Molecular mechanisms of cholesterol-lowering peptides ...

Highlights

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  Peptides are known to mediate the cholesterol-lowering effect of food proteins.

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  Other peptides exhibit statin-like mechanism, that is, inhibit HMG-CoA reductase.

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  Emerging results show that some peptides act by inhibiting PCSK9–LDLR interaction.

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Some food proteins exhibit hypocholesteromic activity, which is largely associated with peptide fragments released after their enzymatic hydrolysis. This review provides a highlight of the recent progress on the hypocholesterolemic mechanisms of food protein-derived peptides, which include bile acid binding, inhibition of cholesterol micellar solubility and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (statin-like activity), and targeting of proprotein convertase subtilisin/kexin type 9 interaction with low-density lipoprotein receptor, and sterol regulatory element-binding protein and hepatocyte nuclear factor 1α pathways.

Introduction

The role of food proteins in health outcome extends beyond nutritional value of supplying amino acids. For instance, peptides derived from protein hydrolysis have several biological effects, including the lowering of lipid levels during dyslipidemia, as demonstrated in both animal and human studies [1, 2]. Available evidence shows that hypocholesteromic peptides act either by targeting exogenous cholesterol, or by modulating endogenous cholesterol level via cholesterol metabolism pathways [2, 3]. The mechanism behind the effect on exogenous cholesterol mostly involves hindering initial intestinal absorption of dietary cholesterol. On the other hand, endogenous cholesterol is thought to be reduced if the active peptides can cross the intestinal barrier and are bioavailable in the liver and adipose tissues. Some peptides hinder enterohepatic circulation of bile acids, while others directly target endogenous cholesterol metabolism in tissues [2, 3], which makes it necessary to establish the absorption, distribution, metabolism, excretion and toxicity (ADMET) of the peptides and their derivatives. Recent studies have reported particular hypocholesteromic mechanisms of food-derived peptides, including inhibition of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCoAR) activity, and targeting of the expression of proteins involved in cholesterol metabolism including sterol regulatory element binding protein 2 (SREBP2), proprotein convertase subtilisin/kexin type 9 (PCSK9), hepatocyte nuclear factor (HNF)-1α, and low density lipoprotein receptor (LDLR). The cholesterol-reducing mechanisms discussed in this review, summarized in Table 1, are from recent reports (2014–2017) involving only peptides, proteins, or protein hydrolysates derived from lupin, soybean, royal jelly (RJ), cowpea, rice bran, and hempseed.

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Section snippets

Physical interaction of peptides with bile acids and micelles

The gastrointestinal tract, especially the intestines, plays an important role in the packaging and transport of dietary cholesterol, and in recirculation of cholesterol metabolites via the enterohepatic route. This provides an opportunity for food peptides to modulate cholesterol metabolism in the gut. The widely proposed mechanism for gut-active hypocholesterolemic peptides involves hydrophobic interaction, at least partially, for bile acid binding and inhibition of cholesterol micellar

Statin-like activity of food peptides

Although cholesterol can be obtained via the diet, the majority of cholesterol in the body is synthesized endogenously. HMGCoAR catalyzes the rate-limiting step of the mevalonate pathway that leads to cholesterol biosynthesis, thus inhibition of its enzymatic activity plays a significant role in lowering endogenous cholesterol level during hypercholesterolemia. Numerous studies have targeted HMGCoAR when developing treatment for hypercholesterolemia, leading to the discovery of a class of

PCSK9-mediated effects of peptides

PCSK9 plays an important role in lipoprotein homeostasis. It binds to the epidermal growth factor-like repeat-A (EGF-A) domain of LDLR in hepatocytes resulting in the degradation of LDLR in endosomes and inhibition of LDLR recycling to the membrane surface for LDL uptake [25]. Inhibition of PCSK9 is emerging as an efficient approach for lowering endogenous cholesterol level. PCSK9 is regulated by its N-terminal prodomain, which is enzymatically cleaved for protein activation. Thus, food

Regulation of transcription factors by peptides

Food-derived peptides have been found to influence the expression of transcriptional activators of genes involved in cholesterol transport and metabolism. SREBP2 is a key transcriptional factor in lipid metabolism and controls the expression of genes involved in cholesterol metabolism, including LDLR, PCSK9 and HMGCoAR [27]. SREBP2 is anchored to the membrane of endoplastic reticulum in its inactive form and is activated by proteolytic cleavage to release the N-terminal domain, which is an

Conclusion and future direction

As discussed in this review, emerging reports have demonstrated that some food protein-derived peptides have multiple cholesterol-lowering mechanisms, in addition to well-known lipid binding and statin-like mechanisms. Particularly, some peptides derived from lupin increase the expression of SREBP2 transcription factor, involved in regulating cholesterol metabolism, and this was associated with increased LDLR protein level and LDL uptake in hepatic cells. Additionally, food peptides target

Funding

The authors did not receive any specific funding for the preparation of this paper.

Conflict of interest

None declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• • of special interest

• •• of outstanding interest

Acknowledgement

The Natural Sciences and Engineering Research Council of Canada (NSERC) funds the research program of CCU through a Discovery Grant, RGPIN 435865-2013.

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