Discovery of analogues of non-β oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism.

Background And Aims: Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications.

Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH.

Background And Aims: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) can advance, if untreated, to liver fibrosis, cirrhosis, hepatocellular carcinoma, liver failure and liver-related death. In the United States, NASH affects approximately 2-5% of the population and an additional 10-30% have NAFLD. The number of drugs in development for NASH is growing steadily, along with nonclinical models to support prediction of clinical success.

Comparative Evaluation of Gemcabene and Peroxisome Proliferator-Activated Receptor Ligands in Transcriptional Assays of Peroxisome Proliferator-Activated Receptors: Implication for the Treatment of Hyperlipidemia and Cardiovascular Disease.

Gemcabene, a late-stage clinical candidate, has shown efficacy for LDL-C, non-HDL cholesterol, apoB, triglycerides, and hsCRP reduction, all risk factors for cardiovascular disease. In rodents, gemcabene showed changes in targets, including apoC-III, apoA-I, peroxisomal enzymes, considered regulated through peroxisome proliferator-activated receptor (PPAR) gene activation, suggesting a PPAR-mediated mechanism of action for the observed hypolipidemic effects observed in rodents and humans. In the current study, the gemcabene agonist activity against PPAR subtypes of human, rat, and mouse were compared with known lipid lowering PPAR activators.

P2Y13 receptor regulates HDL metabolism and atherosclerosis in vivo.

High-density lipoprotein (HDL) is known to protect against atherosclerosis by promoting the reverse cholesterol transport. A new pathway for the regulation of HDL-cholesterol (HDL-c) removal involving F1-ATPase and P2Y13 receptor (P2Y13R) was described in vitro, and recently in mice. However, the physiological role of F1-ATPase/P2Y13R pathway in the modulation of vascular pathology i.