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J. Future Foods Lipid-lowering effect of Hericium erinaceae polypeptide on high-fat diet-induced hyperlipidemia mice

 Last Update: 2022-10-31
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Hericium erinaceus, belonging to the genus Basidiomycetes, Pore Fungi, Dentaceae, Hericium erinaceus, is a large fungus
with dual food and drug use.
It is widely distributed in nature, mainly distributed in the northern temperate broad-leaved or coniferous forest and broad-leaved mixed forest, such as Western Europe, North America, Japan, Russia and other places
.
Modern research has shown that Hericium erinaceus contains peptides, polysaccharides, terpenes, sterols, phenols and other active ingredients, which have a variety of biological activities
such as antioxidant, hypolipidemia, immune regulation, anti-tumor, and liver protection.
Based on the previous functional exploration, Hericium erinaceus has been widely used in the development of medicine, health food and general food, and has a very broad market prospect.

In recent years, with the continuous improvement of isolation methods and in-depth research on the mechanism of action of Hericium erinaceus, many new compounds have been isolated from fruiting bodies and hyphae, and the pharmacological activity of monomeric compounds has also been extensively studied
.
However, the current research on Hericium erinaceus mainly focuses on its polysaccharides, alcohol extracts and water extracts, and the research on Hericium erinaceus protein and peptides has been reported less
.
Studies have shown that Hericium erinaceus has a protein content of up to 24.
8% and contains 17 amino acids, including 8 essential amino acids
.
Proteomics and genomics techniques have been used to study the proteins that regulate the activity of Hericium erinaceus, of which 722 proteins are differentially expressed
.
Some experts speculate that these differential proteins may be related to molecular signal transduction and secondary metabolism and energy metabolism, suggesting that different regulation of Hericium erinaceus biosynthetic genes produces active metabolites
with different pharmacological effects.
Therefore, it is of great value
to study the pharmacological activity of Hericium erinaceus protein and active peptides.
There are currently no reports
of Hericium erinaceus polypeptide (HEP) for the treatment of hyperlipidemia.

Hyperlipidemia is the main risk factor for cardiovascular and cerebrovascular diseases such as atherosclerosis and fatty liver, which seriously affects human physical and mental health
.
According to statistics, 30 million people die every year in the world from diseases related to hyperlipidemia, and this number is increasing
every year.
When blood lipids are elevated, they are easily attacked by free radicals and produce large amounts of lipid peroxides
.
Studies have shown that many metabolic diseases and aging in humans are related
to the degree of oxidative damage of macromolecules caused by reactive oxygen species.
To fundamentally treat and prevent such diseases, we must first remove free radicals in the body and restore the free radical balance
in the body by trapping or destroying oxygen free radicals.
At present, lipid-lowering drugs such as lovastatin have been widely used for clinical diagnosis and maintenance of normal blood lipid levels
.
However, these drugs can have serious side effects in clinical application; Therefore, it is particularly important
to develop functional foods that can restore oxidative damage and increase lipid levels.
Compared with proteins, bioactive peptides are more easily absorbed and utilized by the human body, so they have strong biological activity
in small concentrations.
Bioactive peptides have functional activities
such as lowering blood pressure, antioxidant, immunomodulation, and lowering blood lipids.
In recent years, a lot of research has been carried out on the hypolipidemic effect of new active peptides such as shiitake mushroom peptide, Ganoderma lucidum polypeptide and morel peptide in edible fungi, and progress has been made in the research of its lipid-lowering activity and related mechanisms
.
Therefore, it is of great significance
to study the lipid-lowering activity of HEP.

Dr.
Wang Nan and Professor Liu Tingting of Jilin Agricultural University used ultrasound-microwave-assisted enzymatic method to prepare HEP, and compared the changes of antioxidant activity and hypolipidemic activity of different molecular weight HEP before and after gastrointestinal digestion by simulating the gastrointestinal digestive system, and analyzed their changes
.
By establishing a hyperlipidemia model, the effect of HEP on serum lipids and serum antioxidant indexes in mice was studied, which laid a foundation
for the subsequent study of the hypolipidemic mechanism in HEP.

