Peroxisomal gene expression

Certain phthalate plasticizers such as di-(2-etltylhexyl) phthalate, DEHP, belong to the peroxisome prohferator, PP, family of rodent liver carcinogens. " Here, the evidence for peroxisome proliferator-mediated rodent carcinogenesis in response to PPs will be considered together with an evaluation of the molecular basis for rodent-human species differences in response. Specifically, this chapter will focus on the role and mechanisms of peroxisome proliferator-induced rodent peroxisomal gene expression and the evidence for lack of relevance of this mechanism to humans. 

Dewald O, Sharma S, Adrogue J, et al. Downregulation of peroxisome proliferator-activated receptor-alpha gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity. Circulation. Jul 19 2005 112(3) 407 15. 

Recent evidence confirms that species differences can involve more than one aspect of PPARa-mediated regulation of gene expression. The insensitivity of human liver to rodent peroxisome proliferators is associated with low levels of expression of PPARa in human liver. Marked species differences in the expression of PPARa mRNA have been demonstrated between rodent and human liver, with the latter expressing 1-10% of the levels found in mouse or rat liver (Palmer et al, 1994 Tugwood et al, 1996 Palmer etal, 1998). Using a sensitive and specific immuno/DNA binding assay. Palmer et al (1998) have shown that active PPARa protein is expressed at variable concentrations in human livers. The study compared 20 different human livers and found that those with the highest levels of PPARa protein expression contained less than 10% of the level in mice. Most of the samples (13/20) contained no detectable PPARa activity, but did... 

The absence of a significant response of human liver to induction of peroxisome proliferation and hepatocellular proliferation is explained by several aspects of PPARa-mediated regulation of gene expression. 

Hepatic peroxisome proliferation depends on a nuclear receptor, PPARa, to mediate these responses in mice, based on lack of response to peroxisome proliferators in PPARa-deficient mice. In one study with another peroxisome proliferator, WY-14,643, carcinogenesis was shown to be dependent on the same receptor. Oral administration of di(2-ethylhexyl) phthalate failed to elicit markers of peroxisome proliferation in PPARa-deficient mice, while the same treatment elicited this response in normal mice. Metabolites of di(2-ethylhexyl) phthalate caused activation of PPARa-mediated gene expression in mammalian cell co-transfection assays. Differences between responsive rodents and humans in various aspects of PPARa-mediated regulation of gene expression are consistent with the lack of activity of di(2-ethylhexyl) phthalate metabolites in hepatocyte cultures from 12 people studied to date. 

Covers the effects of diet on the regulation of gene expression, considering the role of peroxisome proliferator-activated receptors (PPARs)... 

The fibrates are another class of antihyperlipidemic drug and are frequently coadministered with a statin. Fibrates act as agonists of the peroxisome proliferator-activated receptors (PPAR), particularly PPAR-a. PPARs are nuclear receptors that influence gene expression and lipid metabolism. Examples of fibrates include gemfibrozil (Lopid, A.110) and fenofibrate (Tricor, A.lll) (Figure A.30). Fenofibrate is hydrolyzed in the body to its active form, fenofibric acid (A.112). Fibrates do not decrease LDL levels as effectively as statins, but fibrates do elevate HDL cholesterol levels. 

Vanden Heuvel JP, Kreder D, Belda B, Hannon DB, Nugent CA, Burns KA, Taylor MJ. Comprehensive analysis of gene expression in rat and human hepatoma cells exposed to the peroxisome proliferator WY14, 643. Toxicol Appl Pharmacol 2003 188 185-198. 

Hasmall SC, James NH, Macdonald N, et al. 2000. Species differences in response to diethylhexylphthalate suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression. Arch Toxicol 74 85-91. 

Kliewer, S. A., Sundseth, S. S., Jones, S. A., Brown, P J., Wisely, G. B., Koble, C. S., Devchand, P., Wahli, W., Willson, T. M., Lenhard, J. M., and Lehmann,J. M. (1997). Fatty Acids and Eicosanoids Regulate Gene Expression Through Direct Interactions with Peroxisome Proliferator-Activated Receptors Alpha and Gamma. Proc. Natl. Acad. Sci. U.S.A. 94, 4318-4323. 

Marx, N., Schonbeck, U., Lazar, M. A., Libby, R, and Plutsky, J. (1998). Peroxisome Proliferator-Activated Receptor Gamma Activators Inhibit Gene Expression and Migration in Human Vascular Smooth Muscle Cells. Circ. Res. 83, 1097-1103. 

Burris TP, Pelton PD, Zhou L, et al. A novel method for analysis of nuclear receptor function at natural promoters peroxisome proliferator-activated receptor y agonist actions on a P2 gene expression detected using branched DNA messenger RNA quantitation. Mol Endocrinol 1999 13 410—417. 

Sugawara, A., Takeuchi, K., Uruno, A., et al. 2001. Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells. Endocrinology 142 3125-3134. 

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