Crocetin exerts hypocholesterolemic effect by inducing LDLR and inhibiting PCSK9 and Sortilin in HepG2 cells.

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 stimu-
lating 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 crocetin on PCSK9 expression and other
key molecular targets involved in hepatic cholesterol metabolism using the human hep-
atoma 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 depen-
dent manner. Overall, our results suggest that crocetin is a LDLR inducer, and an inhibitor
of PCSK9, sortilin and SREBPs, thus making it an effective natural anti-cholesterol agent.