WO2007049818A1 - Composition contre la steatose hepatique ou l’obesite ou a effet hypolipemiant - Google Patents

Composition contre la steatose hepatique ou l’obesite ou a effet hypolipemiant Download PDF

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Publication number
WO2007049818A1
WO2007049818A1 PCT/JP2006/322041 JP2006322041W WO2007049818A1 WO 2007049818 A1 WO2007049818 A1 WO 2007049818A1 JP 2006322041 W JP2006322041 W JP 2006322041W WO 2007049818 A1 WO2007049818 A1 WO 2007049818A1
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Prior art keywords
less
lysine
threonine
isoleucine
leucine
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PCT/JP2006/322041
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English (en)
Japanese (ja)
Inventor
Yasushi Noguchi
Yoshiko Hara
Nahoko Shikata
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Ajinomoto Co., Inc.
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Publication of WO2007049818A1 publication Critical patent/WO2007049818A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to lysine, threonine, leucine, isoleucine and parin for the purpose of suppressing and improving the development of fatty liver (especially caused by ingestion of high fat diet, etc.), 'steatohepatitis, obesity and hyperlipidemia.
  • the present invention relates to a composition for suppressing the onset of and improvement of fatty liver, steatohepatitis, obesity and hyperlipidemia.
  • fatty liver is a lifestyle-related disease It is one of the most important risk factors, and solutions that include dietary ingredients are required.
  • liver is important. Fatty liver is a condition in which excess neutral fat in the liver cells of the liver has accumulated.
  • the liver biosynthesizes fat for use as an energy source, some of which is stored in hepatocytes.
  • the amount of fat biosynthesized is relatively large compared to the fat consumed as energy in the hepatocytes, the fat accumulates in the hepatocytes, and when such a state progresses, it becomes fatty liver.
  • Fatty liver is a pathological condition caused by lifestyle such as eating and drinking, and is one of the factors that cause serious lifestyle-related diseases.
  • the treatment is: In the case of fatty liver associated with increased fat intake, Diet therapy and exercise therapy are the main methods, and in the case of alcoholic fatty liver, the amount of alcohol consumption is mainly reduced. As described above, in order to treat or prevent fatty liver, improvement of daily eating habits occupies a great weight, and a diet component having anti-fatty liver action is required.
  • PUFA polyunsaturated fatty acids
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • PUFA is a series of fatty acid biosynthetic enzymes such as ATP citrate lyase (hereinafter ACL), fatty acid syntha se (hereinafter FAS), stearoyl CoA desaturase 1 (hereinafter S CD 1), etc.
  • ACL ATP citrate lyase
  • FAS fatty acid syntha se
  • S CD 1 stearoyl CoA desaturase 1
  • SREBP lc sterol regulatory element binding protein 1 c
  • PPAR a proliferators-activated receptor-H
  • prevention and improvement of fatty liver or hyperlipidemia by PUFA This is described in Japanese Patent Application Laid-Open No. Hei 8-023881 or Japanese Patent Application Laid-Open No. 91-194362.
  • JP-A-1-242530 describes that an extract obtained by removing starchy protein or the like from corn bran or wheat bran suppresses alcoholic fatty liver.
  • an alcoholic fatty liver inhibitory composition containing at least one of amino acids such as arginine and the like and a thiamine compound that has a glucagon secretion activity has been reported (JP-A-10-158). 1 See No. 70).
  • compositions consisting of amino acids or amino acids having anti-obesity, anti-hyperlipidemia, anti-fatty liver and anti-fatty hepatitis effects.
  • Japanese Patent Application Laid-Open No. 6-24977 is an example, including nine essential amino acids consisting of threonine, proline, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, methionine, tryptophan, histidine, and arginine and 3
  • a composition comprising two types of non-essential amino acids (total of 12 types) as an active ingredient has anti-obesity and anti-hyperlipidemic effects on obesity and hyperlipidemia caused by a high sucrose or high fructose diet. Show. However, this document does not actually show an effect on obesity or hyperlipidemia caused by a high fat diet, which is a problem in chicken. In addition, there is no description or disclosure of anti-fatty liver action.
  • visceral fat increases and especially fatty liver is induced when protein nutrition disorders such as intake of a low protein diet (JP n JP harma co 1. Mar; 1 9 (1) : 74-88 (1 969)).
  • experimental animals such as rats fed diets deficient or low in essential amino acids such as lysine and threonine have fatty liver (JL ipid Res. J ul; 7 (4): 473-8 (1 966)).
  • the effects of ingestion of these proteins and amino acids on visceral fat accumulation and fatty liver have been clarified in the absence of sufficient protein that can be ingested with normal diet.
  • the effects of ingestion of these proteins and amino acids have not been clarified as described above. . Disclosure of the invention
  • An object of the present invention is to provide a composition that significantly suppresses and ameliorates fatty liver (especially caused by intake of a high fat diet), steatohepatitis, manure, and hyperlipidemia. '
  • composition containing lysine, threonine, leucine, isoleucine and parin has an excellent anti-fatty liver 'anti-fatty hepatitis action
  • the present invention was completed.
  • Lysine, threonine, leucine, isoleucine, and valine are each included in a molar ratio of lysine 5.0% to 65.
