JP2000319185A - Lipid metabolism regulator and its use - Google Patents

Abstract

(57) [Summary] [Problem] A composition that can regulate the metabolism of lipids such as cholesterol and suppress the accumulation of visceral fat without worrying about side effects such as gout and can be used for prevention of obesity and the like. ,
Provide food and drink. The present invention relates to a lipid metabolism regulator, a composition and a food or beverage containing uridylic acid and / or uridine as an active ingredient. The present invention also relates to a method for adding uridylic acid and / or uridine to food or drink for the purpose of improving lipid metabolism such as improving cholesterol metabolism in blood and / or suppressing accumulation of visceral fat.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a lipid metabolism regulator containing uridylic acid and / or uridine as an active ingredient, and its use.

[0002]

2. Description of the Related Art With the westernization of dietary habits, diseases considered to be caused by accumulation of visceral fat or abnormal lipid metabolism are increasing. For example, hypercholesterolemia, which is considered as one of the atherosclerosis-causing factors, is one such disease. Most of the cholesterol in the blood is in the low density lipoprotein (LDL) fraction, and the majority of the rest is in the high density lipoprotein (HDL) fraction.
Since LDL acts to supply cholesterol to extrahepatic tissues, when the blood concentration of LDL increases, excess cholesterol is supplied to the blood vessel wall, which increases the risk of arteriosclerosis. On the other hand, HDL transfers excess cholesterol from extrahepatic tissues to the liver.
L has a function exactly opposite to that of L. By increasing the amount of HDL in blood, the risk of developing arteriosclerosis can be reduced.

[0003] In recent years, the physiological functions of nucleotides [adenylic acid (AMP), guanylic acid (GMP), cytidylic acid (CMP), and uridylic acid (UMP)], which are constituents of nucleic acids, have been attracting attention. Changes in lipoprotein concentration in blood can be observed when infants are fed the added milk (Nutr. Res., Vol. 6, p763-
771 (1986), Acta Paediatr., Vol.83, p481-485 (1994),
Pediatr. Res., Vol. 35, pp. 112-116 (1994)).
It has been reported that lowering DL cholesterol level and increasing HDL cholesterol level (Nishizawa et al., The 70th Annual Meeting of the Japanese Society for Agricultural Chemistry, Abstracts of Lecture P. 15 (1996)).

[0004]

In general, it has been pointed out that excessive intake of purine nucleotides increases blood uric acid level and is one of the causes of gout. Therefore, even if the purine nucleotide mixture has a cholesterol metabolism regulating ability, there remains a concern about application to foods and drinks. Further, in all of the conventional reports, a mixture of nucleotides and purine nucleotides is used, and the physiological function of each nucleotide alone has not been clarified at all, and no suggestion can be found.

[0005]

Means for Solving the Problems As a result of repeated studies on the physiological function of nucleotides, the present inventors have found that uridylic acid or uridine alone lowers the blood LDL cholesterol level without using other nucleotides. Let H
The present inventors have found that they have an effect of increasing DL cholesterol level, have an excellent effect of regulating cholesterol metabolism, and suppress accumulation of visceral fat, and have completed the present invention.

That is, the present invention relates to uridylic acid and / or
Alternatively, the present invention relates to a lipid metabolism regulator containing uridine as an active ingredient. The present invention also relates to a composition containing uridylic acid and / or uridine as an active ingredient and having an effect of regulating lipid metabolism in a living body. Furthermore, the present invention relates to a food or drink containing uridylic acid and / or uridine and having a function of regulating lipid metabolism. Furthermore, the present invention relates to a method for adding uridylic acid and / or uridine to food or drink for the purpose of imparting a function of regulating lipid metabolism.

[0007]

DETAILED DESCRIPTION OF THE INVENTION Uridylic acid and / or uridine used in the present invention are known compounds, and commercially available products can be used for each. In addition, uridylic acid,
A uridine 5'-monophosphate having a phosphate residue at the 5 'position may be used, although a phosphate residue may be present at any of the 2', 3 'and 5' positions. I do. Such uridylic acid and / or uridine may be in a free form or in a salt form. Examples of such a salt include alkali metal salts such as sodium salt and potassium salt,
Various metal salts such as alkaline earth metal salts such as calcium salts can be exemplified. Of these compounds,
Particularly preferred is 5'-uridylate disodium (5'UMP-), which has already been approved as a food additive.
2Na).

