Factors modulating fibrates response: therapeutic implications and alternative strategies.

Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates transcription of genes involved both in lipid and glucose metabolism as well as in inflammation. Fibrates are PPARalpha ligands used to normalize lipid and glucose parameters and exert antiinflammatory effects. In fact, fibrates have already been demonstrated to benefit metabolic syndrome, type 2 diabetes and cardiovascular diseases. This article reviews the mechanism of action and the functional roles of fibrates, emphasizing the factors modulating their capacity to activate PPARalpha and affecting their effectiveness. These factors may possibly explain the findings obtained in animal studies and clinical trials with fibrates which showed either untoward effects and/or inefficient hypolipidemic action of PPARalpha activation. We also discuss briefly the natural and synthetic agonists of PPARalphawhich are currently being developed and supposedly display greater effectiveness and fewer adverse effects than fibrates.