Lupin protein exerts cholesterol-lowering effects targeting PCSK9: From clinical evidences to elucidation of the in vitro molecular mechanism using HepG2 cells

• Lupin protein reduces plasma PCSK9 levels in mild hypercholesterolaemic patients.
• Lupin peptides reduce the PCSK9 protein level inhibiting HNF1α in HepG2 cells.
• Lupin peptides reduce the ability of HepG2 cells to secrete mature PCSK9.
• Lupin peptides show a dual hypocholesterolaemic mechanism of action.

PCSK9 inhibition is a novel approach for cholesterol reduction because of its crucial pathophysiological role in cholesterol metabolism. This work aimed at evaluating whether lupin protein/peptides may modulate PCSK9 production. Mild hypercholesterolaemic subjects consumed lupin protein or casein (30 g/day) for 4 weeks. The final level of circulating PCSK9, measured by ELISA, was reduced by 8.5% (p = 0.0454) versus baseline value, whereas it remained unchanged in the control group (casein). For investigating the mechanism of action, HepG2 cells were treated with peptic and tryptic peptides from lupin protein: reductions of PCSK9 production and secretion were observed as well as a decrease of hepatic nuclear factor 1-alpha (HNF1-alpha). For the first time, this work provides evidences that lupin protein/peptides may modulate the PCSK9 protein level production and secretion, contributing to explain the beneficial effects observed in animal and human studies and opening a completely new area of investigation on plant proteins.