PPAR-y

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... 

Current evidence suggests that PPAR activation may limit inflammation and hence atherosclerosis. Both PPAR-a and PPAR-y can reduce T-cell activation, as shown by decreased production of EFN-y. PPAR-a agonists also rqness endothelial VCAM-1 expression and inhibit the inflammatory activation of vascular SMCs, while PPAR-y agonists repress endothelial chemokine expression and decrease macrophage MMP production. 

A peroxisome proliferator-activated receptor (PPAR) binding site was identified in the murine FATP1 promoter. Several reports have shown a positive regulation of mouse FATPs by ligands that activate PPAR-a, PPAR-y, or PPAR-y/RXR heterodimers. 

NSAID use is also implicated in disease flares in patients with UC. NSAIDs may affect production of both nuclear factor kP and peroxisome proliferator activated receptors (e.g., PPAR-y), both of which are involved in regulating the intestinal responses.11... 

Thiazolidinediones are known to increase insulin sensitivity by stimulating peroxisome proliferator-activated receptor gamma (PPAR-y). Stimulation of PPAR-y results in a number of intracellular and extracellular changes, including an increased number of insulin receptors, increased insulin receptor sensitivity, decreased plasma fatty acid levels, and an increase in a host of intracellular signaling proteins that enhance glucose uptake. 

Barroso I et al. Dominant negative mutations in human PPAR-y associated with severe insulin resistance, diabetes melli-tus and hypertension. Nature 1999 402 880-883. 

These agents activate PPAR-y a nuclear transcription factor important in fat cell differentiation and fatty acid metabolism. PPAR-yagonists enhance insulin sensitivity in muscle, liver, and fat tissues indirectly. Insulin must be present in significant quantities for these actions to occur. 

Burgermeister, E., Schnoebelen, A., Flament, A., Benz, J., Stihle, M., Gsell, B., Rufer, A., Ruf, A., Kuhn, B., Marki, H. P., Mizrahi, J., Sebokova, E., et al. (2006). A novel agonist of peroxiome proliferator-activated receptor-y (PPAR y) recruits PPAR y-coactivator-la, prevents triglyceride accumulation, and potentiates insuling signalling in vitro. Mol. Endocrinol. 20, 809-830. 

Ajulemic acid (77) Cannabinoid CP 7075 (IP 751, ajulemic acid, CT-3) (synthetic version) Neurological (neuropathic pain) Suppresses IL-lp and mahix metalloproteinases (MMPs) through a peroxisome proliferator-activated receptor (PPAR) y-mediated mechanism Phase I Cervelo Pharmaceuticals 615-618... 

C) Thiazolidinediones bind a nuclear receptor in tissue termed PPAR-y, which augments the expression of insulin-regulated genes. 

Netoglitazone is an insulin sensitizer currently in Phase II clinical trials. It is able to modulate both PPAR-a and PPAR-y subtypes of peroxisome proliferator-activated receptor (Phase ll). Metaglidasen (MBX-102) is the (—)-enantiomer of the NSAID halofenate. This selective PPAR-y nuclear receptor agonist is being evaluated (Phase II) as an insulin sensitizer. It is structurally different from the currently marketed glitazones (Figure 8.84). ... 

Hypolipoproteinemia is likely to be a rare adverse effect. The measurement of HDL cholesterol and triglycerides before and after staring thiazolidinedione therapy will allow its detection. On withdrawing therapy concentrations return to normal. This effect may be specific to rosiglitazone, as it is becoming apparent that the PPAR-y agonists vary in their effects. 

Recent studies revealed that resveratrol protects from inflammation by acting at different phases of inflammation. Protection at the pro-inflammatory phase appears to be very important for reducing inflammation effectively and promptly. A recent study [Ge et al., 2006] showed that resveratrol inhibits macrophage expression of EMMPRIN by activating PPAR-y. In another similar study, Ma et al., [2006] showed a similar observation, but additionally found a role of nuclear transcription factor kB (NF-kB) in macrophage inhibition. Numerous studies confirmed that resveratrol suppresses the TNF-a... 

Thiazolidinediones stimulate certain peroxisome proliferator-activatedreceptors (PPAR-y). PPAR-y is a nuclear receptor and, through a series of events, increases cellular production of insulin-dependent enzymes. This is an example of upregulation. The cell is then more sensitive to the decreased insulin levels found in a person with type 2 diabetes. The two thiazolidinediones currently on the market are rosiglitazone (Avandia, A.73) and... 

Insulin resistance rosiglitazone is an insulin sensitizer that targets PPAR-y. 

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. 

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