PPARa

In 1990, a reeeptor that mediates the effects of PPs, the peroxisome proliferator activated reeeptor alpha, PPARa, was identified in motrse liver. The isolation of htrman PPARa arrd other isoforms of PPAR (P and y) both from roderrts and humans followed on rapidly. In rats and mice, PPARa is highly expressed in the liver, whereas other forms such as PPARy are expressed predominantly in fatty adipose tissue and in the immune system. This tis-sue-specifie pattern of expression implies a differerrt ftmetion for the PPAR isoforms both in normal tissue homeostasis and in resportse to dmgs and toxicants. 

Health and Safety Issues with Plasticizers and Plasticized Materials 

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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. 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

PPARa NR1C1 Fatty acids, leukotriene B4, fibrates... 

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

Tissue-Specific Expression. In adult rodents, PPAR.a is expressed in liver, kidney, intestine, heart, skeletal muscle, retina, adrenal gland, and pancreas. In adult human, PPARa is expressed in the liver, heart, kidney, large intestine, skeletal muscle (mostly slow-twitch oxidative type I fibers), and in cells of atherosclerotic lesions (endothelial cells, smooth muscle cells, and monocytes/macrophages). Therefore, regardless of... 

Insight from the PPARa Knockout Mouse. PPARa-deficient adult mice are viable, fertile, and healthy, indicating that PPARa is not essential for embryonic development. When adult PPARa-7- mice are treated with fibrates, the characteristic response to PP is abolished, with no liver weight increase, no increase in... 

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

Tissue-Specific Expression. In the adult rat, PPAR8 is expressed in all tissues examined, and often at levels higher than PPARa and PPARy. In human, PPAR8 is ubiquitously expressed, with higher expression in the digestive tract and placenta. 

The expression of all three PPAR isotypes peaks in the rat central nervous system between days 13.5-18.5 of gestation, and while expression of both PPARa and PPARy decline post-natally, expression of PPARS remains high (except for the retina, where all three isoforms are expressed in the adult rodent). An important role for PPARS in CNS development is underscored by the occurrence of defective myelination in the PPARS-null mouse. 

PPARa Liver, heart, skeletal muscle, atherosclerotic lesions TG- and LDL-C-lowering and HDL-C-raising re-directs excess cholesterol from the peripheral tissues to the liver for excretion into the bile via HDL-C slowed progression of atherosclerosis Fatty acids, eico-sanoids (fatty acids derived from FAS ) Fibrates fenofibrate (Tricor ), genfibrozil (Lopid ) Dyslipidemia... 

Lefebvre P, Chinetti G, Fruchart J-C et al (2006) Sorting out the roles of PPARa in energy metabolism and vascular homeostasis. J Clin Invest 116 571-580... 

Peroxisome PPARa RXR(DRI) Fatty acids Peroxisome proliferation... 

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. 

Vohl MC, Lepage P, Gaudet D, Brewer CG, Betard C, Perron P, et al. Molecular scanning of the human PPARa gene. Association of the 1162v mutation with hyperapobetalipoproteinemia. J Lipid Res 2000 41 945-952. 

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]. 

The search for more potent, selective and safe PPARa agonists has been challenging and only a limited number of compounds have progressed into the clinic. A number of phenoxyacetic acid derivatives and other diverse structures have emerged recently. Oral administration of LY-518674 (6) produced a 208% elevation in HDL and a 96% decrease in serum TG in apoA-I transgenic mice [38,39]. Recent clinical studies with compound 6 revealed a decrease in TG and an increase in HDL similar to fenofibrate. However, compound 6 also raised LDL-C in a dose-dependent fashion, and to a much higher level than seen with fenofibrate [28]. Both agents also raised serum creatinine levels above the upper limits of normal in 35-38% of patients [28]. 

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 GR HNF4a 4A 2B6, 2C9, 3A4, 3A5 2A6, 2B6, 2C9, 2D6, 3 A, 7A1 Fatty add metabolism regulation I m munore sponse regulation Carbohydrate, lipid, protein and... 

PPARa Peroxisome proliferators-activated receptor type alpha... 

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