Peroxisome proliferator activated receptor PPARa

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)... 

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... 

Tugwood, J.D., Holden, P.R., James, N.H., Prince, R.A. Roberts, R.A. (1998) A peroxisome proliferator-activated receptor-alpha (PPARa) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARa implications for species differences in responses to peroxisome proliferators. Arch. Toxicol., 72, 169-177 Turner, J.H., Petricciani, J.C., Crouch, M.L. Wenger, S. (1974) An evaluation of the effects of diethylhexyl phthalate (DEHP) on mitotically capable cells in blood packs. Transfusion, 14, 560-566... 

Research has now established that the peroxisome proliferators act on a receptor, called the peroxisome proliferator-activated receptor (PPAR), discovered in 1990. There are now known to be three receptors PPARa, PPARS, and PPARy. These are parts of the nuclear hormone super family. The PPARs are ligand-dependent transcription factors, which have different functions and tissue locations. 

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. 

A GRID/CPCA analysis of the three subtypes of Peroxisome Proliferator-Activated Receptors (PPARs) vas reported by Pirard [18] using three PPARa, eight PPARy, and three PPARd X-ray structures of the ligand binding domain (LED). 

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. 

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