JP2010018523A - Peptidic hypolipidemic agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a highly safe hypolipidemic agent considering that lipid metabolism abnormality, which is a main symptom among metabolic syndrome having constituted a public problem, causes hyperlipidemia, fatty liver, arteriosclerotic diseases and the like. <P>SOLUTION: An effective material for medical treatments and for foods for specific health care is obtained as the highly safe hypolipidemic agent by batching-off of a dipeptide having a specific amino acid sequence of Ser-Tyr, Val-Lys or Lys-Ala as a sequence in a soybean protein from a decomposate of the soybean protein or by a dipeptide synthesis. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a specific sequence present in soybean protein, which relates to a functional food having a lipid lowering action in a living body and a dipeptide useful for medical use.

  In recent years, lifestyle-related diseases such as obesity, hyperlipidemia, diabetes, and hypertension have increased with the westernization of lifestyle and dietary habits. In addition, the metabolic syndrome that combines these has become a social problem. Among them, abnormal lipid metabolism, which is a major symptom, is a major problem due to excessive accumulation of lipids, causing hyperlipidemia, fatty liver, arteriosclerotic diseases, and the like. With regard to lipid-lowering agents that improve lipid metabolism, HMG-CoA reductase inhibitors (trade names: mevalotin, etc.) such as statins are widely used as pharmaceuticals, and plant sterols are also used as pharmaceuticals. In addition, tea ingredients and extracts from other natural plant ingredients that have been developed as foods for specified health use as having lipid-lowering and lipid metabolism-improving effects, and those that have been reported to be effective now It can be seen in various ways.

  On the other hand, soy protein is a soy material as a highly nutritious protein, or a product obtained by extracting and purifying protein is widely used. In recent years, not only nutritional effects but also various physiological effects have been recognized for this soy protein, and some of them relate to lipid lowering effects and lipid metabolism improving effects. Furthermore, it has been reported that soybean peptide obtained by enzymatic degradation of soybean protein has an effect of improving lipid metabolism. However, it is not clear what specific peptides are effective.

  On the other hand, a method of synthesizing a specific oligopeptide having a small number of amino acid residues from a protein sequence and confirming its physiological effect is also performed. However, a dipeptide having a lipid lowering action is not known. From the viewpoint of peptide synthesis, the synthesis is easy and practical because the number of amino acid residues is small. If an effective peptide is found as a dipeptide, it can be a safe and practical lipid lowering agent.

  Development of an effective ingredient that is a dipeptide among food-derived peptides with high safety is desired.

JP 2004-300114 A JP 2005-206545 A JP-A-2005-506326

  To obtain a peptidic lipid-lowering agent derived from soybean protein, which is a general-purpose food ingredient, and is highly safe and effective for medical use and specific health food use.

  The inventors of the present invention fractionated peptides obtained by enzymatic degradation of soybean protein and proceeded with intensive studies such as fractionation / purification of fractions with high lipid-lowering / lipid metabolism-improving effects. The present invention was completed by synthesizing and identifying the identified dipeptide and confirming its effect.

That is, the present invention provides (1) one or more active ingredients selected from dipeptides represented by Ser-Tyr, Val-Lys, Lys-Ala, and salts thereof, which are sequences found in soybean protein. And (2) the lipid-lowering agent reduces the ability to synthesize triglycerides in the liver, and (3) a dipeptide represented by Val-Lys, Lys-Ala and a salt thereof. A liver triglyceride synthesis and secretion inhibitor containing either or both of these as active ingredients.
(4) A phospholipid, cholesterol ester, free cholesterol, or free fatty acid synthesis inhibitor that is a lipid in the liver, comprising as an active ingredient one or both of a dipeptide represented by Val-Lys, Lys-Ala, or a salt thereof. (5) An apolipoprotein B100 secretion inhibitor comprising Ser-Tyr or a salt thereof as an active ingredient.

  According to the present invention, the safety is high, the ingestion form is also versatile, and the method for obtaining can be selected from a plurality of methods such as enzymatic degradation of soybean protein, which is a general food material, or peptide synthesis. It is possible to obtain a dipeptide lipid-lowering agent for medical use and for specific health foods.

  Three types of dipeptides, (1) Ser-Tyr, (2) Val-Lys, and (3) Lys-Ala, which are active ingredients as lipid lowering agents of the present invention, are sequences in soybean protein, It can be obtained by degrading the protein with an appropriate enzyme, fractionating it and purifying the fraction containing the desired peptide, and it can also be obtained by ordinary peptide synthesis methods because the peptide chain length is as short as 2. It is done.

