Abstract 13566: A Novel New Chemical Entity, Gemcabene, Shows Significant Lipid Regulation in PPAR-α Knock-out Mice, Supporting a Mechanism Independent of PPAR-α
Background: In vitro and cell-based assays with a lipid lowering agent, gemcabene (Gem), ruled out a direct activation of PPAR-α, although some PPAR-α target genes were modulated in vivo. Therefore, PPAR-α may not be required for the in vivo lipid lowering efficacy of Gem.
Experiment & Results: WT and PPAR-α KO mice were administered Gem (0.3%), Wy14643 (0.1%), a reference PPAR-α agonist, and a clinical lipid regulator, Gemfibrozil (0.3%) as diet admixtures for 8 days. PPAR-α KO mice exhibited a phenotype consistent with absence of PPAR-α, such as increased plasma triglycerides (TG), VLDL-C, LDL-C, HDL-C, and apoCIII. Hepatic apoCIII mRNA (negatively regulated by PPAR-α) showed upregulation in PPAR-α KO mice compared to WT. In WT mice, there was no change in liver to body weight ratio in the Gem-treated group, but a marked increase (212%) in the Wy14643-treated-group and marginal increase (22%) in gemfibrozil-treated mice. In WT, hepatomegaly was observed only in the Wy14643-treated group, which was associated with peroxisome proliferation, and a 20-fold increase in the PPAR-α target gene, acyl CoA oxidase (ACO). Absence of hepatomegaly in the Wy14643-treated PPAR-α KO mice and no change in ACO mRNA supported PPAR-α mediated effect of Wy14643. In WT, Gem and gemfibrozil showed a 3-fold increase in ACO mRNA. Gem lowered VLDL-C (-47%), LDL-C (-22%), and TG (-46%) in PPAR-α KO mice, suggesting a PPAR-α independent effect on circulating lipids. Wy14643 and Gem significantly reduced apoCIII by -39% and -24% in WT, and -20% and -16% in PPAR-α KO mice, respectively. ApoCIII mRNA was reduced -12% (NS) in Gem-treated and significantly by -46% in Wy14643-treated WT-mice. In KO mice, apoCIII mRNA was reduced by -8% (NS) by Gem and significantly by -20% by Wy14643. ApoCIII mRNA is a direct target of PPAR-α while plasma apoCIII level is influenced by several factors. Wy14643 induced hepatic LPL mRNA in WT, but not in PPAR-α KO mice. Interestingly, hepatic PPARγ expression showed increased level in the PPARα KO mice, suggesting the regulation of the two isoforms may be interdependent.
Conclusions: Taken together, these studies demonstrate that the lipid lowering efficacy of Gem occurs in a PPAR-α -independent manner in vivo.
Author Disclosures: C.L. Bisgaier: Employment; Significant; Gemphire Therapeutics Inc. Ownership Interest; Significant; Gemphire Therapeutics Inc. R. Srivastava: Ownership Interest; Significant; Gemphire Therapeutics Inc. Consultant/Advisory Board; Significant; Gemphire Therapeutics Inc.
- © 2015 by American Heart Association, Inc.