JP4634065B2 - Adiponectin reduction inhibitor - Google Patents

Description

  The present invention relates to an adiponectin decrease inhibitor that suppresses a decrease in blood adiponectin.

The liver is an organ with very strong regenerative power, but when fibrosis occurs during the regeneration process, normal hepatocyte regeneration is hindered. Liver fibrosis occurs when the balance between hepatocyte necrosis caused by external factors such as viruses and alcohol, or internal factors that involve autoimmune abnormalities, and liver regeneration to maintain liver function is lost. It is thought that extracellular matrix such as collagen is excessively deposited to repair liver tissue.
Progression of liver fibrosis often inhibits hemodynamics, impairs the process of liver regeneration, makes the pathology of liver failure irreversible, and often shifts to cirrhosis and liver cancer. In the treatment of chronic hepatitis and the like, it is important to suppress liver cirrhosis and the transition to liver cancer. To that end, it is necessary to suppress liver fibrosis.

  Adiponectin is an animal adipose tissue-specific protein newly isolated from human adipose tissue by Maeda et al. In 1996 (see Non-Patent Document 1), and is abundant in blood as well as adipose tissue. In normal human blood, it exists at a high concentration of 5 to 10 μg / mL (see Non-Patent Document 2). Recent studies have shown that reduced or deficient adiponectin expression is responsible for obesity insulin resistance, and thus obesity and type 2 diabetes (see Non-Patent Document 3). As for the action of adiponectin, the effects of vascular smooth muscle proliferation and cell migration, anti-arteriosclerosis, monocyte and macrophage activation (see Non-Patent Documents 4, 5, and 6), Inflammatory effects (see Patent Document 1) have been reported, and recently, there are effects such as suppression of hepatic stellate cell activation, suppression of extracellular matrix production, suppression of hepatic stellate cell proliferation, and promotion of hepatocyte proliferation. It has been clarified that the conversion is suppressed (see Patent Document 2). Accordingly, it is considered that liver fibrosis and the like can be suppressed if a decrease in the amount of adiponectin in the living body can be suppressed.

On the other hand, diacylglycerol has an inhibitory effect on the increase in blood neutral fat after meal (see, for example, Patent Document 3) and an effect of increasing blood HDL cholesterol (see, for example, Patent Document 4). Used in processed oil and fat foods. However, the action of diacylglycerol on adiponectin has never been known so far.
Japanese Patent No. 3018186 JP 2002-363094 A JP 2003-2835 A JP 2001-64170 A Maeda K, et al. Biochem. Biophys. Res. Commun. 221: 286 (1996) Arita Y et al, Biochem. Biophys. Res. Commun. 257: 79-83 (1999) T. Yamauchi et al, Nature Medicine, Vol. 7, No. 8 (2001) Arita Y et al, Circulation.105 (24), 2893-8. (2002) Ouchi N et al, Circulation.102 (11), 1296-301. (2000) Okamoto Y et al, Circulation. 106 (22), 2767-70. (2002)

  The present invention provides a medicament or food that suppresses the decrease of blood adiponectin and exhibits an effect of suppressing liver fibrosis.

  The present inventors examined a substance that suppresses a decrease in blood adiponectin, and found that diacylglycerol has the effect and also has an effect of suppressing liver fibrosis.

  That is, the present invention provides an adiponectin decrease inhibitor containing diacylglycerol as an active ingredient and a liver fibrosis inhibitor containing diacylglycerol as an active ingredient.

  According to the adiponectin decrease inhibitor of the present invention, it is possible to suppress a decrease in blood adiponectin, improve liver function, and effectively suppress liver fibrosis. Therefore, in the prevention and treatment of chronic liver diseases such as chronic hepatitis, liver regeneration can be promoted, and the transition to cirrhosis and liver cancer can be suppressed.

