Chen Xiaoli, Matthews Jay, Zhou Lubing, Pelton Patricia, Liang Yin, Xu Jun, Yang Maria, Cryan Ellen, Rybczynski Philip, Demarest Keith
Endocrine Therapeutics and Metabolic Disorders, Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, PA, USA.
Metabolism. 2008 Nov;57(11):1516-25. doi: 10.1016/j.metabol.2008.06.005.
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPARalpha agonist that activated both human and rat PPARalpha receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid beta-oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPARalpha-mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPARalpha transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPARalpha agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.
过氧化物酶体增殖物激活受体α（PPARα）是配体激活转录因子核受体家族的成员。它在参与脂质代谢和转运的基因调控中发挥重要作用。化合物A是一种强效且口服活性的PPARα激动剂，可激活人和大鼠的PPARα受体。该化合物在啮齿动物肝癌细胞系和db/db小鼠肝脏中诱导了参与脂肪酸代谢的基因表达。在人肝细胞和人骨骼肌细胞中证实了化合物A刺激脂肪酸β氧化的能力，这证实了PPARα介导的活性的功能性激活。与非诺贝特相比，在动脉粥样硬化大鼠和db/db小鼠模型中，化合物A被证明是一种更有效且更高效的抗血脂异常药物。在人PPARα转基因小鼠中，化合物A使高密度脂蛋白胆固醇水平升高至少部分归因于血清载脂蛋白A-I蛋白浓度的增加。在更高等的肥胖犬模型中进一步证实了其降低甘油三酯的作用。此外，化合物A剂量依赖性地改善了db/db小鼠的高血糖和高胰岛素血症，并改善了葡萄糖耐量。在饮食诱导的肥胖小鼠模型中，化合物A主要通过增加能量消耗和减少脂肪沉积来降低体重。总之，这种新型强效PPARα激动剂在动物模型中改善了脂质谱、胰岛素敏感性和能量平衡。
