Exploring the potential of pomegranate (Punica granatum) peel extract and punicalagin as novel anti-hypercholesterolemic agents

Background: Hypercholesterolemia, characterized by elevated low -density lipoprotein (LDL) cholesterol levels, is a significant risk factor for cardiovascular diseases. Familial and behavioral factors contribute to its onset, and while lifestyle changes offer some benefits, medical interventions are essential to manage this condition effectively. Statins, the primary medications used to lower LDL cholesterol, have limitations, including the unintended upregulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). Therefore, exploring alternative approaches to enhance LDL receptor expression while targeting PCSK9 is crucial, with herbal medicine showing promise in this endeavor. Objective: This study investigates the potential of pomegranate peel extract and punicalagin, a key pomegranate component, in lowering LDL cholesterol in HepG2 cells. The research explores their effects on LDL receptor (LDLR) expression, LDL uptake, and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) gene expression. Methods: HepG2 cells were treated with different concentrations of pomegranate peel extract (37.5, 75, 150, and 300 p.g/ml) and punicalagin (12.5, 25, 50, and 100 p.g/ml). Next, the viability of HepG2 cells, the protein levels of LDL receptors and LDL uptake, and the expression levels of PCSK9 were measured. Results: Pomegranate peel extract (37.5, 75, 150, and 300 p.g/ml) and punicalagin (12.5, 25, 50, and 100 p.g/ml) did not exhibit significant cytotoxicity and significantly increased LDLR protein levels ( P -value = 0.00, after 24 hours) and LDL cholesterol uptake ( P -value = 0.00, after 24 hours). Furthermore, they exhibited a dose -dependent reduction in the expression of PCSK9 (pomegranate: P -value = 0.01; punicalagin: P -value = 0.00). Conclusion: These findings suggest that pomegranate peel extract and punicalagin have the potential to serve as effective agents in managing hypercholesterolemia by enhancing LDL receptor expression and reducing PCSK9 expression in HepG2 cells. Further research is required to explore their effects on transcription factors and PCSK9 function.