CONSTITUTIVE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA-REGULATED GENES IN DWARF MICE

Authors: STAUBER, ANJA - CIIT, RTP, NC; BROWN-BORG, HOLLY - MED./U.NORTH DAKOTA; LIU, JIE - NIEHS, RTP, NC; WAALKES, MICHAEL - NIEHS, RTP, NC; LAUGHTER, ASHLEY - CIIT, RTP, NC; STABEN, REBECCA - CIIT, RTP, NC; COLEY, JAQUELINE - CIIT, RTP, NC; SWANSON, CYNTHIA - CIIT, RTP, NC; Voss, Kenneth; KOPCHICK, JOHN - BIOMED.SCI,OHIO U.,ATHENS; CORTON, J.CHRISTOPHER - TOXICO-GEN,CHAPEL HILL,NC

Submitted to: Molecular Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/29/2004
Publication Date: 3/1/2005
Citation: Stauber, A.J., Brown-Borg, H., Liu, J., Waalkes, M.P., Laughter, A., Staben, R.A., Coley, J.C., Swanson, C., Voss, K.A., Kopchick, J.J., Corton, J. 2005. Constitutive expression of peroxisome proliferator-activated receptor alpha-regulated genes in dwarf mice. Molecular Pharmacology 67(3):681-694.

Interpretive Summary: Fumonisins are fungal toxins found in corn and food. They cause cancer and cardiovascular dysfunction in animals and are considered risk factors for cancer and cardiovascular disease in humans. Fumonisins disrupt metabolism and cause accumulation of sphingosine, a type of fat. Sphingosine can activate a peroxisome proliferator-activated receptor alpha (PPAR-alpha), an important cell signaling molecule, under some conditions. To better understand how fumonisins impact human health, it is important to understand how they affect gene expression. The PPAR-alpha regulates genes involved in fat metabolism, cell growth, stress response and cardiovascular disease, processes that are involved in both cancer development and fumonisin toxicity. Dwarf mice have metabolic defects that are decrease expression of some factors contributing to cancer and cardiovascular disease and peroxisome proliferator compounds such as WY14,643 similarly affect many of these factors in wild-type mice. Studies were therefore undertaken to determine extent to which gene transcription in untreated dwarf and WY14,643-treated wild type mice are similar. The results showed a significant overlap in the expression of genes affecting fat metabolism, stress response, and fibrinogen (a factor for cardiovascular disease) and that expression of the PPAR-alpha gene plays an important role in these changes. The findings increase understanding of role of PPAR-alpha and gene expression in diseases that have been associated with fumonisins.

Technical Abstract: Fumonisin mycotoxins are found in corn and corn-based foods. They are carcinogenic and cause cardiovascular dysfunction in animals. They are suspected risk factors for cancer and possibly cardiovascular disease in humans. There is evidence that fumonisin's mechanism of action involves peroxisome proliferation, possibly as a result of activation of the peroxisome proliferator-activated receptor alpha (PPAR-alpha) by sphingoid bases accumulating in tissues following of fumonisin exposure. Dwarf mice have defects in growth hormone secretion or signaling that are associated with decreases in factors contributing to cancer and cardiovascular disease. Because peroxisome proliferator compounds (PP) similarly affect some of these factors in wild-type mice, studies were done to determine if overlapping gene transcriptional programs seen in untreated dwarf mice and PP-treated wild-type mice underlies these similarities. Transcript profiling showed a significant overlap in the expression of genes differentially regulated in control Snell dwarf mice (Pit-1dw) compared to phenotypically normal heterozygote (+/dw) control mice and those altered by the PP WY-14,643 in +/dw mice. The genes affected included those involved in beta- and omega-oxidation of fatty acids (Acox1, Cyp4a10, Cyp4a14), in stress responses (the chaperonin, T-complex protein1epsilon), and in cardiovascular disease (fibrinogen). The levels of some of these gene products were also altered in other dwarf mouse models, including Ames, Little, and growth hormone receptor-null mice. The constitutive increases in PPAR-alpha-regulated genes may be partly caused by increased expression of PPAR-alpha mRNA and protein as observed in the livers of control Snell dwarf mice. These results suggest that some beneficial effects associated with the dwarf phenotype are caused by constitutive activation of PPAR-alpha and regulated genes. Because fumonisins are suspected peroxisomal proliferators, understanding the role of PPAR-alpha and gene expression during peroxisome proliferation will help elucidate fumonisin's mechanism of action.