According to the present invention, uridylic acid and / or uridine is administered to a pharmaceutical preparation, a pharmaceutical composition, a food or drink or an animal including a human who wants to regulate lipid metabolism (eg, hypercholesterolemia). Or an obese human). For example, when taking the form of food and drink, the target food and drink may be in the form of food and drink that is eaten everyday as well as various hospital foods, nutritional supplement foods, etc., powdered, granular, solid, liquid The type and form of the food, such as semi-liquid, are not particularly limited. For example, by adding uridylic acid and / or uridine at the time of production or eating and drinking, these various foods and drinks can take in uridylic acid and / or uridine in an amount necessary for the expression of the action.

In the case of taking a form of a pharmaceutical preparation or a composition, any preparation method can be prepared according to a conventional method of a pharmaceutical preparation, for example, a liquid form such as a drink or syrup, a tablet, a capsule or a granule. It can be adopted in various forms of oral ingestion such as a solid form.
Carriers, excipients and other additives used in the preparation are not particularly limited, for example, lactose, kaolin, crystalline cellulose, talc, agar, pectin, stearic acid, starch, solid substances such as sodium chloride, Examples thereof include liquid forms such as water, glycerin, peanut oil, polyvinylpyrrolidone, ethanol, benzyl alcohol, and propylene glycol.

The intake or dosage of uridylic acid and / or uridine in the present invention varies depending on the health condition, the degree of blood lipids, age, body weight, sex, etc., but is 1 to 10,000 mg per day for an adult, preferably 1 to 10,000 mg per day. 1-100
The dose may be taken or administered as a single dose or divided into multiple doses with 0 mg as a guideline.

[0011]

According to the present invention, uridylic acid and / or uridine alone can improve lipid metabolism without using other nucleotides, specifically, blood cholesterol metabolism (HDL
It has been found for the first time by the present inventors that the present invention has a physiological function for increasing cholesterol level and lowering LDL cholesterol level) and suppressing accumulation of visceral fat. The lipid metabolism regulator, composition and food / drink of the present invention containing uridylic acid and / or uridine based on such findings is concerned about side effects such as hyperuricemia and gout like purine nucleotides. Cholesterol metabolism in a living body such as lowering blood LDL cholesterol level and increasing HDL cholesterol level in a desirable direction, and accumulating visceral fat. Can also be suppressed. Therefore, the foods and drinks containing uridylic acid and / or uridine of the present invention can be expected to be useful for improving the metabolism of blood lipids, preventing and improving hypercholesterolemia, obesity and the like.

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Example 1 Using an ICR male mouse (5 weeks old)
Three groups are set up to provide each type of feed. 3
Types of feed are Oriental Bio's refined feed (purified food), Oriental Bio's high-fat low-fiber feed (high-fat diet), Clea Japan's C
E-2 (CE-2), and their formulations are shown in Tables 1 and 2. The high-fat diet has a higher proportion of animal fat and a lower proportion of dietary fiber as compared to the refined diet, and these two types of feed do not contain nucleotides. CE-2 is a diet normally consumed by mice and contains nucleotides derived from the diet. CE-
Table 3 shows the ratio of nucleotides and nucleosides in 2.

[0013]

[Table 1]

[Table 2]

[Table 3]

Each group consisted of 9 to 11 animals, and each group contained 10% of an aqueous nucleotide solution having the following composition.
once daily, orally 5 days a week at a rate of 10 ml / kg.
Continued for a week. <Experiment 1> Group giving purified food Purified food + distilled water (10 ml / kg) <Control group> Purified food + 5 'UMP-2Na (100mg / 10m
1 / kg) 3. Purified food +5 'AMP-2Na + 5' UMP-2Na
+5 ′ CMP-2Na + 5 ′ GMP-2Na (each nucleotide 100 mg / 10 ml / kg) <Experiment 2> Group feeding high fat diet 1. High fat diet + distilled water (10ml / kg) <Control group> High fat diet + 5 'AMP-2Na (100mg / 10
ml / kg) 3. High fat diet + 5 'UMP-2Na (100mg / 10
ml / kg) 4. High fat diet + 5 'AMP-2Na + 5' UMP-2N
a + 5 ′ CMP-2Na + 5 ′ GMP-2Na (each nucleotide 100 mg / 10 ml / kg) <Experiment 3> Group giving CE-2 1. CE-2 + distilled water (10 ml / kg) <control group> CE-2 + 5′UMP-2Na (100 mg / 10
ml / kg) 3. CE-2 + 5′UMP-2Na (500 mg / 10
ml / kg)

Ten weeks after the start of the experiment, blood was collected from the abdominal vena cava to separate plasma, and the concentration of lipid contained in blood collected from each individual was measured by a conventional method. The measured lipids were HDL cholesterol and LDL cholesterol in Experiments 1 and 2, and total cholesterol (TC), HDL cholesterol and LDL cholesterol in blood in Experiment 3, and the measurement results are shown in FIGS.
5, 7-9. The arteriosclerosis index (LDL cholesterol value / HDL cholesterol value) was determined from the above measurement results, and the results are shown in FIGS.

