Molecular Characterization of Novel and Selective Peroxisome Proliferator-Activated Receptor α Agonists with Robust Hypolipidemic Activity in Vivo

Abstract

The nuclear receptor peroxisome proliferator-activated receptor ␣ (PPAR␣) 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 PPAR␣ agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPAR␣ 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 PPAR␣ agonists were assessed by transcriptional profiling of mouse liver after short-and long-term treatment. The induction of several known PPAR␣ target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPAR␣ 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 PPAR␣ agonist is realized.Coronary heart disease (CHD) is the single leading cause of death in the United States, representing one of every five fatalities during (Rosamond et al., 2007. Elevated serum triglycerides are an independent risk factor for CHD irrespective of HDL cholesterol (Hokanson and Austin, 1996). The fibric acid derivatives (fibrates) represent one therapeutic option for the treatment of dyslipidemia in that they display robust triglyceride lowering with modest HDL elevation. Significant effort has been put forth in the development of pharmacologic agents that demonstrate clear superiority over the first generation fibrates for the treatment of dyslipidemia and CHD.The fibrates can directly bind and activate a subclass of the nuclear receptor superfamily know as the peroxisome proliferator-activated receptors (PPARs). The PPARs are liganddependent transcription factors that are classified as three subtypes known as PPAR␣, PPAR␤ (␦), and PPAR␥. The PPARs are recognized as major regulators of systemic energy metabolism, in part by controlling the expression of numerous genes involved in lipid and glucose metabolism (Desvergne and Wahli, 1999;Huss and Kelly, 2004).

PPARα (Peroxisome Proliferator-activated Receptor α) Activation Reduces Hepatic CEACAM1 Protein Expression to Regulate Fatty Acid Oxidation during Fasting-refeeding Transition

“…Further studies are needed to delineate the mechanisms and identify co-repressors/co-regulators of Ceacam1 expression by Ppar␣, but ChIP analysis suggests that liganded Ppar␣ directly regulates Ceacam1 expression. Moreover, our observations are consistent with the reported decrease of Ceacam1 mRNA in mice treated with Ppar␣-selective piperidine agonists that are potent Ppar␣ activators (30). Although Ppar␣ is more commonly known to increase expression of genes, such as those involved in fatty acid catabolism, it has also been shown to repress the expression of many liver-specific genes involved in glucose metabolism, cell adhesion, the CYP2C family of steroid hydroxylases, and positive acute-phase response genes induced during inflammation (30,31).…”

PPAR-α as a Key Nutritional and Environmental Sensor for Metabolic Adaptation

“…The piperidine synthetic agonists bind to PPAR-a very strongly with K i values of 74 nM for CP-865529, 24.5 nM for CP-775146, and 10.8 nM for CP-868388. These compounds have been very useful in acute preclinical models for treating dyslipidemia (40).…”

The PPAR-RXR Transcriptional Complex in the Vasculature

“…149 Attempts have also been made to identify novel PPAR␣ agonists. 150 At least one PPAR␣ agonist LY518674, with a PPAR␣ binding as much as 10 000 times greater than the existing fibrates, was tested and abandoned. 151 No PPAR␦ agonist has ever reached approval although PPAR␦-mediated increases in HDL remain appealing.…”