  • isoleucine 0% to less than 35.0% and parin 1.
  • composition for anti-fatty liver or anti-fatty hepatitis comprising 0% or more and less than 35.0%.
  • composition according to (1) wherein the fatty liver is fatty liver induced by intake of a high fat diet.
  • Lysine, threonine, ⁇ isin, isoleucine, and parin as molar constituent ratios with respect to all amino acids in the composition, lysine 5.0% to less than 65.0%, threonine 5.0% to 65% Less than 0%, leucine 1. 0% to less than 35.0%, isoleucine 1. 0% to less than 35.0% and parin 1. 0% to less than 35.0%, and An anti-obesity composition comprising no at least one non-essential amino acid selected from the group consisting of proline, glycine, tyrosine and arginine.
  • Lysine, threonine, leucine, isoleucine and valine as molar constituent ratios with respect to all amino acids in the composition, respectively, lysine 5.0% to less than 65.0%, threonine 5.0% to 65%. Less than 0%, leucine 1., 0% or more
  • a composition for anti-obesity characterized by being contained in a range of 0% or more and less than 35.0% and not containing at least one non-essential amino acid selected from the group consisting of proline, glycine and arginine .
  • Lysine, threonine, leucine, isoleucine and valine are each included in a molar ratio of lysine of 5.0% to 65.
  • Anti-high fat characterized by containing in the range of 0% to less than 35.0% and not containing at least one non-essential amino acid selected from the group consisting of proline, glycine, tyrosine and arginine A composition for blood pressure.
  • Lysine, threonine, leucine, isoleucine, and valine are each included in a molar ratio of lysine 5.0% to 65.
  • Threonine 5.0% or more to less than 65.0%, Leucine 1.0% or more to less than 35.0%, Isoleucine 1.0% or more to less than 35.0% or Palin 1.
  • An antihyperlipidemic composition characterized by not containing at least one non-essential amino acid selected from the group consisting of nin. '
  • Lysine, threonine, leucine, isoleucine, and valine are each included in a molar ratio of lysine 5.0% to 65.
  • a drug for anti-fatty liver or anti-fatty hepatitis containing in the range of 0% or more to less than 35.0%.
  • Lysine ', threonine, leucine, isoleucine and valine as molar constituent ratios with respect to all amino acids in food and drink, lysine 5.0% to less than 65.0%, threonine 5.0% to 65%. , Less than 0%, Loisin 1.0% or more to 35.0% less, Isoleucine 1. 0% or more to less than 35.0% and Palin 1.
  • a food or drink for preventing or improving fatty liver or steatohepatitis which is contained in the range of 0% or more to less than 35.0%.
  • Lysine, threonine, leucine, isoleucine and valine as molar constituent ratios with respect to all amino acids in the drug, respectively, lysine 5.0% to less than 65.0%, threonine 5.0% to 65.0% Less than%, leucine 1. 0% to less than 35.0%, isoleucine 1. 0% to less than 35.0%, and parin 1. 0% to less than 35.0%, and proline.
  • An anti-obesity medicament characterized by not containing at least one non-essential amino acid selected from the group consisting of glycine, tyrosine and arginine.
  • Lysine, threonine, 'leucine, isoleucine, and valine as molar constituent ratios with respect to all amino acids in the drug, respectively, lysine 5.0% to less than 65.0%, threonine 5.0% to 65%. Less than 0%, leucine 1. 0% to less than 35.0%, isoleucine 1. 0% to less than 35.0% and valine 1. 0% to less than 35.0%, and proline
  • An anti-obesity medicament characterized by not containing at least one non-essential amino acid selected from the group consisting of glycine and arginine.
  • Lysine, threonine, leucine, isoleucine and valine as molar constituent ratios with respect to all amino acids in food and drink, respectively, lysine 5.0% to less than 65.0%, threonine 5.0% to 65.0% Less than%, Leucine 1. 0% or more to less than 35.0%, Isoleucine 1. ( ⁇ . /. Or more to less than .0-% and Palin from 1.0% or more to 35.0 or less. And at least one non-essential amino acid selected from the group consisting of proline, glycine and arginine.
  • Lysine, threonine, leucine, isoleucine, and valine are each included in a molar ratio of lysine 5.0% to 65.
  • Antihyperlipidemic characterized by containing in the range of 0% to less than 35.0% and not containing at least one non-essential amino acid selected from the group consisting of proline, glycine, tyrosine and arginine Medicinal drugs.
  • Threonine 5.0% or more to less than 65.0%, Leucine 1.0% or more to less than 35.0%, Isoleucine 1.0% or more to less than 35.0% or Palin 1.0% or more 35.
  • An antihyperlipidemic drug characterized by containing less than 0% and not containing at least one non-essential amino acid selected from the group consisting of proline, glycine and arginine.
  • lysine, threonine, leucine, isoleucine and valine as the molar component ratio to total amino acids in each in food or drink, lysine 5.
  • a food or drink for preventing or ameliorating hyperlipidemia characterized by not containing at least one non-essential amino acid selected from the group consisting of proline, glycine, tyrosine and arginine.