Results and discussion

Evaluation of lipid-lowering ability of Hericium erinaceae polypeptides in vitro

Table 1 shows that the polypeptide components of Hericium erinaceus have adsorption effect on taurocholate and glycocholate in simulated gastrointestinal environment, and their binding rate increases with the increase of polypeptide concentration, showing a clear dose-response relationship
.
In the experimental concentration range, the binding ability of Hericium erinaceus polypeptide components to taurocholate was higher than that of glycocholate, and the binding ability of Hericium erinaceus polypeptide components to taurocholate was
stronger.
In the experimental concentration range, the binding capacity of Hericium erinaceus polypeptide components with taurocholate and glycocholate was: HEP-II> HEP-I> HEP-III
.
At a concentration of 10 mg/mL, HEP-II had binding rates of taurocholate and glycocholate (65.
08±0.
02) and (57.
74±0.
01), respectively, and the adsorption rates of the two bile salts were above
50%.
After simulating the gastrointestinal environment in vitro, we verified that HEP can bind to bile acid in humans and reduce the intensity
of enterohepatic circulation of bile acids in vivo.
Therefore, we preliminarily confirmed that HEP has the potential to assist in lowering blood lipids through cholic acid binding, and its mechanism of action may depend on the hydrophobicity of peptide chain amino acid residues, and the amphiphilic hydrophobic backbone structure of bile acids can effectively bind
to polar functional groups through hydrophobic amino acids.

Table 1 Effect of simulated gastrointestinal environment on cholate binding rate of polypeptide components of Hericium erinaceus

Structural properties of Hericium erinaceus polypeptides

The infrared spectroscopy of HEP-II is shown in Figure 1, showing the telescopic vibration peak
of paraamide N-H at 3 304 cm⁻¹.
The action of amino group production causes C=O to move down to the lower digit, and two strong C=O telescopic vibration peaks
appear at 1 660 cm−1 and 1 650 cm⁻¹.
In addition, at 1 031 cm⁻¹, a telescopic vibration (symmetrical) peak
of aromatic ether=C-O-C linked to oxygen and side chain carbon appeared.
The curved (in-plane) absorption peak
of NH occurs at 1 592 cm⁻¹.
At 1 152 cm−1 and 1 245 cm⁻¹, the C-C telescopic vibration absorption peak and the alkane-C-H-plane bending absorption peak, respectively, are protein characteristic absorption peaks
.
After deconvolution treatment, amide I can separate 5 absorption peaks, differentiate the spectra, and finally use Prota3s software to fit the band
.

The difference in the secondary structure of HEP-II was analyzed by amide I.
band, and the wavenumber was β-folded within 1 610~1 640 cm−1, random curling within 1 640~1 650 cm−1, α-helix within 1 650~1 658 cm⁻¹, and β-angle
within 1 660~1 695 cm⁻¹ 。 Table 2 shows the secondary structure content of HEP-II, which is 23.
15% β-fold, 18.
36% random coil, 47.
71% α-helix and 10.
78%
β-angle.
In the experimental results, HEP-II had the highest proportion of α-helical content, indicating that the peptide had high hydrophobicity
.
Studies have shown that the hydrophobicity of peptides plays an important role
in maintaining their activity in binding to cholesterol.
In summary, the high content of α-helical structure has a certain contribution
to the hypolipidemic effect of HEP-II.

Fig.
1 Infrared spectroscopy analysis of HEP-II

Table 2 Secondary structure analysis of polypeptide components of Hericium erinaceus

Effects of Hericium erinaceae polypeptides on lipid levels in mice induced by a high-fat diet

Hyperlipidemia is caused by abnormal lipid metabolism, mainly manifested as high serum TC, TG, LDL-C levels or low
HDL-C levels.
Abnormally elevated serum TC and TG are associated
with the occurrence of cardiovascular disease.
HDL-C can also be used as a carrier for TC reverse transport, and the increase of HDL-C can accelerate the breakdown
of TC in the blood.

The effect of HEP-II intervention on lipid markers in mice on a high-fat diet is shown in Table 2
.
Compared with the normal control group, the serum TC and TG concentrations of mice in the high-fat model group increased significantly (P<0.
05), LDL-C significantly increased (P<0.
01), and HDL-C decreased significantly (P<0.
05), and the results showed that the mice in the high-fat model group had obvious dyslipidemia<b11>.
Compared with the high-fat model group, the serum TC and TG concentrations of mice in the medium and high dose groups were significantly reduced (P<0.
05), and the concentrations of TC and TG in the low-dose group were also reduced (P>0.
05), and the serum TC and TG concentrations in the high-dose group were not statistically significant compared with the simvastatin group (P>0.
05).

It was shown that a certain dose of HEP-II could inhibit the increase of serum TC and TG concentration in mice, and the concentration was negatively correlated with
the dose.
Compared with the high-fat model group, the serum HDL-C concentration of mice in the low-dose group increased by about 0.
08 mmol/L, and the increase was not significant (P>0.
05).

