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Open AccessArticle

Lupin Peptide T9 (GQEQSHQDEGVIVR) Modulates the Mutant PCSK9D374Y Pathway: in vitro Characterization of its Dual Hypocholesterolemic Behavior

Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy
Author to whom correspondence should be addressed.
Nutrients 2019, 11(7), 1665;
Received: 27 June 2019 / Revised: 14 July 2019 / Accepted: 19 July 2019 / Published: 20 July 2019
(This article belongs to the Special Issue Effect of Bioactive Peptides on Human Health)
GQEQSHQDEGVIVR (T9) is a peptide originated by the tryptic digestion of lupin β-conglutin that is absorbed in human intestinal Caco-2 cells. A previous study has shown that T9 impairs the protein–protein interaction between mutant D374Y Proprotein Convertase Subtilisin/Kexin 9 (PCSK9D374Y) and the low-density lipoprotein receptor (LDLR), thus exerting a hypocholesterolemic effect. Moreover, a bioinformatic study predicting that T9 may potentially act as an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCoAR), has suggested a complementary cholesterol-lowering activity. The present study demonstrates that T9 inhibits in vitro the HMGCoAR functionality with an IC50 value of 99.5 ± 0.56 µM. Through the inhibition of either HMGCoAR or PCSK9D374Y activities, T9 enhances the LDLR protein levels leading to an improved ability of HepG2 cells transfected with the mutant PCSK9D374Y-FLAG plasmid to uptake extracellular LDL with a final cholesterol-lowering effect. In addition, T9 modulates the PCSK9D374Y signaling pathway in transfected HepG2 cells leading to a decrease of PCSK9D374Y and HNF-1α protein levels. All these results indicate that the hypocholesterolemic effects of T9 are due to a dual mechanism of action involving either the modulation of the PCSK9D374Y or LDLR pathways. This may represent an added value from a therapeutic point of view. View Full-Text
Keywords: bioactive peptides; HepG2; LDLR; lupin; PCSK9 bioactive peptides; HepG2; LDLR; lupin; PCSK9
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Lammi, C.; Bollati, C.; Lecca, D.; Abbracchio, M.P.; Arnoldi, A. Lupin Peptide T9 (GQEQSHQDEGVIVR) Modulates the Mutant PCSK9D374Y Pathway: in vitro Characterization of its Dual Hypocholesterolemic Behavior. Nutrients 2019, 11, 1665.

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