  • Lysine, threonine, leu, n, isoleucine and valine as molar constituent ratios with respect to all amino acids in food and drink, respectively, lysine 5.0% to less than 65.0%, threonine 5.0% or more ⁇ 65.0%, leucine 1. 0% to less than 35.0%, isoleucine 1. 0% to 35.0% and valine 1. 0% to 35.0%
  • a food or drink for the prevention or amelioration of hyperlipidemia characterized by not containing at least one non-essential amino acid selected from the group consisting of proline, glycine and arginine.
  • lipid biosynthesis control gene is a SREBP1c gene, a HMG CAS1 gene, an ACL gene, or a FAS gene.
  • Lysine, threonine, leucine, isoleucine and valine as molar constituent ratios with respect to all amino acids in the composition, lysine 5.0% to less than 65.0%, threonine 5.0% to 65.0%
  • Lysine, threonine, leucine, isoleucine and valine as molar constituent ratios with respect to all amino acids in the composition, respectively, lysine 5.0% to 65.0%, threonine 5.0% to 65%. Less than 0%, Leucine 1. 0% or more
  • isoleucine 1 0% to less than 35.0% and valine 1.
  • a composition comprising 0% or more and less than 35.0% and not containing at least one non-essential amino acid selected from the group consisting of proline, glycine, tyrosine and arginine.
  • Lysine, threonine, leucine, isoleucine and valine as molar constituent ratios with respect to all amino acids in the composition, respectively, lysine 5.0% to less than 65.0%, threonine 5.0% to 65.0% Less than%, leucine 1. 0% or more
  • isoleucine 0% to less than 35.0% and parin 1.
  • a method for preventing or treating fatty liver or steatohepatitis comprising administering a composition containing 0% or more to less than 35.0% to the administration subject.
  • Lysine, threonine, leucine, isoleucine and valine as molar constituent ratios with respect to all amino acids in the composition, lysine 5.0% to less than 65.0%, threonine 5.0% to 65.0% Less than%, leucine 1. 0% or more
  • isoleucine 0% to less than 35.0% and parin 1.
  • a composition containing 0% or more and less than 35.0% and not containing at least one non-essential amino acid selected from the group consisting of proline, glycine, tyrosine and arginine is administered to the administration subject A method for preventing or treating obesity.
  • Lysine, threonine, leucine, isoleucine, and valine are each included in a molar ratio of lysine 5.0% to 65.
  • isoleucine 0% to less than 35.0% and parin 1.
  • a composition containing 0% or more and less than 35.0% and containing at least one non-essential amino acid selected from the group consisting of proline, glycine, tyrosine and arginine is administered to a subject.
  • a method for preventing or treating hyperlipidemia is administered to a subject.
  • Lysine, threonine, leucine, isoleucine, and valine are each included in molar ratios of lysine to all amino acids of lysine 5.0% to less than 65.0%, threonine 5.0% to 65.0% %, Leucine 1. 0% to less than 35.0%, isoleucine 1. 0% to less than 35.0% and parin 1. 0% to less than 35.0%.
  • a method for suppressing lipid biosynthesis control gene expression comprising administering to a subject.
  • the molar composition ratio of all amino acids in the composition is lysine 5.0% to less than 65.0%, threonine 5.0% to less than 65.0%, oral isine 1.0% More than 3 to less than 35.0%, isoleucine 1.0% or more to less than 35.0% and parin 1. More than 0% to less than 35.0%, and it consists of proline, glycine, tyrosine and arginine Use of lysine, threonine, leucine, isoleucine and parin for the manufacture of an anti-obesity composition which does not contain at least one non-essential amino acid selected from the group.
  • the molar composition ratio of all amino acids in the composition is lysine 5.0% to less than 65.0%, threonine 5.0% to less than 65.0%, oral isine 1.0% or more ⁇ 35.0%, isoleucine 1. 0% to less than 35.0% and parin 1. 0% or more to less than 35.0%, and a group consisting of proline, dalysin, tyrosine and arginine Use of lysine, threonine, leucine, isoleucine and parin to produce an antihyperlipidemic composition which does not contain at least one non-essential amino acid selected from the above.
  • the molar composition ratio of all amino acids in the preparation is lysine 5.0% to less than 65.0%, threonine 5.0% to less than 65.0%, oral isine 1.0% or more 30.0% or less, isoleucine 1.0% or more to less than 35.0% and parin 1. 0% or more to less than 35.0% Use of lysine, threonine, leucine, isoleucine and parin.
  • the composition containing lysine, threonine, leucine, isoleucine and parin provided by the present invention suppresses fatty liver and steatohepatitis.
  • the composition for anti-fatty liver and steatohepatitis of the present invention is particularly effective in steatohepatitis and steatohepatitis caused by ingestion of a high fat diet.
  • the composition characterized by not containing at least one non-essential amino acid selected from the group consisting of syn, tyrosine and argini is useful for anti-obesity and anti-hyperlipidemia.
  • composition of the present invention comprises an amino acid as an active ingredient, it is highly safe and has few side effects. Therefore, the composition of the present invention can be administered for a long period of time. In fatty liver, steatohepatitis, obesity and hyperlipidemia It can be used advantageously for prevention, treatment and improvement.
  • the lipid biosynthesis regulating gene expression inhibitor of the present invention can be used as an experimental reagent in the fields of physiology and biochemistry in addition to its use as a medicament as described above.
