Peroxisome proliferator-activated receptor mechanisms

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... 

Mechanism of Action Potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) which decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. 

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 Fenofibrate should be withdrawn if higher than normal enzyme activities persist, and a liver biopsy should be considered if liver enzymes do not normalize after withdrawal. 

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... 

Camacho IE, Semeels L, Spittaels K, Merchiers P, Dominguez D, De Strooper B (2004) Peroxisome-proliferator-activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide. J Neurosci 24 10908-10917. 

Figure 2 Basic mechanism of action of peroxisome proliferator-activated receptors. (Reproduced from Vanden Heuvel JP (1999) Toxicological Sciences 47 1-8, with permission from The Society of Toxicology.)...

Tan NS, Michalik L, Desvergne B, Wahli W. Multiple expression control mechanisms of peroxisome proliferator-activated receptors and their target genes. I Steroid Biochem Mol Biol 2005 93 99-105. 

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. 

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