  For the three dipeptides, (1) Ser-Tyr is the 62-63rd in the primary structure of the A2 subunit of soybean glycinin, (2) Val-Lys is the 237-238th, (3) Lys- Ala is present at positions 458-459 in the α subunit. The amino acid sequence of soybean protein is shown in FIGS.

  When the dipeptide of the present invention is obtained by a synthesis method, a chemical synthesis method (solid phase method, liquid phase method), an enzyme synthesis method, and a biological synthesis method using a DNA recombination method, which are used for usual peptide synthesis, are used. Although known, any method may be used. As for the enzymatic method, a method utilizing the reverse reaction of a proteolytic enzyme (protease) (J. Biol. Chem., 7 07-720 (19 9 37) thermostable aminoacyl t-R Although a method using an NA synthase [see Japanese Patent Application Laid-Open No. 5-9-106 2 98] is already known, recently, a production method using a microorganism belonging to the genus Escherichia or Bacillus (International Publication No. 2004/0 5 8 9 6 0) is disclosed.

  Further, the peptide of the present invention obtained by synthesis can be purified by a conventional purification method using reverse phase high performance liquid chromatography, tachromatography, affinity chromatography, etc. using ion exchange resin or high porous polymer resin. . These lipid-lowering peptides can be in the form of powders, tablets, etc., or added to ordinary foods to be ingested as food or drink, and can be directly administered into blood as an infusion or injection It is also possible to use.

  The lipid-lowering peptide of the present invention is effective in suppressing the excessive synthesis and accumulation of major lipid components in the liver, and also in the synthesis and secretion of TG and the like in the liver causing hypertriglyceridemia. Effective for suppression. In addition, triglyceride, cholesterol and phospholipid metabolism influence the intracellular metabolism of apolipoprotein B100, an essential constituent protein of VLDL biosynthesized in the liver, and it is known that triglyceride synthesis is particularly strongly involved. Since the concentration of apolipoprotein B100 in the blood has a positive correlation with the incidence of arteriosclerosis such as coronary artery disease, its excessive secretion is regarded as an independent risk factor. By suppressing the secretion of this apolipoprotein, the effect of suppressing the onset of arteriosclerosis can be obtained.

  The embodiment in which the dipeptide of the present invention is used as a composition for eating and drinking is produced by adding one or more of the above dipeptides as a single intake, preferably 0.01 mg to 10 g, more preferably 100 mg to 1000 mg. The dipeptide of the present invention is a solid or powder that is easy to handle and stable, and has good solubility in water. Absorption from the gastrointestinal tract is also good. Therefore, there are no particular restrictions on the timing and method of addition to food, and it can be used as a powder, solution, suspension, etc., in the raw material stage, intermediate process, and final process of food production by a method commonly used in the food field. It is possible to add.

By ingesting the food and beverage composition containing the dipeptide of the present invention temporarily, intermittently, continuously or daily, inhibition of TG synthesis and secretion in the liver is suppressed, and for example, an effect of lowering serum TG is obtained. It is possible. Examples of the form of food and drink include solid, semi-fluid, and fluid. Examples of the solid food include general foods and health foods in the form of biscuits, sheets, tablets such as tablets and capsules, and granular powders. Examples of the semi-fluid food include paste, jelly, and gel. Examples of the fluid food include general food and health food in the form of juice, soft drink, tea drink, and drink. It is also possible to suppress an increase in serum TG by continuously ingesting the dipeptide of the present invention using food and drink as an energy drink or seasoning.

  In an embodiment in which the dipeptide of the present invention is used as a pharmaceutical composition, the dipeptide of the present invention is administered in the same amount as the above-mentioned composition for eating and drinking. The pharmaceutical composition of the present invention may be temporarily administered to patients with high TG symptoms in order to suppress TG synthesis inhibition and secretion in the patient's liver and consequently reduce serum TG. Since the active ingredient of the pharmaceutical composition of the present invention is derived from a natural product, it can be used safely continuously.

Examples of diseases that can be treated and / or prevented by the pharmaceutical composition of the present invention include high TG plasma. The form of the pharmaceutical composition is preferably an orally administered agent such as a tablet, capsule, powder, granule or syrup. Preparations for parenteral administration include sterile solutions for administration through intravenous, arterial, subcutaneous, muscle, such as tube feeding, or for inhalation through the nasal cavity. The liquid agent may be a dry solid that can be dissolved at the time of use. Intravenous injection preparations can be produced by dissolving the dipeptide as an active ingredient in physiological saline, and by normal aseptic operation into injection preparations or infusions.