  • FIG. 1 shows mRNA expression level of SREB P 1 c gene in liver (A) and AMPK phosphorylation in skeletal muscle (B).
  • A The relative amount of mRNA is expressed by standardizing with the amount of 18 S liposomal RNA. Data represent mean soil standard deviation. There is a significant difference in mean values between experimental groups that do not have the same alphabet.
  • P 0.05 Tukey HSD
  • B Dumps were extracted from soleus muscle and Western blotting was performed using anti-AMPK and anti-AMPK phosphorylated antibodies. The graph is expressed as a relative value with the STD group as 1. Data represent mean soil standard deviation. There is a significant difference in mean values between experimental groups that do not have the same alphabet.
  • Fig. 2 shows typical liver tissue slices in the HFD group and the 8% EAA / HFD group.
  • FIG. 3 shows the liver (A), liver lipid content (B), and blood GOT and GPT values (C) of obZob mice. Data represent mean soil standard deviation. There is a significant difference in mean values between experimental groups that do not have the same alphabet. P ⁇ 0.05 (Tukey HSD)
  • Figure 4 shows the weight gain of (A) HFD group, EAA / HFD group, EAA + Pr ⁇ FD group and EAA + G1y / HFD group. Data represent mean soil standard deviation.
  • (B) STD group, HFD group, E AA / HFD group and E AA + Arg / HFD group Represents fat weight. Data represent mean soil standard deviation. In the figure, * indicates that there is a significant difference in the STD group.
  • (C) Represents blood cholesterol levels in the HFD group, EAAZHFD group, EAA + A rg ZHFD group, and EAA + G 1 y / HFD group. Data represent mean soil standard deviation. In the figure, * indicates that there is a significant difference from the HFD group.
  • Figure 5 shows the weight gain of (A) HFD group, EAA / HFD group, EAA-B ⁇ HFD group, EAA-K / HFD group, and EAA-T / HFD group. Data represent mean soil standard deviation.
  • (B) Shows the total fat weight of HFD, EAA / HFD, EAA-K / HFD, and EAA_TZHFD groups. Data represent mean soil standard deviation.
  • the data represents the average person standard deviation.
  • Data represent average soil standard deviation.
  • Figure 6 shows the weight gain of (A) HFD group, EAAZHFD group, EAA-K 60 HFD group, and EAA-T 6 OZHFD group. Data represent mean soil standard deviation.
  • B Blood levtin concentrations in HFD, EAAZHFD, EAA-K 60 HFD, and EA A-T60 / HFD groups are shown. Data represent mean soil standard deviation.
  • C The blood cholesterol levels of the HFD group, EAA / HFD group, EAA—K 60 HFD group, and EA A—T 60 HFD group are shown. Data represent mean soil standard deviation.
  • D HFD group, EAA / HFD group, EAA—K 60 / HFD group, and And liver weight of EAA-T 6 OZHFD group. Data represent mean soil standard deviation.
  • * indicates a significant difference from the HFD group.
  • Figure 7 shows the liver weights of (A) HFD group, EAAZHFD group, EAA-B / HFD group, EAA-KZHFD group, and EAA-T / HFD group. Data represent mean soil standard deviation.
  • B Triglycerides in the liver of HFD, EAA / HFD, EAA—BZHFD, EAA—KZHFD, and EAA—T / HFD groups. Data represent mean ⁇ standard deviation.
  • C HFD group, EAAZHFD group, EA 8_8 no? Shows liver cholesterol in the ⁇ 1 ⁇ 0 group and the EAA-T / HFD group. Data represent mean soil standard deviation.
  • * indicates a significant difference from the HFD group. ;
  • FIG. 8 shows liver weights of (A) HFD group, EAA-K 6 OZHFD group, and EAA-T60 HFD group. Data represent mean soil standard deviation.
  • Essential amino acids used in the present invention are lysine, threonine, leucine, isoleucine and parin.
  • any of L_ form, D-form, and DL_ form can be used, but L-form is preferably used.
  • an amino acid includes a salt thereof.
  • the amino acids used as the active ingredient in the present invention can be used not only in the form of educts but also in the form of salts for some or all of them.
  • the salt form include acid addition salts and salts with a salt group, and it is preferable to select a salt of the amino acid that is acceptable as a pharmaceutical or a food or drink.
  • the acid to be used include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and phosphoric acid, and organic acids such as acetic acid, lactic acid, citrate, tartaric acid, maleic acid, fumaric acid and monomethylsulfuric acid.
  • the composition of the present invention comprises lysine, threonine, leucine, isoleucine, and parin as molar constituent ratios with respect to all amino acids in the composition, respectively, lysine 5.0% to less than 65.0%, threonine 5.0% or more ⁇ 65.0%, oral isine 1.0% or more to less than 35.0%, isoleucine 1. 0% or more to less than 35.0% and parin 1. 0% or more to less than 35.0% Composition or lysine 5.0% or more to less than 65.0%, Threonine 5.0% or more to 65., less than 0%, Leucine 1.0% or more to less than 35.0%, Isoleucine 1.
