Peroxisome proliferator activator receptor-a

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],... 

Lee, H., Gonzalez, F. J., and Yoon, M. (2006a). Ginsenoside Rf, a component of ginseng, regulates lipoprotein metabolism through peroxisome proliferator-activated receptor a. Biochem. Biophys. Res. Commun. 339,196-203. 

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)... 

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... 

Ward, J.M., Peters, J.M., Perella, C.M. Gonzalez, F.J. (1998) Receptor and nonreceptor-mediated organ-specific toxicity of di(2-ethylhexyl)phthalate (DEHP) in peroxisome proliferator-activated receptor a-null mice. Toxicol. Pathol., 26, 240-246 Weghorst, C.M., Devor, D.E., Henneman, J.R. Ward, J.M. (1993/94) Promotion of hepatocellular foci and adenomas by di(2-ethylhexyl) phthalate and phenobarbital in C3H/HeNCr mice following exposure to N-nitrosodiethylamine at 15 days of age. Exp. Toxicol. Pathol, 45, 423-431... 

Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-a, which modulates the expression of several proteins. LPL, lipoprotein lipase VLDL, very-low-density lipoproteins. 

Diep, Q. N., Touyz, R. M., and Schiffrin, E. L. (2000). Docosahexaenoic acid, a peroxisome proliferator-activated receptors-a ligand induces apoptosis in vascular smooth muscle cells by stimulation of p38 mitogen-activated protein kinase. Hypertension 36, 851-855. 

Morimura K, Cheung C, Ward JM, et al. Differential susceptibility of mice humanised for peroxisome proliferator-activated receptor a to Wy-14643 induced liver tumorigenesis. Carcinogenesis 2005 27 1074-1080. 

Possible mechanisms of fenofibrate-induced liver injury include activation of peroxisome proliferation-activator receptors, a hypersensitivity reaction, and immune -mediated injury from cross-reactivity of the drug with autoantigens. The authors referred to six reported cases of hepatic fibrosis attributed to fenofibrate. Raised transaminase activities occur commonly with fenofibrate but are generally transient, reverse on withdrawal, and do not result in long-term injury. Fenofibrate should be withdrawn if higher than normal enzyme activities persist, and a liver biopsy should be considered if liver enzymes do not normalize after withdrawal. 

Abbreviations. AhR, aromatic hydrocarbon receptor TCDD, tetrachlorodibenzodioxin PXR, pregnenolone-16a-nitrile-X-receptor PCN, pregnenolone-16a-nitrile CAR, constitutive androstane receptor MC, methylcholanthrene PPARa, peroxisome proliferated-activated receptor-a FXR, famesoid-X-receptor LXR, liver-X-receptor RXR, retinod-X-receptor 5-HETE, 5-OH-eicosatetraenoic acid LTB4, leukotriene B4 13-HODE, hydroxyoctadecadienoic acid DMXAA, dimethylxan-thenone-4-acetic acid. 

Feingold and his coworkers demonstrated an important role of nuclear hormone receptor on epidermal differentiation and stratum corneum barrier formation. Activation ofPPARa Peroxisome proliferator-activated receptor a by farnesol also stimulated the differentiation of epidermal keratinocytes.42 Cornified envelope formation, involcrin, and transglutaminase protein, and mRNA levels were also increased by the activation of PPARo . Interestingly, the inflammatory response was also inhibited by the treatment.43 They also showed that topical application of PPARo activators accelerated the barrier recovery after tape stripping or acetone treatment and prevented the epidermal hyperplasia induced by repeated barrier disruption.42 Regulation of the nuclear hormone receptor would open a new possibility for improvement of the cutaneous barrier. 

Vega R, Fluss J, Kelly D. the coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor a in transcriptional of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 2000 20 1868-1876. 

Yu S, Cao W-Q, Kashireddy P, et al. (2001) Human peroxisome proliferator-activated receptor a (PPARa) supports the induction of peroxisome proliferation in PPARa-deficient mouse liver. The Journal of Biological Chemistry 45 42485 2491. 

Lewis DFV, Jacobs MN, Dickins M, Lake BG. Molecular modelling of the peroxisome proliferator-activated receptor a (PPARa) from human, rat and mouse, based on homology with the human PPARr crystal structure. Toxicology 2002 176 51-7. 

Cherkaoui-Malki, M., K. Meyer, W.-Q. Cao, N. Latruffe, A.V. Yeldandi, M.S. Rao, C.A. Bradfield and J.K. Reddy. Identification of novel peroxisome proliferator-activated receptor a (PPARa) target genes in mouse liver using cDNA microarray analysis. Gene Express. 9 291-304, 2001. 

Gonzalez, F.J., J.M. Peters and R.C. Cattley. Mechanism of action of the nongenotoxic peroxisome proliferators role of the peroxisome proliferator-activated receptor a. J. Natl Cancer Inst. 90 1702-1709, 1998. 

Reddy, J.K. and T. Hashimoto. Peroxisomal /3-oxidation and peroxisome proliferator-activated receptor a an adaptive metabolic system. Annu. Rev. Nutr. 21 193-230, 2001. 

Henke, B. Peroxisome proliferator-activated receptor a/ y dual agonists for the treatment of type 2 diabetes. J. Med. Chem. 2004, 47, 4118 127. 

A peroxisome proliferator-activated receptor a/y dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia. Molecular Endocrinology, 19, 1593-1605. 

Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl] methyljglycine [muraglitazar/BMS-298585], a movel peroxisome proliferator-activated receptor a/y dual agonist with efficacious glucose and lipid-lowering activities. Journal of Medicinal Chemistry, 48, 2248-2250. 

Etgen, G.J., Oldham, B.A., Johnson, W.T. et al. (2002) A tailored therapy for the metabolic syndrome the dual peroxisome proliferator-activate receptor-a/y agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in predinical models. Diabetes, 51, 1083-1087. 

Karbowska, J., Kochan, Z. and Smolenski, R.T. (2003) Peroxisome proliferator-activated receptor a is dowmegulated in the failing human heart. Cellular Molecular Biology Letters, 8,49-53. 

Golz, S., Hiitter, J. and Schafer, S. (2006) Activation of peroxisome proliferator-activated receptor-a (PPARa) ameliorates post myocardial infarction heart failure in the rat prevention of cardiac remodeling. European Heart Journal, 27 (Suppl 1),... 

Drew, B.G. and Calkin, A.C. (2007) Drug evaluation K-lll, an insulin-sensitizing peroxisome proliferators activated receptor a agonist. Current Opinion in Investigational Drugs, 8, 324—330. 

Lemberger, T., Desvergne, B., and Wahli, W. (1996) Peroxisome proliferator-activated receptors a nuclear receptor signaling pathway in lipid physiology. Annu. Rev. Cell Dev. Biol. 12, 335-363. 

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