The serum HDL-C concentration of mice in the medium and high dose groups was significantly higher than that in the high-fat model group (P<0.
05), with an increase of 15.
32% and 31.
53%,<b15> respectively.
It was shown that a certain dose of HEP-II could effectively increase the serum HDL-C level of
mice.
Compared with the high-fat model group, the serum LDL-C concentration of mice in the low, medium, and high dose groups was reduced, which was negatively correlated with
the dose increase.
There was no statistically significant difference between the low-dose group and the high-fat model group (P>0.
05).

Compared with the high-fat model group, there was a statistically significant difference between the medium- and high-dose groups (P<0.
05).
<b19> The experimental results showed that HEP-II could effectively reduce the concentration of LDL-C in mice, and the effect was good
in the high-dose group.

Calculate the atherosclerosis index (AI)
based on serum TC and HDL-C.
Compared with the normal control group, the AI value of mice in the high-fat model group was significantly higher (P<0.
01), indicating that a high-fat diet led to the formation of atherosclerosis in<b11> mice.
Compared with the high-fat model group, the AI value of mice in the simvastatin group and the medium- and high-dose groups was reduced
.
The AI value of mice in the low-dose group was significantly reduced (P <0.
05), and the AI value in the simvastatin group and the medium- and high-dose groups were significantly reduced (P<0.
01).
<b13> These results suggest that HEP-II inhibition of atherosclerosis is dose-dependent
.

In summary, the preventive effect of HEP-II on dyslipidemia and cardiovascular disease was confirmed in this study, and the regulatory effect of high HEP-II concentration on blood lipid level was more obvious
.

Table 3 Effect of HEP-II on blood lipid markers in high-fat mice

Conclusion

HEP was prepared by ultrasound-microwave-assisted enzymatic method, and the yield of polypeptide was (65.
14±0.
05)%.

Three polypeptide components with different molecular weight ranges were isolated by 5 kDa and 10 kDa ultrafiltration membranes, which were HEP-I(10.
70±1.
21)%, HEP-II(56.
19±1.
06)% and HEP-III(33.
11±0.
94)%,
respectively.
In this study, the antioxidant and hypolipidemic properties
of polypeptide components before and after digestion were compared and analyzed by simulating gastrointestinal digestion experiments.
The results showed that the polypeptide components of Hericium erinaceus had strong antioxidant and lipid-lowering ability before and after gastrointestinal digestion, and the overall activity of the polypeptide components after gastrointestinal digestion was small, and the gastrointestinal stability was high
.
Among them, HEP-II with a molecular weight of 5~10 kDa has the strongest antioxidant and hypolipidemic ability, which may be because the secondary structure of HEP-II is mainly composed of irregular coiling (18.
36%) and α-helical structure (47.
71%), which is conducive to the antioxidant and hypolipidemic ability
of HEP-II.
Animal experiments have shown that HEP-II has significant hypolipidemic effect
by improving blood lipid lowering and improving liver antioxidant capacity.
Combined with pathological observation and analysis, the authors found that HEP-II improves fatty lesions and lipid metabolism disorders in the liver, and can reduce the accumulation of lipids in the liver, thereby protecting the liver and reducing the risk
of fatty liver disease.
Taken together, these results suggest that HEP is a promising functional ingredient for relieving blood lipids
.

About the first author

Nan Wang, Ph.
D.
, mainly focuses on the deep processing of edible and medicinal mushrooms and the mechanism of
action of functional ingredients.

Tong Zheng, master's degree, his main research direction is the deep processing of edible and medicinal mushrooms and the mechanism of
action of functional ingredients.

About the corresponding author

Liu Tingting, Ph.
D.
, professor and master tutor of Jilin Agricultural University, young top talent of Jilin Agricultural University, concurrently serves as the executive director of Jilin Health Care Association, the standing director of Jilin Dietitian Association, and a member of
the 17th Changchun Youth Joint Committee 。 Mainly engaged in the research of the deep processing of the main grain and oil plant protein, the deep processing of edible and medicinal bacteria and the development of functional foods, he has successively presided over the "13th Five-Year Plan" national key research and development plan, Jilin Province key science and technology research, Jilin Province Youth Scientific Research Fund, Changchun science and technology support plan and enterprise horizontal cooperation scientific research projects 17 projects, published more than 40 scientific research papers, obtained 80 national invention patents, and transferred 22 national invention patents
.
He has won 5 first prizes of Jilin Province Science and Technology Award and 2 second prizes of
Jilin Province Science and Technology Award.

