Department of Biochemistry & Molecular Biology, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Center for Precision Medicine and Division of Cardiovascular Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA.
Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, China; Department of Pharmacy, The Third Hospital of Changsha, Changsha, China.
Eur J Pharmacol. 2022 Sep 15;931:175195. doi: 10.1016/j.ejphar.2022.175195. Epub 2022 Aug 11.
Curcumin nicotinate (Curtn) is a synthesized ester derivative of curcumin and niacin. Our previous study has shown that Curtn lowers serum low-density lipoprotein cholesterol (LDL-C) levels in apoE mice and promotes LDL-C uptake into HepG2 cells in vitro. The present study was to test the hypothesis that Curtn decreases serum LDL-C levels through decreased expression of pro-protein convertase subtilisin/kexin type 9 (PCSK9) and subsequent increase in LDL receptor expression. Male Wistar rats on high-fat diet (HFD) were treated with Curtn or rosuvastatin. Curtn or rosuvastatin treatment significantly decreased serum levels of total cholesterol (TC) and LDL-C in rats on HFD with increased liver LDL receptor expression. LDL-C-lowering effect of Curtn was not observed in LDL receptor deficient (LDLR) mice on HFD, while rosuvastatin still decreased serum lipid levels in LDLR mice, indicating that the reduction of serum LDL-C levels by Curtn treatment was LDL receptor-dependent. Curtn treatment also significantly decreased the protein expression of PCSK9 in Wistar rats and LDLR mice. In HepG2 cells with overexpression of human PCSK9, Curtn treatment significantly increased LDL-C uptakes into hepatocytes, and increased LDL receptor distribution on cell surface in association with decreased PCSK9 protein expression. RNAi-LDLR significantly attenuated the effect of Curtn on LDLR distribution on cell surface. These data indicates that Curtn would decrease serum LDL-C level at least partially through inhibition of PCSK9 expression, and subsequent increase in LDL receptor expression and distribution in hepatocytes, serving as a potential novel compound to treat hyperlipidemia.
烟酸姜黄素 (Curtn) 是姜黄素和烟酸的合成酯衍生物。我们之前的研究表明 Curtn 可降低载脂蛋白 E 小鼠的血清低密度脂蛋白胆固醇 (LDL-C) 水平，并促进 HepG2 细胞摄取 LDL-C。本研究旨在验证 Curtn 通过降低前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9 (PCSK9) 的表达，从而增加 LDL 受体的表达，从而降低血清 LDL-C 水平的假说。高脂饮食 (HFD) 喂养的雄性 Wistar 大鼠给予 Curtn 或瑞舒伐他汀治疗。Curtn 或瑞舒伐他汀治疗可显著降低 HFD 大鼠的血清总胆固醇 (TC) 和 LDL-C 水平，并增加肝脏 LDL 受体的表达。在 LDL 受体缺失 (LDLR) 的 HFD 小鼠中，并未观察到 Curtn 的 LDL-C 降低作用，而瑞舒伐他汀仍可降低 LDLR 小鼠的血脂水平，表明 Curtn 治疗降低血清 LDL-C 水平依赖于 LDL 受体。Curtn 治疗还可显著降低 Wistar 大鼠和 LDLR 小鼠的 PCSK9 蛋白表达。在过表达人 PCSK9 的 HepG2 细胞中，Curtn 治疗可显著增加肝细胞摄取 LDL-C，并与 PCSK9 蛋白表达降低相关，增加 LDL 受体在细胞表面的分布。RNAi-LDLR 可显著减弱 Curtn 对 LDLR 分布在细胞表面的作用。这些数据表明， Curtn 通过抑制 PCSK9 表达，从而增加 LDL 受体的表达和分布，至少部分降低血清 LDL-C 水平，作为治疗高脂血症的潜在新型化合物。
