Investigations on the hypocholesterolaemic activity of LILPKHSDAD and LTFPGSAED, two peptides from lupin β-conglutin : focus on LDLR and PCSK9 pathways

P5 (LILPKHSDAD) and P7 (LTFPGSAED) are two peptides from lupin protein that are absorbed in Caco-2 cells. Recent in silico docking studies had suggested that they could potentially function as inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCoAR) activity. This paper confirms that both peptides inhibit in vitro the HMGCoAR functionality and it reports the characterisation of the molecular mechanism through which they modulate the cholesterol metabolism in HepG2 cells. Through the inhibition of HMGCoAR activity, P5 and P7 are able to improve the LDLR protein levels leading to a better ability of HepG2 cells to uptake extracellular LDL molecules with a final hypocholesterolaemic effects. The modulation of PCSK9 intracellular processing was also evaluated: only P5 was able to decrease the PCSK9 and HNF1-alpha protein levels leading to a decrease of mature PCSK9 secretion by HepG2 cells.