  • EAAZNEAA ratio essential amino acid Z non-essential amino acid ratio
  • the anti-fatty liver or anti-fatty hepatitis composition of the present invention comprises lysine, threonine, leucine, isoleucine and norin as active ingredients, and a composition for suppressing and improving fatty liver or steatohepatitis It is a thing.
  • the anti-fatty liver or anti-fatty hepatitis composition of the present invention is effective against any fatty liver and steatohepatitis, but is particularly effective against fatty liver and steatohepatitis caused by intake of a high-fat diet.
  • the anti-obesity composition and anti-hyperlipidemic composition of the present invention contain lysine, threonine, leucine, isoleucine and valine as active ingredients, and at least one selected from proline, glycine, tyrosine and arginine.
  • One non-essential amino acid is not contained. Among these non-essential amino acids, it is preferable not to contain at least one non-essential amino acid selected from proline, dalysin and arginine.
  • the anti-obesity composition of the present invention is effective in suppressing the decrease or increase in body weight and body fat of obese people.
  • the antihyperlipidemic composition of the present invention is effective against hyperlipidemia associated with abnormal lipid metabolism such as obesity, fatty liver and diabetes.
  • the molar composition ratio of five amino acids to all amino acids Lysine 5.0 or more to less than 65.0, threonine 5.0 or more to less than 65, leucine 1.0 or more to less than 35.0, isoleucine 1.0 or more to less than 35.0, noble phosphorus 1.0 or more The range is less than 35.0.
  • composition for anti-fatty liver is used as a pharmaceutical composition and a food composition.
  • examples of the subject of administration include mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, sushi, hidges, monkeys, etc.).
  • the dosage form when used as a pharmaceutical is not particularly limited. However, it can pass through general administration routes such as oral administration, rectal administration, injection, and administration by infusion. Oral dosage forms include granules, fine granules, powders, coated tablets, tablets, suppositories, powders, (micro) capsules, chewables, syrups, juices, solutions, suspensions, emulsions.
  • general dosage forms of pharmaceutical preparations such as those for direct intravenous injection, infusions for infusion administration, and other preparations that prolong the release of active substances can be adopted as injections.
  • the dosage in the case of using the composition of the present invention as a pharmaceutical (pharmaceutical composition) varies depending on the age, weight or pathological state, dosage form, or administration method of the subject patient.
  • the dosage of the acid is usually 100 m to 50 g, preferably 500 mg to 15 g.
  • the dosage of amino acid as an active ingredient of the anti-obesity composition is usually 100 mg to 50 g, preferably 50 Omg to 15 g.
  • the dose of amino acid as the active ingredient of the anti-hyperlipidemic composition is usually 1 O Omg to 50 g, preferably 500 mg to: 15 g .
  • the daily dose can be administered once or divided into several (eg, three) doses. It does not matter before, during, after, or between meals. Preferably after meal, for example, 0 hours to 2 hours after meal, preferably 0 hours to 1 hour after meal, more preferably 0 hours to 0.5 hour after meal.
  • the administration period is not particularly limited. ,
  • medicaments can be formulated by conventional methods.
  • Various pharmacologically acceptable pharmaceutical substances can be added as required by the pharmaceutical preparation.
  • the drug substance can be appropriately selected depending on the dosage form of the drug product.
  • pharmaceutical substances include magnesium carbonate, titanium dioxide, ratatoose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, , Solvents (eg, sterilized water, monohydric or polyhydric alcohols such as glycerol), and the like.
  • Solvents eg, sterilized water, monohydric or polyhydric alcohols such as glycerol
  • composition for anti-fatty liver comprises an anti-fatty liver agent, an anti-fatty hepatitis agent, an anti-obesity agent and an anti-high Used as a lipemia agent.
  • the composition of the present invention is excellent in safety and can be easily used in the form of food and drink.
  • any form may be used as long as it is in the form of a general food or drink containing a high content of these active ingredients.
  • an appropriate flavor can be added to make a drink (eg, soft drink, powdered drink).
  • juice, cow Can be mixed with milk, confectionery, jelly, etc.
  • functional foods include anti-fatty liver, anti-fatty hepatitis, anti-obesity and / or anti-high foods. Included are foods and drinks that are labeled as being used for lipidemia, especially foods for specified health use or functional nutritional foods.
  • composition of the present invention can be used as a concentrated liquid food or a food supplement.
  • a food supplement When used as a food supplement, it can be prepared in the form of tablets, capsules, powders, granules, suspensions, chewables, syrups and the like.
  • the food supplement in the present invention refers to those taken for the purpose of supplementing nutrition in addition to those taken as food, and includes nutritional supplements and supplements.
  • composition of the present invention contains an amino acid as an active ingredient, it has extremely low toxicity, and its dosage can be set in a very wide range.
  • the intake of amino acids in the food or drink for preventing or ameliorating fatty liver or steatohepatitis according to the present invention under the condition that the protein energy ratio of the daily meal is 10% or more is usually 0.5%.
  • daily intake is lg ⁇ 50 g, preferably, intake is 1-5 g at a time, and daily intake is 3-15 g.
  • the intake of amino acids in the food or drink for preventing or ameliorating obesity according to the present invention under the same conditions is usually 0.5 to 10 g, and the daily intake is lg to 50 g.
  • the intake is 1-5 g at a time, and the daily intake is 3-15 g.
