Peroxisome PPARy

Antidiabetic Drugs other than Insulin. Table 2 Tissue expression, ligands, genes activated, and biological actions of the peroxisome proliterator-activated receptor-y (PPARy)... 

Thiazolidinediones (PPARy-agonists) Thiazolidine-diones ( pioglitazone, rosiglitazone) lower blood glucose levels in animal models of insulin resistance and also in insulin resistant patients. They are agonists of the peroxisome proliferator-activated receptor y (PPARy). Because they enhance the effect of insulin and reduce serum insulin levels in insulin resistant patients, thiazolidinediones are usually referred to as insulin sensitizers . 

Thiazolidinediones (synonyms glitazones, insulin sensitizers rosiglitazone, pioglitazone) are a novel class of oral antidiabetic drugs that activate the transcription factor peroxisome proliferator-activated receptor (PPARy). Thiazolidinediones ameliorate insulin resistance in obese animal models and in individuals... 

Finally, it has to be mentioned that LPA also has an intracellular target site, which is the nuclear transcription factor, peroxisome proliferator-activated receptor-y (PPARy). LPA competes for thiazolidinedione binding and activates PPARy-dependent gene transcription. Thereby, LPA induced neointima formation in a rat carotid artery model. 

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... 

Peroxisome Proliferator-Activated Receptors. Table 2 PPARy target tissues, cellular effects, and physiological effects... 

Peptide deformylase inhibitors, 44 (2006) 109 Peroxisome proliferator-acrtvated receptor gamma (PPARy) ligands, 42 (2004) 1 Pharmacology of Alzheimer s disease,... 

TF transcription factor, R receptor, Fur ferric uptake regulation protein, NF-kB nuclear factor-kB, AP-1 activator protein-1, Egr-1 early growth response-1, VDR la,25-dihydroxy-vitamin D3 receptor, RXR retinoid X receptor, PPARy peroxisome proliferator-activated receptor y NFAT nuclear factor of activated T-cells, HSF heat shock factor, p53 tumor suppressor p53, HIF-1 hypoxia inducible factor-1. ... 

Han, K. L., Jung, M. H., Sohn, J. H., and Hwang, J.-K. (2006). Ginsenoside 20(S)-protopanax-atriol (PPT) activates peroxisome proliferator-activated receptor y (PPARy) in 3T3-L1 adipocytes. Biol. Pharm. Bull. 29,110-113. 

The farnesoid X receptor is a member of the class of nuclear hormone receptors, which have key roles in development and homeostasis, as well as in many diseases like obesity, diabetes and cancer. The farnesoid X receptor shows structural similarity to the estrogen receptor (ER ), which mediates a broad spectrum of physiological functions such as regulation of reproduction, modulation of bone density, cholesterol transport and breast cancer. The farnesoid X receptor also shows similarity with the peroxisome proliferation-activated receptor y (PPARy), which is involved in fat metabolism, inflammatory and immune responses. The estrogen receptor (ER ), the peroxisome proliferation-activated receptor y (PPARy) and the farnesoid X receptor (FXR) can be clustered in a... 

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. 

Induction of peroxisome proliferation following treatment with DEHP is not due to the parent compound, but to DEHP metabolites. Studies with MEHP in vitro have demonstrated that the proximate peroxisome proliferators are mono(2-ethyl-5-oxohexyl) phthalate (metabolite VI) and mono(2-ethyl-5-hydroxyhexyl) phthalate, (metabolite IX) and that for 2-ethylhexanol, the proximate proliferator is 2-ethylhexanoic acid (Elcombe and Mitchell 1986 Mitchell et al. 1985a). Similar findings were observed by Maloney and Waxman (1999), who showed that MEHP (but not DEHP) activated mouse and human PPARa and PPARy, while 2-ethylhexanoic acid activated mouse and human PPARa only, and at much higher concentrations. Based on its potency to induce enzyme activities, such as the peroxisomal fatty acid (3-oxidation cycle and carnitine acetyltransferase, DEHP might be considered a relatively weak proliferator. 

Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A. et al. (1995). An Antidiabetic Thi-azolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-Activated Receptor y (PPARy). /. Biol. Chem. 270, 12953-12956. 

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