JP2855290B2 - Lipid metabolism improver - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a lipid metabolism-improving agent having a serum lipid elevation inhibitory action, a liver lipid elevation inhibitory action, a sterol excretion promoting action, and the like.

[Conventional technology]

In recent years, mortality from cardiovascular disease has been increasing year by year,
Combined with diseases caused by arteriosclerosis such as myocardial infarction and cerebral infarction, they are the leading cause of adult death.

Although there are various causes of arteriosclerosis, elevated serum lipids, especially serum cholesterol, are regarded as one of the most important risk factors.

Genetic disorders are the primary cause of elevated serum cholesterol. In this case, drugs such as cholesterol synthesis inhibitors, nicomol, clofibrate, ion-exchange resins, and anabolic steroids are used for severely ill patients at the same time as dietary therapy. Side effects such as gastrointestinal disorders and carcinogenicity.

Another major cause of elevated serum cholesterol levels is the overdose of fat due to recent changes in dietary habits, which is becoming more pronounced among younger people. Dietary hypercholesterolemia usually does not lead to severe hypercholesterolemia, but the problem is that cholesterol gradually accumulates in blood vessels from a young age and causes arteriosclerosis in adults. Yes, there is a risk of myocardial or cerebral infarction in combination with hypertriglyceridemia. For this type of hyperlipidemia, dietary treatment in which fat intake is restricted to an appropriate range is more important than drug therapy which has problems such as side effects. However, dietary restriction is accompanied by emotional distress and enjoys eating habits, so it is difficult to implement it strictly and its effect is often limited.

Excess cholesterol in serum accumulates in the blood vessel wall and causes arteriosclerosis, but after it is taken up by the liver, it is converted to bile acids without accumulating there and released into the intestinal tract as it is If it is excreted with feces outside the body, the pool of cholesterol in the body is also reduced, and arteriosclerosis by the above mechanism is prevented. Therefore, it is expected to have not only a serum cholesterol level lowering action but also a liver cholesterol level lowering action and a bile acid excretion promoting action, but conventionally, none of them showing such three actions alone is known. .

JP-A-59-80610 discloses that a fraction obtained by removing a component having a molecular weight of about 3500 or less from a protease-treated product of a Streptococcus microorganism has cholesterol-lowering activity. The publication states that the cells of a microorganism belonging to the genus Bifidobacterium or Lactobacillus have a cholesterol-lowering effect. Each of them is described to have a serum cholesterol elevation inhibitory effect, but it is not described that it exhibits an effect more effective for improving lipid metabolism.

[Problems to be solved by the invention]

In view of the above problems, an object of the present invention is to comprehensively reduce dietary hypercholesterolemia, such as suppressing the elevation of serum lipids and hepatic lipids accompanying high-fat diet intake and promoting excretion of sterols into feces. It is an object of the present invention to provide a lipid metabolism improving agent which is effective for prevention of inflammation and is safe even if taken for a long time.

[Means for solving the problem]

The present invention, which has successfully achieved the above object, provides a lactic acid bacterium hot water extraction residue or a substance obtained by treating the hot water extraction residue with a protease further as an active ingredient, suppressing hepatic lipid elevation and sterols in feces. An object of the present invention is to provide a lipid metabolism-improving agent having an effect of promoting excretion and the like. However, the “residue of hot water extraction” in the present invention means that the cells are suspended in water.
It means an extraction residue obtained by performing hot water extraction accompanied by pretreatment left at 50 to 70 ° C for 1 to 5 hours.

First, the method for producing the lipid metabolism improving agent of the present invention will be described.
Lactobacillus belonging to the genus Lactobacillus is suitable, and Lactobacillus casei is particularly preferred. A preferred specific example is Lactobacillus casei YIT9018 strain (Microtechnical Laboratory No. 665).

The lactobacilli used in the lipid metabolism improving agent of the present invention may be those cultured by an ordinary method in an arbitrary medium. However, in consideration of the use, they are cultured in a corn steep liquor medium consisting of glucose 5% and corn steep liquor 14%. Is desirable.

The cells are collected from the medium by a conventional method and washed. Subsequently, the cells were suspended in water at a concentration of 20-80 g / 50-70 ° C.
And then kept at 100-121 ° C for 10-30 minutes.

After the treatment, the extraction residue is collected by a conventional method of cell separation such as centrifugation, and freeze-dried. The dried product can be used as it is as the first lipid metabolism improving agent of the present invention.

When this is further treated with a protease, it is treated with an actinase, trypsin or other protease capable of degrading the bacterial protein for an appropriate time until most of the bacterial protein is hydrolyzed, and then And fractionation by molecular weight to remove protein hydrolysates. The fractionation is performed by means of ultrafiltration, dialysis, molecular sieve, or the like which can remove a fraction containing a protein hydrolyzate having a molecular weight of about 50,000 or less. The high molecular weight fraction in which the active ingredient is present is concentrated under reduced pressure, lyophilized, and used as the second lipid metabolism improving agent of the present invention.