  • the intake of amino acids in the food or drink for preventing or ameliorating hyperlipidemia of the present invention under the same conditions is usually 0.5 to 10 g at a time, and the daily intake is lg ⁇ 50 g, preferably, intake is 1 to 5 g at a time, and ⁇ is 3 to 15 g.
  • the above intake can be packaged in one unit.
  • the above amount may be packaged in the form of the intake unit amount per meal, and when the food is a health drink, Above quantity This is a form in which Dori Siku, suspended or dissolved, is put in a bottle bowl in the form of a drink per serving.
  • the essential amino acid / non-essential amino acid ratio (hereinafter referred to as EAAZNEAA ratio (molar ratio)) in plant or animal protein that can be ingested as a diet is 0.46 for cereals, vegetables, seafood, meat and milk, respectively.
  • the total amount of essential amino acids represented by lysine, threonine, leucine, isoleucine and parin is small compared to the total amount of non-essential amino acids, and is constant at 0.50, 0.69, 0.68 and 0.75.
  • an increase in the total intake of Tajipa can also put a burden on the kidneys and liver. Therefore, there is a need for a composition that can efficiently take only the necessary essential amino acids.
  • an essential amino acid comprising lysine, threonine, leucine, isoleucine and parin so that the EAA NEAA ratio in the composition is about 0.50 to 3.50, preferably about 0.85 to 1.70.
  • the composition of the present invention containing the active ingredient may be additionally taken, or the EAA / NEAA ratio in the food ingredients may be within the above range.
  • the EAA / / NEAA ratio in food ingredients ingests food of the present invention designed to be within the range of the ratio is, the amino acids from amino acids and proteins that is part of the food product, the additional Designed so that the EAA / NEAA ratio for the total amount of lysine, threonine, leucine, isoloicin, and valine formulated together is about 0.50 to 3.50, preferably about 0.85 to about I.70 To do.
  • the lipid biosynthesis control gene expression inhibitor of the present invention is an expression inhibitor of a gene controlling lipid biosynthesis, characterized by containing lysine, threonine, leucine, isoleucine and parin as active ingredients.
  • the molar composition ratio (%) of each amino acid to all amino acids is lysine 5.0 or more to less than 65.0, threonine 5.0 or more to 65 5 Less than 0, Leucine 1. 0 to less than 35.0, Isoleucine 1. 0 to less than 35.0, Phosphorus 1. 0 to less than 35.0.
  • the inhibitor of the present invention is a gene expression level of SREBP 1 c that controls fatty acid biosynthesis in the liver, a gene group of fatty acid biosynthetic enzymes such as FAS and ACL, and genes related to cholesterol biosynthesis in the liver. It is possible to suppress the gene expression level of a certain 3-Hydroxy-3-methylgutaryl-CoA synthase 1 (hereinafter, HMGCAS 1) under conditions of high fat diet intake. As a result, an increase in visceral fat weight induced by an increase in dietary fat intake due to intake of a high fat diet or the like, and in particular, an increase in lipid content in the liver can be suppressed.
  • HMGCAS 1 3-Hydroxy-3-methylgutaryl-CoA synthase 1
  • composition of the present invention can activate AMP activated protein kinase (AMPK) in skeletal muscle and increase energy consumption in skeletal muscle.
  • AMPK AMP activated protein kinase
  • a group containing 7% (hereinafter referred to as weight%) lard hereinafter referred to as STD group
  • a group containing 30% lard hereinafter referred to as HFD group
  • 30% In addition to lysine, lysine, threonine, leucine, isoleucine and valine total 2% (hereinafter referred to as 2% EAAZHFD group), 4% (hereinafter referred to as 4% EAA / HFD group), 8% (hereinafter referred to as 8%) EAA / HFD group), 1 5% (hereinafter referred to as 1 2% EAA ZHFD group)
  • the prepared diet was ingested by C 5 7 B 6 mice for 8 weeks I let you.
  • the amino acid composition prepared based on the amino acid composition of casein is the sum of amino acid compositions other than casein and casein. 2 Corrected to 3%. For the 1 2% EAAZHFD group, the casein content was set to 11%. In addition to 30% lard, all groups ingesting diets containing a high content of lysine, threonine, leucine, isoleucine and valine are designated as EA AZHFD groups.
  • Amino acid compounds based on casein composition contain: 2.5% His, 4.5% Phe, 8.8% Hys-HCl, 1.1% Trp, 3.8% Thr, 2. 4% Met, 4.5% l ie, 5. 7% Val
  • EA A added represents the total of lysine hydrochloride, threonine, leucine, isoleucine and parin added in addition to casein and amino acid mixtures based on casein composition.
  • Total amino acid represents the sum of casein, amino acid mixture based on casein composition and the amount of EAA added.
  • Result 1 Body weight, organ weight, blood biochemistry parameters
  • Table 3 shows the gene expression levels of genes related to lipid biosynthesis in the liver (SREB Plc gene, HMGCAS1 gene, ACL gene and FAS gene) at the time when the diet of Table 1 was ingested for 8 weeks.
  • E AAZHFD it was found that the gene expression levels of SREBP 1 c and HMGCAS 1 increased in the HFD group could be significantly suppressed.
