|Voss, Kenneth - Ken|
Submitted to: Toxicological Sciences
Publication Type: Abstract Only
Publication Acceptance Date: 1/30/2005
Publication Date: 3/15/2005
Citation: Corton, J.C., Apte, U., Anderson, S.P., Limaye, P., Yoon, L., Latendresse, J., Everitt, J., Voss, K.A., Kimbrough, C., Wong, J.S., Gill, S.S., Chandraratna, R.A., Kwak, M., Kensler, T.W., Stuling, T.M., Steffensen, K.R., Gustaffson, J., Mehendele, H.M. 2005. Role of PPAR alpha in caloric restriction effects in mouse liver [abstract]. Toxicological Sciences. 84(S1):12. Interpretive Summary: Abstract - no summary)
Technical Abstract: The obesity epidemic in industrialized countries is associated with increases in cardiovascular disease (CVD) and certain types of cancer. In animal models, caloric restriction (CR) su ppresses these diseases as well as chemical-induced tissue damage. These beneficial effects of CR overlap with those altered by agonists of nuclear receptors (NR) under control of the fasting-responsive transcriptional co-activator, peroxisome proliferator-activated co-activator 1alpha (PGC-1alpha). In a screen for compounds that mimic CR effects in the liver, we found statistically significant overlaps between the CR transcript profile in wild-type mice and the profiles altered by agonists of lipid-activated NR including peroxisome proliferator-activated receptor alpha (PPAR), liver X receptor and their obligate heterodimer partner, retinoid X receptor. The overlapping genes included those involved in CVD (lipid metabolism, inflammation) and cancer (cell fate). Based on this overlap, we hypothesized that some effects of CR are mediated by PPAR. As determined by transcript profiling, 19% of all gene expression changes in wild-type mice were dependent on PPAR including Cyp4a10 and Cyp4a14, involved in fatty acid omega-oxidation, acute phase response genes and epidermal growth factor receptor but not increases in PGC-1alpha. CR protected the livers of wild-type mice from damage induced by thioacetamide, a liver toxicant and hepatocarcinogen. CR protection was lost in PPAR-null mice due to inadequate tissue repair. These results demonstrate that PPAR mediates some of the effects of CR and indicate that a pharmacological approach to mimicking many of the beneficial effects of CR may be possible.