The present invention will be specifically described below. First, experimental materials and cell culture will be described.

(Cultivated cells and reagents used in the experiment)
HepG2 cells were purchased from Dainippon Sumitomo Pharma Co., Ltd. (Osaka). Bovine serum albumin (BSA, fatty acid-free) and Dulbecco's modified Eagle's medium (DME medium) were purchased from Sigma Aldrich (St. Louis, MO, USA). Fetal calf serum (FCS), penicillin and streptomycin were purchased from MP Biomedicals, Inc. (Ohio, USA). Trypsin was purchased from Difco Laboratories (Detroit, MI, USA). Cell culture dishes and other culture equipment were manufactured by Nunc (Roskilde, Denmark). [14C] Acetic acid was purchased from Amersham, Inc. (Buckinghamshire, England). Silica gel 70 plate was purchased from Wako Pure Chemical Industries, Ltd. (Osaka). BCA (bicinchoninic acid) Protein Assay Reagent was purchased from Pierce Biotechnology, Inc. (Rockford, IL, USA). Cyntisol Ex-H was purchased from Dojin Chemical Laboratory (Kumamoto).

(HepG2 cell culture method)
The cells were cultured in a 100 × 20 mm cell culture dish using 10 ml of DME medium. DME medium containing 10% FCS, penicillin (100 IU / ml) and streptomycin (100 μg / ml) was used for subculture. Cell culture was performed under conditions of 37 ° C., 95% air, and 5% carbon dioxide, and the medium was replaced every 3 days. When the cells became confluent, they were subcultured by the following method. All the medium in the dish was removed, and the cells were quickly washed with PBS (phosphate buffered saline), and then an appropriate amount of 0.3% trypsin solution (containing 0.03% EDTA) was added and incubated at 37 ° C. for 2 minutes. Thereafter, an appropriate amount of DME medium containing 10% FCS was added to stop the trypsin reaction, and the cells were well suspended. The suspension was centrifuged at 190 × g for 3 minutes and the cells were collected. After dividing the cells into 1/3, the cells were cultured in a DME medium containing 10% FCS until the number of cells available for the experiment was reached. The number of cells was counted using a cytometer. Before starting the experiment, cells (5 × 10 5 cells / dish) were seeded in a 3.5 cm dish and cultured using 2 ml DME medium (containing 10% FCS) per dish. When the cells became confluent, they were washed with PBS and pre-cultured in 1% BSA-DME medium containing 0.5 mM oleic acid for 24 hours. After pre-culture, the test medium was replaced, and at the same time, 18.5 kBq of [14C] acetic acid, which is a radioactive lipid precursor, was added and cultured for 24 hours. These cells and media were collected and subjected to analysis.

(Medium preparation method and dipeptide concentration used in the test)
DME medium was used as the basic medium. The preculture medium was supplemented with 0.5 mM oleic acid as a 1% BSA complex. The oleic acid-BSA complex was prepared by sonication for 15 minutes at a microchip limit using an ultrasonic generator (Sonifier 250, Branson Ultrasonic Co., Danbury, CT, USA). In the test medium, 1% BSA-DME medium was used for the control group, and each dipeptide was added to the test group at 5 mg / ml in the 1% BSA-DME medium. These media were sterilized by filtration through a 0.45 μm filter (DISMIC-25cs Cellulose Acetate 0.45 μm, Toyo Roshi Kaisha, Ltd, Tokyo).

(Measurement method of lipid)
The content of triglycerides (hereinafter abbreviated as TG) synthesized intracellularly and the content of TG secreted extracellularly, and the content of lipid synthesized in cells other than TG and the content of lipid secreted extracellularly by the following methods It was measured. In addition to the TG, the following five types of lipids were measured. PL: phospholipid, CE: cholesterol ester, FC: free cholesterol, DG: diglyceride, FFA: free fatty acid

(Analytical sample adjustment method)
Lipids synthesized in the cells were extracted by the following method. Moreover, a cell culture solution was used for the measurement of the lipid content secreted outside the cell.
According to a report by Yotsumoto et al. (Planta Med. 63 (2): 141-5, 1997.), [14C] acetic acid (Amersham, Inc. (Buckinghamshire, England)) was used. That is, HepG2 cells were pre-cultured in 1% BSA-DME medium for 24 hours and then replaced with each test medium. [14C] Acetic acid was added to the test medium at 18.5 kBq, and the cells were cultured for 24 hours, and then separated into cells and medium. Further, the cells were washed with PBS, 2 ml of PBS was added, and the cells were collected using a cell scraper. The collected cells and medium were stored frozen at −35 ° C. until analysis.
The collected cells were thawed and crushed using an ultrasonic generator to prepare a cell homogenate. Protein was quantified using BCA Protein Assay Reagent (Smith PK et al. Measurement of protein using bicinchoninic acid. Anal Biochem. 150 (1): 76-85, 1985).

