Evaluation of the effects of natural isoquinoline alkaloids on low density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) in hepatocytes, as new potential hypocholesterolemic agents

Maharjan, Binita; Payne, Daniel T.; Ferrarese, Irene; Giovanna Lupo, Maria; Kumar Shrestha, Lok; Hill, Jonathan P.; Ariga, Katsuhiko; Rossi, Ilaria; Sharan Shrestha, Shyam; Panighel, Giovanni; Lal (Swagat) Shrestha, Ram; Sut, Stefania; Ferri, Nicola and Dall'Acqua, Stefano (2022). Evaluation of the effects of natural isoquinoline alkaloids on low density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) in hepatocytes, as new potential hypocholesterolemic agents. Bioorganic Chemistry, 121, article no. 105686.

DOI: https://doi.org/10.1016/J.BIOORG.2022.105686

Abstract

Nine different isoquinoline alkaloids, berberine, govaniadine, stylopine, adlumine, adlumidine, bicuculline, sanguinarine, protopine and californidine have been evaluated for their effects on a cellular model of hepatocyte for their effect on low density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression compared to simvastatin. Berberine, californidine and govaniadine induced LDLR with an effect similar to 2.5 µM simvastatin. Californidine and berberine at tested doses reduced the expression of PCSK9, with an opposite behaviour to simvastatin on this target. Govaniadine, on the other hand, showed a statin-like effect, although less potently, by increasing both LDLR and PCSK9 levels. Berberine californidine and govaniadine were then tested on the same cellular model to assess possible effect of reduction of total cholesterol, compared to simvastatin. All compounds were able to reduce total cholesterol level in the hepatocytes.