The Peroxisome Proliferator Activated Receptor

The thiazolidinediones have also been reported to act as inhibitors of the respiratory chain at high concentrations, and this appears to account for their ability to activate AMGPK in cultured cells. However, the primary target of the thiazolidinediones appears to be the peroxisome proliferator-activated receptor-y ( PPAR-y), a member of the nuclear receptor superfamily expressed in adipocytes. One of the major effects of stimulation of PPAR-y in adipocytes is the release ofthe... 

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 . 

Di- and mono-esters of phthalic acid, an ortho-dicarboxylic acid derivative of benzene. These compounds are widely used as industrial plasticizers to coat polyvinylchloride surfaces of plastics used in food packaging and medical devices (iv drip bags, blood storage bags, etc.) and are common environmental contaminants. Several phthalate mono-esters are peroxisome proliferator chemicals and can activate the peroxisome proliferator-activated receptor PPAR. 

Both MOZ and MORF have also been linked to control of transcription. In initial analyses, these MYST HATs were found to contain potent trans-activation domains in their C-termini (Champagne et al, 1999 2001). Follow-up studies demonstrated that the two proteins can indeed function as transcriptional co-activators for two Runt-domain transcription factors - Runxl and 2 (also referred to as AMLl 3) (Kitabayashi et al., 2001a Pelletier et al., 2002). Furthermore, MORF has been found in the co-activator complex associated with the peroxisome proliferator-activated receptor alpha in rat liver (Surapureddi et al., 2002). 

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... 

The 3,4-dihydro-22/-l,3-benzoxazin-4-one derivative DRF-2519 587, bearing a 2,4-thiazolidinedione moiety in the side chain attached to the nitrogen atom, proved to be an activator of the a- and y-types of the peroxisome proliferator-activated receptors (PPAR-a and -7), which endowed it with antidiabetic and hypolipidemic potential. Compound 587 demonstrated significant plasma glucose-, insulin-, and lipid-lowering activity in mice and improvement in lipid parameters in fat-fed rats <2006BMC584>. 

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... 

Miyata, K.S., McCaw, S.E., Patel, H.V., Rachubinski, R.A. Capone, J.P. (1996) The orphan nuclear hormone receptor LXR a interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling. J. biol. Chem., 271, 9189-9192... 

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. 

Proteins in a family of ligand-activated transcription factors, the peroxisome proliferator-activated receptors (PPARs), respond to changes in dietary lipid by... 

The exact mechanism of these drugs is unclear, but they probably work by binding to a specific nuclear receptor known as the peroxisome proliferator activated receptor.52,141 This receptor, found primarily in the liver and adipose tissues, affects the transcription of genes that affect lipid metabolism.89 Fibrates activate this receptor, thereby mediating several changes at the nuclear level that ultimately cause a decrease in triglycerides and other beneficial changes in plasma lipid metabolism.30,52 In a manner similar to the statins, fibrates may also exert anti-inflammatory, antioxidant, and other beneficial effects in addition to their positive effects on plasma lipids.42,49... 

Lemberger T, Saladin R, Vazquez M, et al. Expression of the peroxisome proliferator-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J Biol Chem 1996 271 1764-1769. 

The fibrates are another class of antihyperlipidemic drug and are frequently coadministered with a statin. Fibrates act as agonists of the peroxisome proliferator-activated receptors (PPAR), particularly PPAR-a. PPARs are nuclear receptors that influence gene expression and lipid metabolism. Examples of fibrates include gemfibrozil (Lopid, A.110) and fenofibrate (Tricor, A.lll) (Figure A.30). Fenofibrate is hydrolyzed in the body to its active form, fenofibric acid (A.112). Fibrates do not decrease LDL levels as effectively as statins, but fibrates do elevate HDL cholesterol levels. 

In this study, the peroxisome proliferator-activated receptor... 

While the thiazolidindiones enhance insulin-mediated glucose transport via binding to the peroxisome proliferator-activating receptor (PPAR-y), the presence of this receptor in vascular smooth muscle cells, inflammatory cells, and endothelial cells likely facilitates the drug s ability to inhibit vascular smooth muscle cell proliferation, reduce inflammation, improve dyslipidemia, and, by extension, reduce in-stent restenosis. 

Park EY, Cho IJ, Kim SG. Transactivation of the PPAR-responsive enhancer module in chemopreventive glutathione S-transferase gene by the peroxisome proliferator-activated receptor-gamma and retinoid X receptor heterodimer. Cancer Res 2004 64 3701-3713. 

Cristiano, F., Bernardo, A., and Ceru, M. P. (2001). Peroxisome proliferator-activated receptors (PPARs) and peroxisomes in rat cortical and cerebellar astrocytes. J. Neurocytol. 30, 671—683. Cullingford, T. E., Bhakoo, K., Peuchen, S., Dolphin, C. T., Patel, R., and Clark, J. B. (1998). Distribution of mRNAs encoding the peroxisome proliferator-activated receptor alpha, beta, and gamma and the retinoid X receptor alpha, beta, and gamma in rat central nervous system. J. Neurochem. 70, 1366-1375. 

Cuzzocrea, S., Di Paloa, R., Mazzon, E., Genovese, T., Muia, C., Centorrino, T., and Caputi, A. P. (2004). Role of endogenous and exogenous ligands for the peroxisome proliferators activated receptors alpha (PPAR-alpha) in the development of inflammatory bowel disease in mice. Lab. Invest. 84, 1643-1654. 

Ricote, M., Li, A. C., Willson, T. M., Kelly, C.J., and Glass, C. K. (1998b). The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391, 79—82. 

Issemann I, Prince RA, Tugwood JD, et al. 1993. The peroxisome proliferator-activated receptor retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. J Mol Endocrinol 1137-47. 

Lee SST, Pineau T, Drago J, et al. 1995. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 15(6) 3012-3022. 

Zhu, Y., Alvares, K., Huang, Q., Rao, M. S., and Reddy, J. K. (1993). Cloning of a New Member of the Peroxisome Proliferator-Activated Receptor Gene Family from Mouse Liver./. Biol. Chem. 268, 26817-26820. 

---