Zhang Yanrong, Ph.
D.
, second-level professor of Jilin Agricultural University, doctoral supervisor, senior expert of Jilin Province, young and middle-aged professional and technical talents
with outstanding contributions in Jilin Province.
Mainly engaged in food science, grain and oil plant protein deep processing, food and medicine bacteria deep processing and functional food development and other aspects of research work
.
Presided over or mainly participated in 29 national key research and development plans, national "863", national major scientific and technological support, transformation of national major scientific and technological achievements, key scientific and technological research in Jilin Province, major scientific and technological research in Changchun and horizontal cooperation with enterprises; It has obtained more than 80 national invention patents, transferred 28 patents and special technologies, and created direct economic benefits of more than 10 million yuan
for the school.
Won 8 national and provincial scientific research achievements; He has won 4 first prizes of Jilin Province Science and Technology Progress Award and 3 second prizes of
Jilin Province Science and Technology Progress Award.
He is the chief editor and co-editor of 6 textbooks and books published in the "Eleventh Five-Year Plan", and has published more than 110 academic papers in SCI, EI journals and Chinese important journals
.
He has taught 12 undergraduate and graduate courses
in the past 31 years.
More than 50 doctoral and master students have
been trained.

Effects of Hericium erinaceus polypeptide on lowering blood lipids of mice with hyperlipidemia induced by a high-fat diet

Nan Wang^a,b,#, Zhengquan Tong^a,c,#, Dawei Wang^a,c, Yanrong Zhang^a,c,*, Tingting Liu^a,c,^*

^a School of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China

^b Key Laboratory of Technological Innovations for Grain Deep-Processing and High-Effeciency Utilization of By-products of Jilin Province, Changchun 130118, China

^c Engineering Research Center of Grain Deep-Processing and High-Effeciency Utilization of Jilin Province, Changchun 130118, China

*Corresponding authors.

E-mail address: xcpyfzx@163.
com

ltt1984@163.
com

Abstract

Hericium erinaceus polypeptide (HEP) was prepared by an ultrasound-microwave assisted enzymatic method.
Using an ultrafiltration membrane with molecular weights of 5 and 10 kDa, HEP was fractionated into three fractions, namely, (HEP-I (< 5 kDa), HEP-II (5–10 kDa), and HEP-III (> 10 kDa)).
In vitro chemical methods were used to compare the antioxidant and hypolipidemic abilities of the polypeptide fractions from H.
erinaceus before and after simulated gastrointestinal digestion .
By constructing a hyperlipidemia model, the hypolipidemic ability of the high active fraction (HEP-II) was verified.
The results showed that the antioxidant and hypolipidemic abilities of the polypeptide fractions from H.
erinaceus did not change dramatically during simulated gastrointestinal digestion in vitro.
The polypeptide fractions from H.
erinaceus exhibited high tolerance to simulated gastrointestinal digestion in vitro, with strong antioxidant and hypolipidemic activities.
HEP-II with a molecular weight of 5–10 kDa had the best stability, antioxidant, and hypolipidemic abilities in gastrointestinal digestion.
The secondary structure of HEP-II was mainly composed of random coil (18.
36%) and α-helix (47.
71%) structures, which was beneficial to the hypolipidemic ability of HEP-II.
Animal experiments showed that compared to the high-fat model group, HEP-II could inhibit the weight gain of the mice, decrease the liver index and serum levels of the serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), nitric oxide synthase (NOS), alanine aminotransferase (AST), and glutamic-pyruvic transaminase (ALT), increase the levels of glutathione peroxidase (GSH-Px) and high-density lipoprotein cholesterol (HDL-C), decrease the arteriosclerosis index (AI), and improve the hemorheological indices of the mice.
In addition, the whole blood and plasma viscosities of the mice decreased, and HEP-II increased the level of superoxide dismutase (SOD) in the liver, reducing the level of malondialdehyde (MDA), and the degree of oxidative stress in the liver of hypolipidemia mice.
Furthermore, HEP-II improved liver steatosis.
These results indicated that the polypeptide fractions from H.
erinaceus all had a potential hypolipidemic effect, and HEP-II had the strongest potential hypolipidemic effect.

Reference:

WANG N, TONG Z Q, WANG D W, et al.
Effects of Hericium erinaceus polypeptide on lowering blood lipids of mice with hyperlipidemia induced by a high-fat diet[J].
Journal of Future Foods, 2022, 2(4): 346-353.
DOI:10.
1016/j.
jfutfo.
2022.
08.
006.

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