Korea Food Research Institute, Seongnam City, Republic of Korea.
Food Funct. 2017 Dec 13;8(12):4582-4591. doi: 10.1039/c7fo00562h.
Statins mediate the transactivation of PCSK9, which in turn limits their cholesterol-lowering effects via LDL receptor (LDLR) degradation. The objective of the present study was to investigate the mechanism of action by which Welsh onion (Allium fistulosum L. [family Amaryllidaceae]) extract (WOE) regulates LDLR and PCSK9. HepG2 cells were cultured under lipid depletion conditions using a medium supplemented with delipidated serum (DLPS). WOE (50, 100, 200, and 400 μg ml) significantly attenuated the DLPS-mediated increases in LDLR, PCSK9, and SREBP2 gene expression. While WOE treatment maintained the DLPS-mediated increases in LDLR protein expression, it dose-dependently and significantly attenuated the DLPS-mediated increases in the protein content of PCSK9. The suppression of PCSK9 was associated with the WOE-mediated reductions in SREBP2, but not HNF1α. WOE also dose-dependently reduced PCSK9 protein expression that was otherwise markedly induced by concomitant statin treatment. WOE-mediated PCSK9 inhibition contributed to LDLR lysosomal degradation suppression, and subsequent LDLR protein stabilization. HPLC analysis indicated that WOE contains kaempferol, quercetin, ferulic acid, and p-coumaric acid. Kaempferol and p-coumaric acid contributed to the maintenance of LDLR expression by inhibiting PCSK9 in lipid depleted HepG2 cells. Altogether, these findings suggest that WOE inhibits PCSK9 transcription and protein expression via the reduction of SREBP2, and decreased PCSK9 further contributes to LDLR degradation prevention and LDLR protein stabilization under conditions of lipoprotein deficiency. The PCSK9 inhibition-mediated mechanism of WOE was likely attributed to the action of kaempferol and p-coumaric acid present in WOE.
他汀类药物介导 PCSK9 的反式激活，PCSK9 进而通过 LDL 受体 (LDLR) 降解来限制其降低胆固醇的作用。本研究的目的是探讨 Welsh onion (Allium fistulosum L. [Amaryllidaceae 科]) 提取物 (WOE) 调节 LDLR 和 PCSK9 的作用机制。使用含有脱脂血清 (DLPS) 的培养基在脂质耗竭条件下培养 HepG2 细胞。WOE（50、100、200 和 400μg/ml）可显著减弱 DLPS 介导的 LDLR、PCSK9 和 SREBP2 基因表达的增加。虽然 WOE 处理维持了 DLPS 介导的 LDLR 蛋白表达增加，但它剂量依赖性地显著减弱了 DLPS 介导的 PCSK9 蛋白含量增加。PCSK9 的抑制与 WOE 介导的 SREBP2 减少有关，但与 HNF1α 无关。WOE 还剂量依赖性地降低了 PCSK9 蛋白表达，而同时给予他汀类药物治疗则显著诱导了 PCSK9 蛋白表达。WOE 介导的 PCSK9 抑制有助于抑制 LDLR 溶酶体降解，并随后稳定 LDLR 蛋白。HPLC 分析表明，WOE 含有山奈酚、槲皮素、阿魏酸和对香豆酸。山奈酚和对香豆酸通过抑制脂质耗竭的 HepG2 细胞中的 PCSK9 来维持 LDLR 表达。总之，这些发现表明，WOE 通过降低 SREBP2 抑制 PCSK9 的转录和蛋白表达，并且在脂蛋白缺乏的情况下，减少的 PCSK9 进一步有助于 LDLR 降解的预防和 LDLR 蛋白的稳定。WOE 的 PCSK9 抑制介导机制可能归因于 WOE 中存在的山奈酚和对香豆酸的作用。
