Abstract 261: Dissociation of Anti-inflammatory from Normolipemic Properties of PPARalpha
The nuclear receptor PPARα is a pharmacological target improving major atherogenic risk factors such as dyslipidemia and inflammation. PPARα normolipemic actions involve activation of lipid metabolism related genes via a DNA binding-dependent mechanism termed “transactivation”. Furthermore, PPARα controls inflammation by repressing the expression of inflammatory genes by a “transrepression” mechanism based on protein/protein interactions. The goal of this study is to determine the ill-defined relative contribution of anti-inflammatory from normolipemic actions of pharmacologically activated PPARαon atherogenesis. We propose a new concept: dissociation of anti-inflammatory from normolipemic effects of PPARα. Our strategy is based on the introduction of mutations in the DNA binding domain of PPARα in order to abolish transactivation without affecting transrepression. Ligand activation of PPARα mutants was investigated in vitro and in vivo under basal and inflammatory conditions. Gel retardation assays confirmed that PPARα mutants do not bind DNA. Transfection experiments demonstrated that PPARα mutants do not activate transcription of lipid metabolism PPARα target genes but still repress cytokine-stimulated transcription of inflammatory genes in human hepatoma cells. In addition, overexpression of PPARα mutants in hepatoma cells prevents the cytokine-stimulated expression of endogenous inflammatory responsive genes. Compared to PPARα, overexpression of PPARα mutants in PPARα-deficient mice treated with PPARα agonists does not restore their normolipemic effects but renders mice unresponsive to inflammatory cytokines. In conclusion, the integrity of the transrepression function of PPARα is unaffected by the impaired transactivation function both in vitro and in vivo. We validated in vivo the concept of dissociated anti-inflammatory from normolipemic properties of PPARα. It is conceivable that some PPARα agonists may be predominantly normolipemic whereas some others may be preferentially anti-inflammatory. Therefore, the development of a set of PPARα agonists aimed at exerting selective modulation of atherogenic risk factors becomes a rationale perspective.