From the above results, in the growing mouse,
Compared to the control group, the uridylic acid alone administration group can lower the blood LDL cholesterol level and increase the HDL cholesterol level even when administered to the group bred with any of the three diets, and can increase the atherosclerosis index. And improved cholesterol metabolism. On the other hand, there was no change in LDL cholesterol level in the group to which adenylic acid (partially deaminated and inosinic acid or inosine was presumed to be absorbed), and the arteriosclerosis index was improved compared to the control group. It was never done. Furthermore, even in a group in which uridylic acid and several other nucleotides are used in combination, the LDL cholesterol level in blood can be reduced and HDL can be reduced.
Although the cholesterol level could be raised, the arteriosclerosis index was lowered, and the cholesterol metabolism was improved, so-called additive or synergistic effects were not observed, which were higher than those obtained in the uridylic acid alone administration group. This suggested that the lipid metabolism regulating function was provided by uridylic acid or uridine dephosphorylated and absorbed in the intestine.

[0017]

Example 2 ICR male mice (5 weeks old) were divided into four groups, and a purified diet or a high fat diet shown in Table 1 was used as a feed, and each group received one aqueous nucleotide solution having the following composition.
Orally at a rate of 0 ml / kg once a day, 5 days a week,
Continued for 10 weeks. 1. 1. Purified food + distilled water (10 ml / kg) 2. High fat diet + distilled water (10 ml / kg) <Control group> High fat diet + 5 'AMP-2Na (100mg / 10
ml / kg) 4. High fat diet + 5 'UMP-2Na (100mg / 10
10 weeks after the start of the experiment, the epididymal fat weight and the perirenal fat weight were measured and calculated as the total value of the epididymal fat and the perirenal fat per 100 g of body weight. The result is shown in FIG.

From the above results, in the growing mouse,
It was found that the total fat weight around the epididymis and kidney was reduced in the uridylic acid-administered group compared to the control group.
On the other hand, such an effect was not observed in the group administered with adenylic acid alone. Therefore, it was shown that the suppression of the accumulation of visceral fat in the abdominal cavity is specific to uridylic acid or uridine which is a form absorbed in the intestine.

[0019]

Example 3 Since lipids increased during hyperlipidemia and fatty liver caused by excessive intake of alcohol are mainly triglycerides (triglycerides), the blood of uridylic acid in ethanol-induced hypertriglyceridemia rats The effect on medium lipids was examined. <Experiment 4> Using Wistar female rats (3 weeks old)
Three groups are set up to feed each of the three feeds.
The feeds of the three groups are as follows. 1. Nucleotide-free diet: manufactured by Oriental Bio
1. Purified diet based on 20% casein Nucleotide diet: 5 'AMP-2Na, 5' GMP-2Na, 5 'UM for purified diet based on 20% casein
P-2Na and 5'CMP-2Na were each added to 0.12
5% content 3. UMP diet: 0.5% 5 'UMP-2Na in a purified diet based on 20% casein. Table 4 shows these formulations.

[Table 4] These three types of feeds are slightly varied in the components and proportions to equalize the calories.

Each group was bred on each feed and 7
From the week, 38% ethanol was orally administered once a day at a rate of 10 ml / kg and continued for 10 weeks. 10 from the start of the experiment
After breeding for 3 weeks (3 weeks after ethanol administration), blood was collected from the abdominal aorta. Blood collection was performed 5 hours after ethanol administration,
The plasma was separated, and the concentration of lipid contained in blood collected from each individual was measured by a conventional method. The measured lipids were blood total cholesterol, triglyceride, LDL cholesterol, and HDL cholesterol, and the measurement results are shown in FIGS. The arteriosclerosis index (LD
L cholesterol level / HDL cholesterol level), and the results are shown in FIG.

From the above results, both the blood total cholesterol level and the blood triglyceride level were reduced in the UMP diet administration group. In addition, it was confirmed that LDL-cholesterol level in blood could be lowered, HDL-cholesterol level could be raised, arteriosclerosis index was lowered, and cholesterol metabolism was improved. Furthermore, the effect of improving blood lipids was also observed with the nucleotide diet, but no additive or synergistic effect was observed that was higher than the results obtained with the UMP diet. Therefore, it was shown that the effect of improving blood lipids in ethanol-induced hypertriglyceridemia rats was specific to uridylic acid or uridine, which is a form absorbed in the intestine.