  • the expression of genes related to fatty acid biosynthesis such as FAS and ACL can be significantly reduced.
  • SREB P 1 c it became clear that the gene expression level can be suppressed depending on the increase in the intake of essential amino acids (Fig. 1A).
  • AM PK AMP-activated protein kinase
  • HMOCAS 1 3-hydroxy-3-methylglutaryl-CoA synthase 1 1.00 ⁇ . 0.29 b 1.53 ⁇ 0.25 a 0.90 ⁇ 0.34 b
  • Table 4 shows the lipid content and fatty acid composition in the liver when the diet of Table 1 was ingested for 8 weeks.
  • EAAZHFD EAAZHFD
  • MUFA monounsaturated fatty acids
  • Triglycerides Medium mg g 49.1 4 o 3317.3 a 46.8 t 14. ⁇ »32-0 ⁇ 12.3
  • Typical liver tissue slices in the HFD group and 8% E AAZHFD group when the diet of Table 1 was ingested for 8 weeks are shown (Fig. 2). As a result, it was found that lipid droplets and fatty degeneration were significantly suppressed in the ⁇ HFD group.
  • EAAZHFD group a group in which 1% of proline which is a non-essential amino acid is added to 6% in total of lysine, threonine, leucine, isoleucine and parin
  • EAA + Pro / HFD group C 57 B 6 mice were ingested for 2 weeks with a diet prepared so that 2% glycine was added
  • the inhibitory effect of lysine, threonine, leucine, isoleucine, and parin on the body weight gain phenomenon caused by ingestion of a high-fat diet can be inhibited by simultaneous intake of glycine or proline. all right.
  • HFD group a group containing 30% lard
  • lysine, threonine, leucine, isoloicin, and valine total 6% plus 2% non-essential amino acid arginine hereinafter referred to as EAA + A rg / HFD group
  • the C5 7 B 6 mice were ingested for 2 months with a diet prepared to add 2% glycine to the group (hereinafter referred to as EAA + G 1 y / HFD group), and the effects of non-essential amino acids were observed. .
  • EAA + G 1 y / HFD group a diet prepared to add 2% glycine to the group
  • arginine or glycine was taken at the same time as the intake of lysine, threonine, leucine, isoleucine, and parin against the increase in blood total cholesterol level due to high fat diet. It was found to be inhibited by doing.
  • composition range of each amino acid when a composition containing lysine, threonine, leucine, isoleucine, and valine exerts anti-obesity, anti-hyperlipidemia, and anti-fatty liver effects was evaluated as follows. .
  • Table 5 shows lysine, threonine, leucine, isoleucine and valine in addition to 30% lard (hereinafter referred to as HFD group), 30% lard. 4 Diet prepared so that the total composition would be 8% (EAA / HFD group, EAA-B / HFD group, EAA-K / HFD group, EAA—T / HFD group) were ingested by C 57 B 6 mice for 8 weeks, and the blending ratios of five types of amino acids and their effects were observed. In addition, the £ 8 //? 1? 0 group has the same bait composition as the 8% £ 8A group in Table 1.
  • composition range of each amino acid is determined using ob / ob mice, which are non-alcoholic fatty liver model mice. And evaluated.
  • Table 5 shows lysine, threonine, leucine, isoleucine and valine in addition to 30% lard (hereinafter referred to as HFD group), 30% lard. 4 Ob diet mice prepared with a total composition of 8% (EAA / HFD group, EAA—BZHFD group, EAA—K ⁇ HFD group, EAA—TZHFD group) Ingested for 2 weeks, the mixing ratio of 5 types of amino acids and their effects were observed. As a result, as shown in Figs. It has become clear that there is a decrease or a tendency to decrease.
  • composition containing lysine, threonine, leucine, isoleucine and parin provided by the present invention suppresses fatty liver and steatohepatitis.
  • the composition for anti-fatty liver and steatohepatitis of the present invention is particularly effective in steatohepatitis and steatohepatitis caused by ingestion of a high fat diet.
  • the invention is characterized in that it contains lysine, threonine, leucine, isoleucine and valine provided by the present invention, and does not contain at least one non-essential amino acid selected from proline, dalysin, tyrosine and arginine.
  • the composition is useful for anti-obesity and anti-hyperlipidemia. Furthermore, since the composition of the present invention comprises an amino acid as an active ingredient, it is highly safe and has few side effects. Therefore, the composition of the present invention can be administered for a long period of time. In fatty liver, steatohepatitis, obesity and hyperlipidemia It can be used advantageously for prevention, treatment and improvement.
  • the lipid biosynthesis regulating gene expression inhibitor of the present invention can be used as an experimental reagent in the fields of physiology and biochemistry in addition to its use as a medicament as described above.

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Abstract

La présente invention concerne une composition contre la stéatose hépatique ou la stéato-hépatite comprenant de la lysine en une quantité non inférieure à 5,0 % et inférieure à 65,0 %, de la thréonine en une quantité non inférieure à 5,0 % et inférieure à 65,0 %, de la leucine en une quantité non inférieure à 1,0 % et inférieure à 35,0 %, de l’isoleucine en une quantité non inférieure à 1,0 % et inférieure à 35,0 % et de la valine en une quantité non inférieure à 1,0 % et inférieure à 35,0 % en mole, par rapport à la quantité totale d’acides aminés de la composition. L'invention concerne également une composition contre l'obésité ou hypolipémiante comprenant de la lysine, de la thréonine, de la leucine, de l’isoleucine et de la valine dans les mêmes quantités que précédemment et ne contenant pas l’un au moins des acides aminés du groupe comprenant proline, glycine, tyrosine et arginine.