  The diacylglycerol used in the adiponectin lowering inhibitor and liver fibrosis inhibitor of the present invention preferably has 8 to 24 carbon atoms, particularly 16 to 22 carbon atoms. In addition, it is desirable that the unsaturated fatty acid is 70% by weight (hereinafter simply referred to as%) or more in all the constituent fatty acids. In particular, from the viewpoint of enhancing the effect of the present invention, the unsaturated fatty acid amount / saturated fatty acid amount (weight ratio) is preferably 5.5 or more, more preferably the unsaturated fatty acid amount / saturated fatty acid weight ratio is 8 or more. More preferably, it is 10-25. The saturated fatty acid content is desirably 10% or less, more preferably 6% or less. Here, examples of the unsaturated fatty acid amount include oleic acid, α-linoleic acid, α-linolenic acid, cis-dihomoγ-linolenic acid, cis-arachidonic acid, cis-eicosapentaenoic acid, cis-docosahexaenoic acid, and the like. Saturated fatty acids include palmitic acid, stearic acid, arachidonic acid and the like.

In the adiponectin decrease inhibitor and liver fibrosis inhibitor of the present invention, the diacylglycerol is preferably diacylglycerol having a purity of 100%, but an oil / fat composition slightly containing triacylglycerol, monoacylglycerol or the like is used. It may be.
In this case, the monoacylglycerol content is preferably 2% or less, particularly preferably 1.5% or less, and diacylglycerol is 35% or more, preferably 50% or more, more preferably 60% or more, and still more preferably 80%. It is desirable to contain above.

An oil and fat composition containing diacylglycerol can be obtained by the following method.
That is, as disclosed in JP-A-6-247849, fats and oils having a target constituent fatty acid and glycerin are subjected to a transesterification reaction, or lipase acts on a mixture of the target constituent fatty acid or its ester and glycerin. However, in order to prevent isomerization during the reaction, an esterification reaction using lipase is more preferable. Moreover, also in the esterification reaction using lipase, in order to prevent isomerization in the purification means after completion of the reaction, the purification means is also preferably performed under mild conditions so that fatty acid isomerization does not occur.

  Normal vegetable oil contains about 0.05 to 1.2% of plant sterol. An oil and fat composition containing diacylglycerol can be obtained by the above method, but the plant sterol may be lowered by the production method. For example, when the fatty acid obtained by distillation generally marketed is used as a raw material, the amount of plant sterols in a composition will fall. In such a case, you may add a plant sterol so that it may become 0.05% or more. Moreover, the upper limit of plant sterol content is not specifically limited. Here, as plant sterols, ferries such as α-sitosterol, β-sitosterol, stigmasterol, campesterol, α-sitostanol, β-sitostanol, stigmasteranol, campestanol, cycloartenol, and the like Fatty acid esters, ferulic acid esters, and cinnamic acid esters.

  In addition, the oil-and-fat composition containing diacylglycerol can be obtained by fractionating natural edible oils and fats in addition to the above production method, and such oil-and-fat compositions can also be used in the present invention.

  Adiponectin is an animal adipose tissue-specific protein that exists in high concentrations in normal human blood (Non-patent Document 2), suppresses liver fibrosis (Patent Document 2), and promotes vascular smooth muscle proliferation and cell migration. It has inhibitory action, anti-arteriosclerotic action, monocyte and macrophage activation inhibitory action (see Non-Patent Documents 4, 5, and 6), anti-inflammatory action (Patent Document 1), and the like. The diacylglycerol of the present invention significantly suppresses a decrease in blood adiponectin concentration induced by a high sucrose diet and has a liver fibrosis inhibitory effect in rats as shown in Examples below. Therefore, such diacylglycerol can suppress liver fibrosis in chronic liver diseases such as chronic hepatitis, and is useful as a material for pharmaceuticals or foods effective for suppressing the transition to cirrhosis and liver cancer. is there.