  Lipids from cells and medium were extracted and purified according to the Bligh and Dyer method (Bligh EG et al. Can J Biochem Physiol. 37 (8): 911-7, 1959). A certain amount of cell homogenate and medium were placed in a test tube with a stopper, 4.5 ml of chloroform: methanol (1: 2) was added and stirred well, 1.5 ml of chloroform was added, and the mixture was heated at 37 ° C. for 1 hour. Then, water was added so that it might finally become a mixed liquid of chloroform: methanol: water (1: 1: 0.8), and centrifuged at 1,750 × g for 15 minutes. The lower chloroform layer was collected, concentrated with nitrogen gas, dissolved in a certain amount of petroleum ether, and subjected to lipid analysis.

(Measurement method of TG content)
The TG content synthesized intracellularly and the TG content secreted extracellularly (in the medium) were measured with a liquid scintillation counter using each lipid extract prepared as described above.
An aliquot of the lipid extract was placed in a vial, the organic solvent was evaporated and dissolved in a liquid scintillation cocktail (Scintisol Ex-H). The radioactivity was counted with a liquid scintillation counter (WALLAC 1440TM, Pharmacia, Finland), and this was taken as the total count.

Regarding the measurement of lipids synthesized inside and outside cells other than TG,
The lipid content synthesized intracellularly and the lipid content secreted extracellularly (in the medium) were measured by fractionation by thin layer chromatography using the lipid extract prepared above. (Thin layer chromatography, TLC) method (Yanagita T et al. Biochim Biophys Acta. 919 (1): 64-70, 1987 and Cha JY et al. Biosci Biotechnol Biochem. 62 (3): 508-13, 1998.)
In addition to the TG, the following five types of lipids were measured. PL: phospholipid, CE: cholesterol ester, FC: free cholesterol, DG: diglyceride, FFA: free fatty acid
Commercially available silica gel 70 plates were used for TLC, and petroleum ether: diethyl ether: acetic acid (82: 18: 1, v / v / v) was used as a developing solvent. After the completion of development, the plate was wrapped with a wrap film, placed in a cassette so that the exposure surface of the imaging plate and the plate were aligned, and contact exposure was performed for several hours. Thereafter, the radioactivity was measured using a bioimaging analyzer (BAS1000, Fuji Photo Film, Kanagawa). Radioactivity was calculated from the area ratio of each band obtained and the total count.
The data obtained in the experiment was subjected to multiple testing using Duncan's multiple range test (Biometrics. 11 (1): 1-42, 1955.).

[Method for measuring apolipoprotein secretion]
The apolipoprotein in the present invention was measured according to the following method.
Quantification of apolipoprotein B100 in a human liver-derived HepG2 cell line was measured by ELISA using Total Human Apolipoprotein B ELISA assay (ALerCHEK, Inc., Maine, USA). Data obtained from experiments were subjected to multiple tests using Duncan's multiple range test

Examples will be described below, but the technical idea of the present invention is not limited to these examples.

Preparation of peptides Among the peptides present in soybean protein by the usual peptide solid-phase synthesis method, six dipeptides of Ala-Leu, Ala-Tyr, Ala-Val, Lys-Ala, Ser-Tyr, and Val-Lys were synthesized. Synthesized and confirmed its physiological effect.

[Investigation of the effects on intracellular TG synthesis and extracellular TG secretion]
The effects of dipeptides isolated and identified from soybean peptides on TG synthesis inside and outside the cells were examined using the synthesized peptides by adjusting the sample by the method described above and measuring the TG content inside and outside the cells. .
The results are shown in FIGS.

  As shown in FIG. 1, the amount of cellular TG synthesized from [14C] acetic acid after 24 hours of culture was 50% for Lys-Ala, 25% for Ser-Tyr, and Val-Lys compared to the group without peptide addition. A significant decrease of 44% was observed. On the other hand, as is apparent from FIG. 2, the amount of TG taken up into the medium after taking up [14C] acetic acid in the cells was 37% with Lys-Ala, 39% with Ser-Tyr, and 52 with Val-Lys. A significant decrease in% was observed.

