Bergamot (Citrus bergamia) peel extract as new hypocholesterolemic agent modulating PCSK9 expression

Citrus bergamia extracts have been studied for the management of hypercholesterolemia disorders. Up to now limited information is available concerning the activity of its main phytoconstituents towards the main targets of the cholesterol homeostasis. In the present study, the effects of bergamot peel extract and isolated constituents, namely glycosidic and non-glycosidic flavonoids, one coumarin and one limonoid on the low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) were evaluated by using cultured HuH7 cell line. Furthermore, for the first time the effects of bergamot peel extract were studied to describe a potential hypolipidemic action. Significant differences were observed due to glycosylation and different substitution on flavanone moiety (O-methylation). Considering the thirteen isolated compounds, both naringenin-7-O-rutinoside (NA-rut) and apigenin-6,8-C-glicoside induced the expression of the LDLR while no effect was observed on PCSK9. However, hesperetin (HE) and its derivatives, hesperetin-7-O-glucoside and hesperetin-7-O-neohesperidoside (HE-glu, HE-neo) and eriodictyol (ER) showed a statin-like effect since a significant increase of both LDLR and PCSK9 expression were detected. Furthermore, bergamot peel extract (BE) firstly demonstrated a significant reduction of PCSK9 expression, indicating a potential adjuvant action to statins. BE, HE-neo, and NA-rut reduced intracellular sterols and the expression of PCSK9 transcription factor HNF1-α. BE also significantly improved the LDL uptake u Huh7 cells. Based on the present data, bergamot peel constituents can play a role in the management of hypercholesterolemia, on one hand they may produce an adjuvant action in combination with statins, while on the other hand they may have a statin-like effect. Additionally, BE may be a good candidate as an adjuvant to statins action.