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Title: Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors

Author
item CORTON, J. CHRISTOPHER - TOXICOGENOMICS, RTP, NC
item APTE, UDAYAN - TOXICOL., U LA, MONROE,LA
item ANDERSON, STEVEN - GLAXOSMITHKLINE, RTP, NC
item LIMAYE, PALLAVI - TOXICOL., U LA, MONROE,LA
item YOON, LAWRENCE - GLAXOSMITHKLINE, RTP, NC
item LATENDREASSE, JOHN - PAI/NCTR, JEFFERSON,AR
item DUNN, CORRIE - CITT/CEN.HLTH.RES, RTP,NC
item EVERITT, JEFFREY - PAI/NCTR, JEFFERSON,AR
item Voss, Kenneth
item SWANSON, CYNTHIA - CITT/CEN.HLTH.RES, RTP,NC
item WONG, JEAN - U OF CA, RIVERSIDE, CA
item GILL, SARJEET - U OF CA, RIVERSIDE, CA
item CHANDRARATNA, ROSH - ALLGERAN, DAVIS, CA
item KWAK, MICHELE - JOHNS HOPKINS U,BALTIMORE
item KENZLER, TOM - JOHNS HOPKINS U,BALTIMORE
item STULNIG, THOMAS - NOVUM KAROL.INST,SWEDEN
item STEFFENSEN, KNUT - NOVUM KAROL.INST,SWEDEN
item GUSTAFSSON, JAN-AKE - NOVUM KAROL.INST,SWEDEN
item MEHENDELE, HARIHARA - TOXICOL/U LA, MONROE,LA

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/12/2004
Publication Date: 12/30/2004
Citation: Corton, J., Apte, U., Anderson, S.P., Limaye, P., Yoon, L., Latendreasse, J., Dunn, C., Everitt, J.X., Voss, K.A., Swanson, C., Kimbrough, C., Wong, J.S., Gill, S.S., Chandraratna, R., Kwak, M.K., Kensler, T.W., Stulnig, T., Steffensen, K.R., Gustafsson, J., Mehendele, H. 2004. Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors. Journal of Biological Chemistry. 279:46204-46212.

Interpretive Summary: Fumonisins are fungal toxins found in corn and food. They cause cancer in rodents and possibly in humans. To better understand how fumonisins might impact human health, it is important to understand both their direct and indirect effects in cells and tissues. Fumonisins disrupt fat metabolism and cause accumulation of a fat known as sphingosine. Sphingosine activates a molecule called the peroxisome proliferator-activated receptor alpha (PPARalpha) under some conditions. PPARalpha regulates expression of some genes involved in fat metabolism and cell growth, processes that are involved in both cancer development and fumonisin toxicity. To better understand how the PPARalpha works, gene activation in response to restricted access to food (caloric restriction) and to selected drugs were compared in intact mice and in genetically altered mice lacking the PPARalpha. Expression of some important genes regulating fat metabolism and cell growth depended on the PPARalpha. This and other findings suggest that, depending on the situation, PPARalpha-dependent gene expression can be beneficial or harmful. Promotion of cell growth or conversion of lipids to their reactive oxidized forms are examples of adverse consequences of PPARalpha activation that could contribute to cancer development in fumonisin-exposed animals. Further studies on the interactions between fumonisins, sphingosine, the PPARalpha, and PPARalpha-dependent gene expression will improve our understanding of how fumonisins cause cancer in animals and how they might affect human health.

Technical Abstract: Fumonisin mycotoxins are produced by Fusarium verticillioides and occur in corn and corn-based foods. They are nongenotoxic carcinogens when fed to rodents. Their affect on human health is unclear, however, fumonisins are implicated as a risk factor for some cancers. Fumonisins inhibit ceramide synthase, cause apoptosis and affect tissue regeneration but the molecular events linking enzyme inhibition to apoptosis, regeneration and neoplasia are unknown. Sphingosine, which increases in tissues as a result of ceramide synthase inhibition, binds to the peroxisome proliferators-activated response element alpha (PPARalpha) in vitro, suggesting that PPARalpha-dependent pathways are involved in fumonisin carcinogenicity. To further characterize the role of PPARalpha-related pathways in carcinogenesis, gene transcription in liver of wild type mice (WT) and mice lacking the PPARalpha (null mice) was evaluated following caloric restriction (CR) and exposure to agonists of the PPARalpha and related lipid-activated nuclear receptors involved in fasting. The genes found to be regulated by these receptors are involved in lipid metabolism and cell growth, processes also affected by fumonisins. Comparing the transcription profiles of WT and null mice revealed that gene expression following CR alone or CR-mediated antagonism of liver injury caused by the nongenotoxic carcinogen thioacetamide (TA) was PPARalpha dependent. Further, compensatory cell division in the liver following TA exposure was increased in WT but not in null mice suggesting that PPARalpha-dependent pathways play multiple roles in liver injury; protecting against acute or subacute injury while enhancing carcinogenicity by promoting cell division and increasing lipid oxidation. Additional studies on the mechanistic role of the PPARalpha in fumonisin toxicity and carcinogenicity are warranted and will contribute to science-based risk assessments of this mycotoxin.