PCT/JP2006/322041 2005-10-27 2006-10-27 Composition contre la steatose hepatique ou l’obesite ou a effet hypolipemiant WO2007049818A1 (fr)

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WO2021112217A1 (fr) * 2019-12-05 2021-06-10 味の素株式会社 Composition permettant de supprimer l'augmentation de la quantité de graisse hépatique neutre
CN114364264A (zh) * 2019-07-19 2022-04-15 飞滤森有限公司 用于癌症治疗和代谢干预疗法的组合物、方法、试剂盒和系统以及其他用途
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EP1865944A2 (fr) * 2005-03-29 2007-12-19 Ajinomoto Co., Inc. Compositions contenant des acides amines pour la prevention ou le traitement dans le muscle squelettique de personnes agees
EP1865944A4 (fr) * 2005-03-29 2012-03-07 Ajinomoto Kk Compositions contenant des acides amines pour la prevention ou le traitement dans le muscle squelettique de personnes agees
JP2009536016A (ja) * 2006-01-20 2009-10-08 インエル ビョルク， アミノ酸を含む食品組成物
JP2008247896A (ja) * 2007-03-07 2008-10-16 Shizuokaken Koritsu Daigaku Hojin 透析患者用経口アミノ酸組成物
WO2008120797A1 (fr) * 2007-03-30 2008-10-09 Ajinomoto Co., Inc. Activateur d'ampk
JP2014519842A (ja) * 2011-06-23 2014-08-21 インノヴァフード アクチエボラグ 改善された食品組成物
US10750771B2 (en) 2011-06-23 2020-08-25 Innovafood Ab Food supplement comprising amino acid and chromium
WO2012177215A1 (fr) * 2011-06-23 2012-12-27 Innovafood Ab Composition alimentaire améliorée
US11937624B2 (en) 2011-06-23 2024-03-26 Innovafood Ab Food composition
WO2017089612A1 (fr) 2015-11-27 2017-06-01 Doublegood Ab Complément alimentaire et composition alimentaire pour traiter le syndrome métabolique
CN108366610A (zh) * 2015-11-27 2018-08-03 倍佳有限公司 用于治疗代谢综合征的食品补充剂和组合物
JP2018537974A (ja) * 2015-11-27 2018-12-27 ダブルグッド アクチエボラグＤｏｕｂｌｅｇｏｏｄ Ａｂ メタボリックシンドローム治療用栄養補助食品および食品組成物
US11957651B2 (en) 2017-07-28 2024-04-16 Professional Dietetics S.P.A. Compositions comprising amino acids for use in the treatment of mitochondrial dysfunction-related diseases
WO2019160103A1 (fr) * 2018-02-15 2019-08-22 国立大学法人東北大学 Agent abaissant les lipides hépatiques
EP3586837A1 (fr) * 2018-06-27 2020-01-01 Professional Dietetics S.p.A. Compositions comprenant des acides aminés destinés à être utilisés dans la prévention et le traitement des maladies du foie
CN112334129A (zh) * 2018-06-27 2021-02-05 专业营养学国际有限公司 用于预防和治疗肝病的包含氨基酸的组合物
JP2021529731A (ja) * 2018-06-27 2021-11-04 プロフェッショナル ダイエテティクス インターナショナル エス．アール．エル． 肝疾患の予防および治療に使用されるアミノ酸を含む組成物
JP7347744B2 (ja) 2018-06-27 2023-09-20 プロフェッショナル ダイエテティクス エス．ピー．エー． 肝疾患の予防および治療に使用されるアミノ酸を含む組成物
WO2020003013A1 (fr) * 2018-06-27 2020-01-02 Professional Dietetics S.P.A. Compositions comprenant des acides aminés pour une utilisation dans la prévention et le traitement de maladies hépatiques
IT201800006725A1 (it) * 2018-06-27 2019-12-27 Composizioni comprendenti aminoacidi per l'uso nella prevenzione e nel trattamento di malattie epatiche
CN114364264A (zh) * 2019-07-19 2022-04-15 飞滤森有限公司 用于癌症治疗和代谢干预疗法的组合物、方法、试剂盒和系统以及其他用途
EP3998869A4 (fr) * 2019-07-19 2023-09-06 Filtricine, Inc. Compositions, méthodes, kits et systèmes pour le traitement du cancer et la thérapie d'intervention métabolique, ainsi que d'autres utilisations
WO2021112217A1 (fr) * 2019-12-05 2021-06-10 味の素株式会社 Composition permettant de supprimer l'augmentation de la quantité de graisse hépatique neutre
CN114980752A (zh) * 2020-04-03 2022-08-30 三菱瓦斯化学株式会社 体脂减少剂
EP4129403A4 (fr) * 2020-04-03 2023-06-21 Mitsubishi Gas Chemical Company, Inc. Agent réduisant la graisse corporelle

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