[0022]

[Brief description of the drawings]

FIG. 1 shows the blood LDL cholesterol level in Experiment 1. The number 1 on the horizontal axis is purified food + distilled water (10 ml / kg), 2 is purified food + 5′UMP-2Na
(100mg / 10ml / kg), 3 is purified food + 5'A
MP-2Na + 5'UMP-2Na + 5'CMP-2N
a + 5'GMP-2Na is shown (FIGS. 2 and 3 are the same). * In the figure is 5% risk ratio compared to the value of the control group.
Less than indicates a significant difference, and ** indicates a significant difference at a risk factor of less than 1% as compared to the value of the control group (the same applies to the following figures).

FIG. 2 shows the blood HDL cholesterol level in Experiment 1.

FIG. 3 shows the arteriosclerosis index of Experiment 1.

FIG. 4 shows the blood LDL cholesterol level in Experiment 2. No. 1 on the horizontal axis is high fat diet + distilled water (10 ml / kg), 2 is high fat diet + 5 'AMP-2N
a (100 mg / 10 ml / kg), 3 is high fat diet +
5 ′ UMP-2Na (100 mg / 10 ml / kg),
4 is a high fat diet + 5 'AMP-2Na + 5' UMP-2N
a + 5 ′ CMP-2Na + 5 ′ GMP-2Na (each nucleotide 100 mg / 10 ml / kg) is shown (FIGS. 5 and 6 are also the same).

FIG. 5 shows the blood HDL cholesterol level in Experiment 2.

FIG. 6 shows the arteriosclerosis index of Experiment 2.

FIG. 7 shows the total blood cholesterol level in Experiment 3. Number 1 on the horizontal axis is CE-2 + distilled water (1
0 ml / kg), 2 is CE-2 + 5′UMP-2Na
(100mg / 10ml / kg), 3 is CE-2 + 5 '
8 shows UMP-2Na (500 mg / 10 ml / kg) (FIGS. 8, 9 and 10 are also the same).

FIG. 8 shows the blood LDL cholesterol level in Experiment 3.

FIG. 9 shows the blood HDL cholesterol level in Experiment 3.

FIG. 10 shows the arteriosclerosis index of Experiment 3.

FIG. 11 shows the total weight of peri-renal fat and epididymal fat per 100 g of body weight. Number 1 on the horizontal axis is purified food + distilled water (10 ml / kg), 2
Is a high-fat diet + distilled water (10 ml / kg), 3 is a high-fat diet + 5 ′ AMP-2Na (100 mg / 10 ml / k)
g), 4 is a high fat diet + 5 ′ UMP-2Na (100 mg
/ 10 ml / kg).

FIG. 12 shows the blood total cholesterol level in Experiment 4. Number 1 on the horizontal axis indicates a nucleotide-free diet, 2 indicates a nucleotide diet, and 3 indicates a UMP diet. (The same applies to FIGS. 13, 14, 15, and 16).

FIG. 13 shows blood triglyceride levels in Experiment 4.

FIG. 14 shows the blood LDL cholesterol level in Experiment 4.

FIG. 15 shows the blood HDL cholesterol level in Experiment 4.

FIG. 16 shows the arteriosclerosis index of Experiment 4.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07H 19/10 C07H 19/10

Claims (8)

[Claims] 1. A lipid metabolism regulator comprising uridylic acid and / or uridine as an active ingredient. 2. The lipid metabolism regulator according to claim 1, wherein the regulation of lipid metabolism relates to improvement of cholesterol metabolism in blood and / or suppression of accumulation of visceral fat. 3. A composition containing uridylic acid and / or uridine as an active ingredient and having an action of regulating lipid metabolism in a living body. 4. The composition according to claim 3, wherein the adjustment of lipid metabolism relates to improvement of cholesterol metabolism in blood and / or suppression of accumulation of visceral fat. 5. A food or drink containing uridylic acid and / or uridine and having a function of regulating lipid metabolism. 6. The food or drink according to claim 5, wherein the function of regulating lipid metabolism relates to improvement of cholesterol metabolism in blood and / or suppression of accumulation of visceral fat. 7. A method for adding uridylic acid and / or uridine to food or drink for the purpose of imparting a function of regulating lipid metabolism. 8. The method according to claim 7, wherein the function of regulating lipid metabolism relates to improvement of cholesterol metabolism in blood and / or suppression of accumulation of visceral fat.