[Influence on cellular lipid synthesis and extracellular secretion other than TG]
The sample was prepared by the method already described ([0023], “0025”), and the lipid content synthesized in cells other than TG and the lipid content secreted extracellularly were measured and isolated and identified from soybean peptide. The effect of the dipeptides on the intracellular and extracellular lipid synthesis was examined using the synthesized dipeptides.
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    From Table 1, as for lipid synthesis, first, synthesis of phospholipids and free fatty acids was significantly suppressed by Lys-Ala, Ser-Tyr, and Val-Lys. Furthermore, Lys-Ala significantly suppressed diglyceride and Ser-Tyr significantly suppressed cholesterol ester synthesis. Ala-Val also significantly reduced the synthesis of free fatty acids. Regarding the secretion of lipid into the medium, from Table 2, Lys-Ala, Ser-Tyr, and Val-Lys significantly suppressed the secretion of free fatty acids. Furthermore, Lys-Ala significantly suppressed the secretion of cholesterol ester, and Ser-Tyr significantly suppressed the secretion of free cholesterol and cholesterol ester. However, phospholipid secretion increased in Ala-Leu, Ala-Tyr, and Ala-Val.

[Effect on apolipoprotein B100 secretion]
Samples were prepared by the method described above, and the effects of dipeptides isolated and identified from soybean peptides on the secretion of apolipoprotein from liver cells were examined using synthesized dipeptides. The results are shown in Figure 3.

  As is clear from FIG. 3, the dipeptide Ser-Tyr markedly decreased the apolipoprotein 100 secretion amount by 35% compared to the peptide-free group.

[Supplementary Experiment] Preparation and Identification of Peptide by Enzymatic Degradation and Fractionation of Soy Protein Hereinafter, the embodiment of the present invention will be described in more detail with respect to the preparation method, identification and effect of dipeptide.

  First, the enzymatic degradation of soybean protein will be described. As a raw material for soy protein, soy milk, concentrated soy protein, or separated soy protein, defatted soybean, soy whey protein, and the like can be used, and among them, isolated soy protein is preferable. The concentration of soybean protein in the enzyme reaction solution may normally be about 1 to 30% by weight, preferably 5 to 15% by weight, more preferably 8 to 12% by weight.

  The proteolytic enzyme (protease) used is not particularly limited in origin, and specifically, serine protease (animal trypsin, chymotrypsin, microbial subtilisin, carboxypeptidase, etc.), thiol protease (plant-derived papain, ficin) , Bromelain, etc.), carboxyproteases (animal-derived pepsin, etc.) can be used. Specifically, "Protin FN" derived from Aspergillus oryzae (manufactured by Daiwa Kasei Co., Ltd.), "Actinase" derived from Streptomyces griseus (manufactured by Kaken Pharmaceutical Co., Ltd.), "Alcalase derived from Bacillus liqueformis" ("Novozymes Japan Ltd.") and "Protin" (manufactured by Daiwa Kasei Co., Ltd.) derived from Bacillus subtilis. In addition, “Protease S” (manufactured by Amano Pharmaceutical Co., Ltd.), “Thermolysin” (manufactured by Daiwa Kasei Co., Ltd.) and the like can be used. These enzymes can be enzymatically decomposed alone or in combination.

[Experiment 1] Isolation and identification of dipeptide from soybean protein (1) Production of soybean peptide (SCP-LD3) 30 kg of separated soybean protein (Fuji Oil Co., Ltd., "New Fuji Pro-F") with pH 7.0 It is made into a 9% aqueous solution, 1.2 kg of proteolytic enzyme (“Protin AY”, manufactured by Amano Pharmaceutical Co., Ltd.) is allowed to act on it and hydrolyzed at 60 ° C. for 5 hours (15% TCA solubility: 85%), then 30 Heat-inactivate for 5 minutes, then remove the insoluble material by a centrifuge, filter the supernatant with a 0.45 micron filter (Kuno Co., Ltd.), dry it by spray drying, and add 18 kg of peptide powder SCP-LD3. Obtained.

(2) Isolation and identification of dipeptide from soybean peptide (SCP-LD3) After adjusting 5kg of SCP-LD3 obtained above to 20%, a column (diameter 30cm x 30cm) loaded with hydrophobic resin HP-21 (Mitsubishi Kasei) The peptide having a high hydrophobicity was adsorbed and removed by passing the solution through a height of 90 cm), and the non-adsorbed fraction containing the peptide rich in hydrophilicity was collected and dried to obtain 2 kg.

