Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease.
OBJECTIVE
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.
Division of Gastroenterology and Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA. Zoltan_Derdak@brown.edu
Zoltan
Z
Derdak
Charles H
CH
Lang
Kristine A
KA
Villegas
Ming
M
Tong
Nicholas M
NM
Mark
Suzanne M
SM
de la Monte
Jack R
JR
Wands
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000378:metabolism / Q000473:pathology; D005635:Fructosediphosphates / Q000378:metabolism; D005943:Gluconeogenesis; D007333:Insulin Resistance / Q000502:physiology*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013045:Species Specificity; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C533952:Bbc3 protein, rat; D004272:DNA, Mitochondrial; D005635:Fructosediphosphates; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D016159:Tumor Suppressor Protein p53; C027652:fructose 2,6-diphosphate; D011065:Poly(ADP-ribose) Polymerases; D000410:Alanine Transaminase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3