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

• Published in: Journal of hepatology 2011-01, Vol.54 (1), p.164-172
• Main Authors: Derdak, Zoltan, Lang, Charles H, Villegas, Kristine A, Tong, Ming, Mark, Nicholas M, de la Monte, Suzanne M, Wands, Jack R
• Format: Article
• Language: English
• Subjects: Alanine Transaminase - metabolism; Animals; Apoptosis - physiology; Apoptosis Regulatory Proteins - metabolism; Biological and medical sciences; Caspase 3 - metabolism; Disease Models, Animal; DNA Damage; DNA, Mitochondrial - metabolism; Fatty Liver, Alcoholic - metabolism; Fatty Liver, Alcoholic - pathology; Fructose-2,6-bisphosphate; Fructosediphosphates - metabolism; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gluconeogenesis; Hepatocellular death; Insulin Resistance - physiology; Liver Diseases, Alcoholic - metabolism; Liver Diseases, Alcoholic - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Other diseases. Semiology; Oxidative Stress; Poly(ADP-ribose) Polymerases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; PTEN; PTEN Phosphohydrolase - metabolism; PUMA; Rats; Rats, Inbred F344; Rats, Long-Evans; Rats, Sprague-Dawley; Signal Transduction; Species Specificity; Sterol Regulatory Element Binding Protein 1 - metabolism; TIGAR; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2010.08.007

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.