Inhibition of PGC-1α increases mortality after cholestasis induction. Role of oxidative stress

Resumen del póster presentado al International Symposium on Redox Signaling and Oxidative Stress in Health and Disease, IV Spanish and Portuguese Meeting on Free Radicals; celebrado en Valencia (España) del 5 al 7 de junio de 2012.-- et al.Cholestatic liver disorders are caused by genetic defects, mechanical aberrations, toxins or dysregulations in the immune system that damage the bile ducts and cause accumulation of bile and hepatic damage. The accumulation of toxic bile acids in the liver promotes severe mitochondrial dysfunction in rodents and in humans. Peroxisome proliferator-activated receptor-coactivator 1α (PGC-1α) has been shown to be a major regulator of mitochondrial function and respiration in many tissues. The objective of this study is to evaluate the role of PGC-1α in hepatic cholestasis. The survival curve performed after bile duct ligation in PGC-1α knockout mice showed that PGC-1α knockout mice mean lifespan was 2 days and the maximum lifespan was 6 days. However, wild type mean life span was 16 days and the maximum lifespan was 56 days. Oxidative stress parameters were measured with significant elevation of oxidation markers levels: GSA (glutamic semialdehyde), AASA (aminoapidic semialdehyde), CEL (Carboxyethyl-lysine), and MDAL (malondialdehyde-lysine). We also assessed the direct effect of PGC-1α on the activation of gluconeogenesis. In our model gluconegenesis-to-glycolisis shift was observed in the cholestatic PGC-1α knockout mice,with significant rise in ribose-5-phosphate levels. It is not causative of hypoglycemic shock, due to the increase of intake in these animals. In conclusion, we have shown that PGC-1α is critical for the survival of cholestatic mice. It could be due to the decrease of the antioxidant defense and the metabolic changes in PGC-1α knockout mice.Peer Reviewe