Lupin Peptides Lower Low-Density Lipoprotein (LDL) Cholesterol through an Up-regulation of the LDL Receptor/Sterol Regulatory Element Binding Protein 2 (SREBP2) Pathway at HepG2 Cell Line

Abstract

Previous experiments in suitable animal models and in mild hypercholesterolemic individuals have shown that the consumption of lupin proteins may be useful for controlling total and low-density lipoprotein (LDL) cholesterol levels. With the objective of providing evidence that peptides deriving from the hydrolysis of lupin proteins may be responsible of the observed activities and for investigating the mechanism of action, HepG2 cells were treated with lupin peptides obtained by either pepsin (P) or trypsin (T) hydrolysis, and molecular and functional investigations were performed on the LDL receptor/SREBP2 pathway. For the first time, this paper provides experimental evidence that lupin peptides are able to interfere with the HMGCoAR activity, up-regulating the LDL receptor (136 and 84% vs the control for P and T peptides, respectively, at 1 mg/mL) and SREBP2 proteins (148 and 73% vs the control for P and T peptides, respectively, at 1 mg/mL) via the activation of PI3K/Akt/GSK3β pathways and increasing the LDL uptake at HepG2 cell line (40 and 50% vs the control for P and T peptides, respectively, at 1 mg/mL). These results may be useful in explaining the activities observed in vivo in animals and humans treated with lupin protein.

The health benefits of sweet lupin seed flours and isolated proteins

“…These experimental evidences (Table 4) In this context, Lammi and co-workers showed, for the first time, the involvement of Akt/GSK3β activation in LDLR-SREBP-2 pathway regulation after treatment of human hepatic cells with lupin peptides (Lammi et al, 2014). Both P and T peptides enhanced the LDLR protein levels and induced an increased fluorescent LDL-uptake at HepG2 cells (Table 4), but the LDL uptake was blocked in the presence of 1 µM wortmannin (CAS number 19545-26-7), a potent well-known inhibitor of PI3K/Akt (Feldman & Shokat, 2011).…”

“…Very recently, a study on human hepatic HepG2 cells has provided a detailed elucidation of the molecular mechanism by which lupin peptides exert their hypocholesterolaemic activities (Lammi, Zanoni, Scigliuolo, D'Amato, & Arnoldi, 2014). These experimental evidences (Table 4) In this context, Lammi and co-workers showed, for the first time, the involvement of Akt/GSK3β activation in LDLR-SREBP-2 pathway regulation after treatment of human hepatic cells with lupin peptides (Lammi et al, 2014).…”

Lupin as a perspective protein plant for animal and human nutrition – a review

“…The protein hydrolyzate was effective in reducing plasma and hepatic triglycerides and showed promising effects on glucose metabolism as well as protection against dietary-induced renal alterations. Lammi et al (2014Lammi et al ( , 2015 state that their findings indicate that peptides obtained from the hydrolysis of lupin proteins are able to interfere with the 3-hydroxy-3-methyl-glutarylCoA reductase activity. Immunoblotting experiments showed that the treatments with lupin peptides induce an up-regulation of the sterol regulatory element binding protein 2 (SREBP2) protein level and consequently to the up-regulation of the LDL receptor.…”

The Role of Food Peptides in Lipid Metabolism during Dyslipidemia and Associated Health Conditions

“…Hepatic MTP functions in VLDL assembly and secretion and its downregulation was thought to have contributed to the observed hypolipidemic events in the liver cells. Moreover, other peptides exhibited in vitro inhibition of the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR), which catalyzes the rate-limiting step of endogenous cholesterol biosynthesis [29,35]. This activity is expected to modulate dyslipidemia by lowering hepatic and plasma cholesterol levels.…”

“…Despite the prospects, there is still a knowledge gap on interaction of the food-derived peptides with upstream molecular events associated with the transcription factors. Recently, the SREBP2-mediated effect of lupin peptides was suggested to be due to the activation of phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt) pathways, which led to increased expression of hepatic LDLR proteins and LDL uptake in the cultured cells [35]. As observed in the study, HMGCoAR protein (coded by a SREBP-responsive gene) was elevated in hepatocytes due to SREBP2 activation [35], but the cellular enzymatic activity was not evaluated to ascertain if the hepatic enzyme can be directly inhibited by the lupin peptides (as demonstrated in vitro in the study) towards inhibition of de novo lipogenesis.…”