Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important post- transcriptional regulator of plasma levels of low- density lipoprotein cholesterol (LDL-C). Inhibition of PCSK9 has emerged as an attractive strategy in recent years to combat hypercholesterolemia stimulating the search for PCSK9 inhibitors. The carotenoid crocetin exhibits hypocholesterolemic effect. However, it is unknown whether the beneficial effect is mediated through PCSK9 modulation. We hypothesized that crocetin inhibits PCSK9 and therefore, in our quest for natural and safe PCSK9 inhibitors, we investigated the effect of crocetin on PCSK9 expression and other key molecular targets involved in hepatic cholesterol metabolism using the human hepatoma cell line HepG2 as a model system. We demonstrate for the first time that crocetin treatment significantly decreases PCSK9 and Sterol regulatory element binding proteins (SREBP) expression in a dose dependent manner, accompanied by a concomitant increase in the hepatic Low-Density lipoprotein receptor (LDLR) expression. Additionally, crocetin significantly downregulates the levels of both mRNA and protein expression of sortilin, a key sorting receptor that facilitates PCSK9 transport in the trans Golgi network in a dose dependent manner. Overall, our results suggest that crocetin is a LDLR inducer, and an inhibitor of PCSK9, sortilin and SREBPs making it an effective natural anti-cholesterol agent.

前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 是低密度脂蛋白胆固醇 (LDL-C) 血浆水平的重要转录后调节剂。近年来，抑制 PCSK9 已成为对抗高胆固醇血症的一种有吸引力的策略，刺激了对 PCSK9 抑制剂的研究。类胡萝卜素藏红花素表现出降胆固醇作用。然而，尚不清楚这种有益效果是否是通过 PCSK9 调制介导的。我们假设藏红花素抑制 PCSK9，因此，在我们寻求天然和安全的 PCSK9 抑制剂时，我们使用人肝癌细胞系 HepG2 作为模型系统研究了藏红花素对 PCSK9 表达和其他参与肝胆固醇代谢的关键分子靶点的影响。我们首次证明藏红花素治疗以剂量依赖性方式显着降低 PCSK9 和甾醇调节元件结合蛋白 (SREBP) 的表达，同时伴随肝脏低密度脂蛋白受体 (LDLR) 表达的增加。此外，藏红花酸显着下调分选蛋白的 mRNA 和蛋白质表达水平，分选蛋白是一种关键的分选受体，可促进 PCSK9 在trans Golgi 网络以剂量依赖的方式。总体而言，我们的结果表明，藏红花素是一种 LDLR 诱导剂，并且是 PCSK9、sortilin 和 SREBPs 的抑制剂，使其成为一种有效的天然抗胆固醇剂。