SD) and LE rats were fed ethanol-containing or control liquid diet for 8 weeks. Histopathological and biochemical changes were assessed. Results: Here, we demonstrate that chronic ethanol feeding in rats promotes p53 activation, hepatic steatosis, oxidative stress, PUMA, and PTEN expression, which contribute to hepatocellular death and diminished insulin signaling in the liver. Such changes are pronounced in the LE, less prominent in SD, and virtually absent in the F rat strain. More importantly, there is activation of Tp53-induced glycolysis and apoptosis regulator (TIGAR) in the ethanol-fed LE rat. This event generates low hepatic fructose-2,6-bisphosphate (Fru-2,6-P2) levels, reduced lactate/pyruvate ratio and may contribute to increased basal glucose turnover and high residual hepatic glucose production during euglycemic hyperinsulinemic clamp. Conclusions: p53 activation correlates with the susceptibility to ethanol-induced liver damage in different rat strains. p53 not only orchestrates apoptosis and suppresses cell survival, but by activating TIGAR and decreasing hepatic Fru-2,6-P2 levels it promotes insulin resistance and therefore, contributes to the metabolic abnormalities associated with hepatic steatosis.

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