College of Pharmacy Engineering Research Center for Medicine, Harbin University of Commerce, 150076, Harbin, China.
Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, 261053, Weifang, China.
Arch Pharm Res. 2020 Aug;43(8):788-797. doi: 10.1007/s12272-020-01255-w. Epub 2020 Aug 10.
LXRα agonists have attracted significant attention due to their potential biological activities on promoting cholesterol efflux. This study was designed to investigate whether setosphapyrone C and D have potential lipid-lowering capacity and the underlying mechanisms in vitro. Our data showed that setosphapyrone C and D had weak cytotoxicity compared to the liver X receptor α (LXRα) agonist T0901317. In RAW 264.7 macrophages, setosphapyrone C and D significantly enhanced [H]-cholesterol efflux by ~ 21.3% and 32.4%, respectively; furthermore, setosphapyrone C and D enhanced the protein levels of ATP-binding cassette transporter (ABC) A1 and LXRα by 58% and 69%, and 60% and 70% (8 µM), respectively; however, they had no effect on the protein levels of ABCG1 and scavenger receptor B type 1; additionally, they had minor effect on the mRNA expression of lipogenic genes. Of note, setosphapyrone C and D significantly enhanced LXRα/ABCA1pathway in mice primary macrophages. In BRL cells, setosphapyrone C and D significantly improved the protein levels of ABCA1 and ABCG1; setosphapyrone D significantly enhanced the protein expression of low-density lipoprotein. Collectively, setosphapyrone C and D with weak cytotoxicity exhibited effective lipid-lowering effect via enhancing LXRα/ABC pathways. Setosphapyrones possess potential application for the treatment of hyperlipidemic diseases.
LXRα 激动剂因其促进胆固醇外排的潜在生物学活性而引起了广泛关注。本研究旨在探讨麦角甾醇吡嗪 C 和 D 是否具有体外潜在的降脂能力及其作用机制。与肝 X 受体α（LXRα）激动剂 T0901317 相比，麦角甾醇吡嗪 C 和 D 的细胞毒性较弱。在 RAW264.7 巨噬细胞中，麦角甾醇吡嗪 C 和 D 分别显著增强[H]-胆固醇外排约 21.3%和 32.4%；此外，麦角甾醇吡嗪 C 和 D 分别使 ATP 结合盒转运蛋白（ABC）A1 和 LXRα 的蛋白水平增加 58%和 69%（8μM）和 60%和 70%（8μM），但对 ABCG1 和清道夫受体 B 型 1 的蛋白水平没有影响；此外，它们对脂肪生成基因的 mRNA 表达也没有影响。值得注意的是，麦角甾醇吡嗪 C 和 D 显著增强了小鼠原代巨噬细胞中的 LXRα/ABCA1 通路。在 BRL 细胞中，麦角甾醇吡嗪 C 和 D 显著提高了 ABCA1 和 ABCG1 的蛋白水平；麦角甾醇吡嗪 D 显著增强了低密度脂蛋白的蛋白表达。综上所述，麦角甾醇吡嗪 C 和 D 具有较弱的细胞毒性，通过增强 LXRα/ABC 通路表现出有效的降脂作用。麦角甾醇吡嗪类化合物具有治疗高脂血症疾病的潜在应用价值。
