Peroxisome proliferator-activated receptor action mechanisms

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. 

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.)...

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. 

Peters, J. M., Rusyn, I., Rose, M. L., Gonzalez, F. J., and Thurman, R. G. (2000). Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells implications for the mechanism of action of peroxisome proliferators in hepatocardnc enesis. Carcinogenesis 21, 823-826. 

Gervois, P., Fruchart, J. C., and Staels, B. Drug Insight mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nat Clin Pract Endocrinol Metab 3 (2007) 145-156. 

Overall, fibrates decrease plasma triglyceride levels much more dramatically than they decrease plasma cholesterol levels. They significantly decrease VLDL levels, cause a moderate Increase In HDL levels, and have variable effects on LDL concentrations. As an example of this latter point, gemfibrozil will raise LDL levels In patients with hypertriglyceridemia but lower LDL levels in patients with normal triglyceride levels. The exact mechanisms for these actions have not been fully elucidated however, studies have shown that this class of compounds can produce a variety of beneficial effects on lipoprotein metabolism. Many of these effects have been proposed to be mediated through the activation of peroxisome proliferator-activated receptors (PPARs) and an alteration of gene expression. Specifically, fibrates bind to PPARa (7,15,27,44). 

Fig. 5.3. Schematic model of the mechanism of formation and action of J-series prostaglandins (PGJ) in the activation of nuclear peroxisome proliferator-activated receptor-y (PPARy).

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