The lipid metabolism-improving agent according to the present invention not only suppresses a rise in serum cholesterol level but also suppresses a rise in cyclic lipids and promotes the excretion of sterols into feces. It is extremely effective in preventing illness. Protease treated products are particularly excellent in these effects.

The lipid metabolism improving agent of the present invention can be orally administered as it is or mixed with excipients and other auxiliaries usually used for the production of pharmaceuticals. Since it is almost tasteless and odorless, it can be administered daily by blending it with any food or drink.

〔Example〕

Production Example 1 Lactobacillus gasei YIT9018 was inoculated into corn steep liquor medium 400, and the medium pH was increased to 6.0 at 35 ° C. for 2 hours.
While culturing. Thereafter, the cells were collected and washed by centrifugation to obtain 2.4 kg of dried cells.

The cells were suspended in 48 water and left at 55 ° C. for 2 hours while controlling the pH at 7. Then, the mixture was heated to 100 ° C. for 10 minutes to elute the soluble components. The soluble fraction is removed by centrifugation, and the bacterial cell hot water extraction residue (hereinafter referred to as formulation A)
1.5 kg (dry weight) were obtained.

Production Example 2 300 g of the hot water extraction residue obtained from Production Example 1 was 1/15
After suspending in M · phosphate buffer (pH 8.6) 3 and homogenizing with a high-pressure homogenator, 12 g of protease / actinase (Kaken Pharmaceutical Co., Ltd.) was added and reacted at 50 ° C. for 16 hours. To prevent decay during the reaction, toluene was added as a preservative.

After the completion of the reaction, the fraction having a molecular weight of 50,000 or less is removed by ultrafiltration, and then linked and dried.
100 g were obtained.

Test Example 1 Four-week-old male SD rats were divided into three groups of six rats, and each group was allowed to freely take the feed shown in Table 1 and bred for 2 weeks. In addition, all the rats were bred in advance on a standard diet for control for one week.

The feed intake for 2 weeks after grouping was 235 ± 18 in the control group.
g, 233 ± 22 g in the control group and 247 ± 25 g in the test group, and there was no difference between the groups. Then, after fasting for 18 hours, blood was collected from the abdominal vena cava under anesthesia. After blood collection, the liver was excised while perfusing physiological saline, immediately cooled on ice, weighed, and then frozen and stored. In addition, feces were collected for two days before fasting.

The collected blood was centrifuged to collect serum and analyzed for serum lipids. For the liver, the dried sample was extracted with a chloroform-methanol mixture (2: 1), and the liver lipid was analyzed. The stool was dried, extracted with hot ethanol, and analyzed for the extract.

The analysis results are shown in Tables 2 to 4. The total fat cholesterol, VLDL + LDL cholesterol, and atherosclerosis index were increased in the control group by feeding a high fat diet to which cholesterol was added. In the test group to which Formulation A was added also in the diet, the numerical increase was significantly suppressed in all of the above analysis items. In addition, serum triglyceride levels also tended to decrease in the test group.

Test Example 2 The same test as in Test Example 1 was carried out using eight 4-week-old male SD rats per group. However, as the lipid metabolism improving agent to be mixed with the feed of the test group, the formulation A according to Production Example 2 was used instead of the formulation A.

The feed intake for 2 weeks after grouping was 232 ± 24 g in the standard diet control group, 229 ± 22 g in the high fat diet control group, and 239 ± 16 g in the test group, and there was no difference between each group. .

Table 5 shows the results of analysis of serum lipids, liver lipids and fecal lipids.
7, the total fat cholesterol level, the VLDL + LDL cholesterol level and the atherosclerosis index increased in the control group when the high fat diet supplemented with cholesterol was added. In the test group, the increase was significantly suppressed in all of the above analysis items. In addition, the serum triglyceride level also tended to slightly decrease in the test group.

[Effects of the Invention] As described above, the lipid metabolism-improving agent of the present invention comprising a hot-water extract of lactobacilli or a proteolytic enzyme-treated product thereof has a remarkable inhibitory effect on serum lipid elevation, hepatic lipid elevation inhibition, cholesterol and It has the effect of promoting the excretion of bile acids into feces, and is extremely effective in preventing arteriosclerosis and other diseases caused by cholesterol accumulation.

Moreover, lactobacilli are safe bacteria without pathogenicity, as is clear from the fact that they have been used for the production of lactic acid-fermented foods for a long time. No mortality was observed even at a dose of 8 g / kg when administered, and there is no problem in safety even if administered for a long time.

Therefore, the lipid metabolism-improving agent of the present invention is extremely advantageous, which is suitable not only for use as a medicament for oral administration, but also for admixing it with food and ingesting it daily to help prevent arteriosclerosis and promote health.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-61-109729 (JP, A) JP-A-62-258323 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 35/74 A23L 1 / 30,1 / 305 A61K 38 / 01,38 / 02

Claims (3)

(57) [Claims] 1. An agent for improving lipid metabolism comprising a hot water extraction residue of lactobacilli as an active ingredient. 2. A lipid metabolism-improving agent comprising, as an active ingredient, a processed product of a lactobacilli hot water extraction residue proteolytic enzyme. 3. The method according to claim 1, wherein the lactobacillus is Lactobacillus casei.