PPARa receptor

In those species, which are responsive (i.e., have a functioning receptor) such as the rat, treatment with drugs, which interact with the PPARa receptor such as clofibrate, will cause a number of effects, such as induction of a number of enzymes, increased cell growth and turnover, and liver tumors in almost all the animals as a direct result of interaction with the receptor and changes in gene transcription. This will be discussed in more detail in chapter 7. 

It is now known that the effect is mediated by a receptor, the PPARa receptor. Transgenic mice lacking this receptor do not show either the effect of increased peroxisome number and liver size or the liver tumors. 

Refractory species such as guinea pig seem to have fewer PPARa receptors in the liver, and observations suggest there are significant differences between rodents and humans in a number of aspects of the response. Recent studies in cynomologous monkeys treated with ciprofibrate have detected peroxisomal proliferation but only found slight changes in certain parameters [e.g., messenger RNA (mRNA) induction for acyl CoA oxidase] of minimal oxidative stress, and despite hypertrophy, cell proliferation was not detected. 

Fibrates (such as clofibrate) are hypolipidemic drugs. They cause a number of biological and biochemical effects, including enzyme induction, peroxisomal proliferation, liver hypertrophy and hyperplasia, and liver cancer. The mechanism is believed to be mediated through the PPARa receptor. Animals lacking this receptor do not show these effects. 

Corticotropin-releasing factor (CRF) receptor modulators CRF antagonists may act on depression, various other neuropsychiatric disorders and immune diseases. PPARs, an essential group of nuclear receptors PPARa receptors are involved in dyslipemias, atherosclerosis and obesity PPARy receptors are mainly involved in diabetes but also in dyslipemias, hypertension, inflanunation and cancer PPARS receptors, in addition to dyslipemia control, are involved in fertility and cancer. ... 

The only major study on regulation is work by Johnson and his associates [180] in hnman hepatoma HepG2 cells. The gene is regulated by the PPARa receptor, which regulates some other subfamily 4A P450s. 

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes. Figure 1 General mechanism for transcriptional activation of CYP genes by xenochemicals that activate their cognate xeno-receptor proteins. In the case of Ah receptor, the receptor s heterodimerization partner is Arnt, whereas in the case of the nuclear receptors CAR, PXR, and PPARa, the heterodimerization partner is RXR. The coactivator and basal transcription factor complexes shown are each comprised of a large number of protein components. 

PPARs PPARa NR1C1 PPAR8 NR1C2, PPAR 3, NUC1, FAAR (fatty acid-activated receptor) PPARy NR1C3... 

Peroxisome Proliferator-Activated Receptors. Table 1 PPARa target tissues, cellular effects, and physiological effects... 

Peroxisome-proliferator activated receptors (PPARs) are lipid-activated transcription factors exerting several functions in development and metabolism. PPARa is implicated in the regulation of lipid metabolism, lipoprotein synthesis, and inflammatory response in liver and other tissues. 

Another group has evaluated self-organizing maps [63] and shape/ pharmacophore models [64]. They developed a new method termed SQUIRREL to compare molecules in terms of both shape and pharmacophore points. Thus from a commercial library of 199,272 compounds, 1926 were selected based on self-organizing maps trained on peroxisome proliferator-activated receptor a (PPARa) "activity islands." The compounds were further evaluated with SQUIRREL and 7 out of 21 molecules selected were found to be active in PPARa. Furthermore, a new virtual screening technique (PhAST) was developed based on representation of molecules as text strings that describe their pharmacophores [65]. 

In addition to PXR, the expression of UGT1A1 and several other UGT isoforms have also been reported to be regulated by several other nuclear receptors, including constitutive androstane receptor (CAR) [25,27,28] and peroxisome proliferator activated receptor a (PPARa) [29,30],... 

PPARa Peroxisome proliferators-activated receptor type alpha... 

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

Studies of peroxisome proliferator-activated receptor a (PPARa)... 

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. 

Aoyama, T., Peters, J.M., Iritani, N., Nakajima, T., Furihata, K., Hashimoto, T. Gonzalez, F.J. (1998) Altered constitutive expression of fatly acid-metabohzing enzymes in mice lacking the peroxisome proliferator-activated receptor a (PPARa). J. biol. Chem., 213, 5678-5684... 

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