The adiponectin decrease inhibitor and hepatic fibrosis inhibitor of the present invention can be administered in combination with diacylglycerol alone to humans and animals, or in various foods, medicines, pet foods and the like.
Examples of food forms include drinks such as drinks, powdered drinks such as powdered juice, confectionery such as candy, drop, jelly, cookies, chocolate, cake, yogurt, gum, seasonings, cooking oil, dairy products, bread In addition to processed rice, etc., foods based on the concept of improving liver function such as tablets, capsules and granules, foods for the sick, and foods for specified health use can be obtained. Such foods include, for example, sweeteners, colorants, antioxidants, emulsifiers, vitamins, fragrances, minerals, and other food ingredients such as proteins, lipids, carbohydrates, carbohydrates, dietary fiber, and diacylglycerol. It can be prepared by mixing and making various food forms according to conventional methods.

  When used as a pharmaceutical, for example, oral solid preparations such as tablets and granules, and oral liquid preparations such as oral liquids and syrups can be used. When preparing an oral solid preparation, after adding an excipient, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, a corrigent and the like to the diacylglycerol of the present invention. Tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods. When an oral liquid preparation is prepared, an oral solution, syrup, elixir and the like can be produced by a conventional method by adding a corrigent, a buffer, a stabilizer, a corrigent and the like.

  The blending amount of diacylglycerol to be blended in each of the above preparations is generally 0.1 to 100% by weight, particularly preferably 1 to 90% by weight.

  The dose (effective intake) of the adiponectin lowering inhibitor and the liver fibrosis inhibitor of the present invention is preferably 0.03 to 25 g, more preferably 5 to 20 g, and particularly preferably 6 to 15 g per day as diacylglycerol.

Example 1
The diacylglycerol used in the following examples was produced by the following method.
A diacylglycerol having the fatty acid composition shown in Table 1 was obtained using a commercially available lipase preparation (trade name “Lipozyme IM-20”, manufactured by Book Industries AS Co., Ltd.) as an immobilized 1,3-position selective lipase. It was.
Next, a high sucrose diacylglycerol (DAG) combination meal (product of the present invention) having the composition shown in Table 2 was produced. In addition, a high sucrose triacylglycerol (TAG) combination diet (comparative product) and a control diet (control product) were produced in the same manner.

Example 2 Blood Adiponectin Decrease Inhibitory Effect and Liver Fibrosis Inhibitory Effect <Experimental Method>
When a high sucrose diet is loaded on Wistar rats, it induces an increase in blood glucose level, an increase in serum neutral fat, an increase in visceral fat mass, and insulin resistance (Metabolism. 36, 11 (1987), Obes. Res. 4, 6 (1996), Am. J. Physiol. 271 (1996), J Appl physiol. 91 (2001), J. Nutr. 133 (2003)). Thus, 7-week-old Wistar rats were used, divided into 3 groups of 6 animals each, and reared with the product of the present invention, comparative product and control product prepared in Example 1 as shown in Table 2. 1, 2, and 11 months later, blood was collected from the jugular vein under ether anesthesia, and the blood adiponectin concentration was measured using a mouse / rat adiponectin ELISA kit manufactured by Otsuka Pharmaceutical Co., Ltd. After 12 months, the liver was collected, fixed in formalin and embedded in paraffin, and then the section was stained with silver of Watanabe, and the fibrosis state of the liver (score according to Shininuyama classification; Journal of Japanese Society of Gastroenterology Vol.96 No. 4 377-384) was observed. In addition, the amount of blood hyaluronic acid, which is one index of liver fibrosis, was measured. The results are shown in Tables 3 and 4.

<Result>

  From Table 3, the comparison product administration group showed a significant decrease in adiponectin concentration compared to the control group, but the product administration group of the present invention was equivalent to the control group and suppressed the reduction of blood adiponectin.

  From Table 4, although the fibrosis of the liver was recognized in the comparison product administration group compared with the control group, the administration product of the present invention suppressed the fibrosis of the liver. The blood hyaluronic acid concentration, which is one index of liver fibrosis, was significantly higher in the comparison product administration group than in the control group, but the product administration group was equivalent to the control group. That is, the present invention product administration group effectively suppressed liver fibrosis.

Claims (1)

A liver fibrosis inhibitor containing diacylglycerol as an active ingredient.