(3) 1 g of this peptide powder was dissolved in 30% acetonitrile (CH3CN) + 0.1% trifluoroacetic acid (TFA), gel-filtered with a Bio-Rad Superdex Peptide HR10 / 30 column (1.0 x 30 cm), and divided into 4 fractions. Fractionation was performed, and a fourth fraction rich in dipeptide was collected and lyophilized to obtain F4 fraction. This operation was performed several times to obtain a final F4 fraction of about 100 mg.

(Gel filtration conditions)
Column: Bio-Rad Superdex Peptide HR10 / 30 column (1.0 x 30 cm)
Eluent: Eluent 30% CH3CN / 0.1% TFA,
Flow rate: 0.3ml / min,
Detection: 220nm wavelength
Column temperature: 35 ° C

  (4) About 10 mg of this F4 fraction was subjected to ODS open column chromatography (20 × 60 mm), 0% CH3CN / 0.1% TFA fraction, 20% CH3CN / 0.1% TFA fraction, 50% CH3CN / 0.1 Fractionated into 3 fractions of% TFA fraction. When the fluctuation of lipid metabolism was examined in HepG2 cells, it was found that the 0% CH3CN / 0.1% TFA fraction was the most active.

(Fractionation conditions on ODS column)
Column: ODS open column chromatography (20 x 60 mm)
Eluent: 0% CH3CN / 0.1% TFA, 20% CH3CN / 0.1% TFA, 50% CH3CN / 0.1% TFA Eluent Flow rate: Flow rate 0.3ml / min
Detection: 220nm
Column temperature: (35 ℃)

(5) Isolation and identification from 0% CH3CN / 0.1% TFA fraction The 0% CH3CN / 0.1% TFA fraction with the highest activity was analyzed by reversed-phase high performance liquid chromatography (COSMOSIL 5C18-AR-II column (4.6 × 250 mm ), A flow rate of 0.3 ml / min, a detection wavelength of 220 nm, a column temperature of 35 ° C.), and 12 peaks were collected. Next, RP-HPLC (COSMOSIL 5C18-AR-300 column (4.6 × 250 mm), flow rate 0.3 ml / min, detection wavelength 220 nm, column temperature 35 ° C.) for each peak obtained with the 5C18-AR-II column Re-sorted by The amino acid sequence of each peak was determined by Shimadzu PPSQ-21 Protein Sequencer by automatic Edman degradation.
As a result, Ala-Leu, Ala-Tyr, Ala-Val, Lys-Ala, Ser-Tyr, Val-Lys, and Leu-Val were confirmed.
The conditions are described below.
Column: COSMOSIL 5C18-AR-II column (4.6 x 250 mm)
Eluent:
Flow rate: Flow rate 0.3ml / min
Detection: 220nm
Column temperature: (35 ℃)

  A dipeptide having a sequence in soy protein that is generally eaten can safely inhibit lipid metabolism (lipid synthesis, lipid absorption) in a living body.

Effects of soy peptide-derived dipeptides on lipid synthesis in liver cells Significantly different between different symbols P <0.05 Effect of dipeptide derived from soybean peptide on TG secretion from liver cells Significant difference between different symbols P <0.05 Effect of soy peptide-derived dipeptide on apolipoprotein B100 secretion in HepG2 liver cells Significant difference between different symbols P <0.05 Amino acid sequence of soybean glycinin subunits Amino acid sequence of subunit of soybean β-conglycinin

Claims (5)

A lipid lowering agent in a living body comprising one or more dipeptides represented by Ser-Tyr, Val-Lys, Lys-Ala, and salts thereof, which are sequences found in soybean protein, as an active ingredient. The lipid-lowering agent according to claim 1, which reduces the ability to synthesize triglycerides in the liver. A triglyceride synthesis and secretion inhibitor in the liver, which contains either or both of the dipeptide represented by Val-Lys and Lys-Ala and a salt thereof as an active ingredient. An inhibitor of synthesis of phospholipids, cholesterol esters, free cholesterol, and free fatty acids, which are lipids in the liver, containing either or both of the dipeptides represented by Val-Lys and Lys-Ala and their salts as active ingredients. An apolipoprotein B100 secretion inhibitor comprising Ser-Tyr or a salt thereof as an active ingredient.

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