Molecular characterization of novel and selective peroxisome proliferator-activated receptor alpha agonists with robust hypolipidemic activity in vivo.

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after short- and long-term treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the down-regulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism, suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Whereas these compounds are efficacious in acute preclinical models, extended safety studies and further clinical testing will be required before the full therapeutic promise of a selective PPARalpha agonist is realized.

A critical role for peroxisomal proliferator-activated receptor-alpha nuclear receptors in the development of cardiomyocyte degeneration and necrosis.

Peroxisomal proliferator-activated receptor (PPAR)-alpha is a ligand-activated transcriptional factor that regulates genes involved in lipid metabolism and energy homeostasis. PPAR-alpha activators, including fibrates, have been used to treat dyslipidemia for several decades. In contrast to their known effects on lipids, the pharmacological consequences of PPAR-alpha activation on cardiac metabolism and function are not well understood. Therefore, we evaluated the role that PPAR-alpha receptors play in the heart. Our studies demonstrate that activation of PPAR-alpha receptors using a selective PPAR-alpha ligand results in cardiomyocyte necrosis in mice. Studies in PPAR-alpha-deficient mice demonstrated that cardiomyocyte necrosis is a consequence of the activation of PPAR-alpha receptors. Cardiac fatty acyl-CoA oxidase mRNA levels increased at doses in which cardiac damage was observed and temporally preceded cardiomyocyte degeneration, suggesting that peroxisomal beta-oxidation correlates with the appearance of microscopic injury and cardiac injury biomarkers. Increased myocardial oxidative stress was evident in mice treated with the PPAR-alpha agonists coinciding with increased peroxisomal biomarkers of fatty acid oxidation. These findings suggest that activation of PPAR-alpha leads to increased cardiac fatty acid oxidation and subsequent accumulation of oxidative stress intermediates resulting in cardiomyocyte necrosis.