Composition for preventing or treating metabolic dysfunction-associated liver disease comprising oenotein b

Abstract

The present invention relates to a composition for preventing or treating metabolic dysfunction-associated liver disease comprising oenotein B, wherein oenotein B reduced elevated liver-related parameters in an animal model of metabolic dysfunction-associated steatotic liver disease, reduced body weight, liver weight, and white adipose tissue to alleviate liver steatosis, reduced inflammation, and inhibited liver fibrosis. Therefore, the composition has the effect of being able to be effectively used for preventing or treating metabolic dysfunction-associated liver disease including liver steatosis, metabolic dysfunction steatohepatitis, and liver fibrosis.

Description

Composition for preventing or treating metabolic liver disease containing oenothein B

[0001] The present invention relates to a composition for preventing or treating metabolic liver disease comprising oenothein B.

[0002] The liver is a large organ located in the upper abdominal cavity on the right side of the body, weighing approximately 1.5 kg in adults. A normal liver is visually reddish and has a smooth surface. However, its shape and size can change as liver disease develops. A typical example is excessive alcohol consumption, which causes fat to accumulate in the liver, causing it to enlarge and take on a yellowish tint. Conversely, as cirrhosis progresses, the liver shrinks and its surface becomes uneven. The liver is a vital organ with numerous functions, which can be summarized as follows. First, the liver processes various nutrients in the body, i.e., performs metabolic functions. Food absorbed from the intestines is appropriately transformed in the liver for use by various tissues. After nutrients are utilized by these tissues, waste products are transported back to the liver for processing. Second, the liver stores several nutrients necessary for the body. Third, it produces bile acids, which are essential for nutrient absorption in the intestines, and excretes them through the bile duct into the intestines. Without these bile acids, various nutrients cannot be absorbed, leading to nutritional deficiencies. Fourth, it produces substances absolutely essential for the proper functioning of our bodies (albumin, blood clotting proteins, cholesterol, etc.). Finally, it detoxifies alcohol, drugs, and various toxins produced in the body (Eugene Brainward, et al. Harrison's principles of internal medicine. 15th edition. 2001).

[0003] Metabolic dysfunction-associated steatotic liver disease (MASLD) is a disease caused by abnormal fat accumulation in the liver due to metabolic disorders. It is defined as a disease with hepatic steatosis and at least one of the five cardiometabolic risk factors. This disease was previously defined as non-alcoholic fatty liver disease (NAFLD), but in June 2024 in Korea and in 2023 overseas, the name and definition of non-alcoholic fatty liver disease was changed to MASLD (metabolic dysfunction-associated steatotic liver disease) by international liver societies in the United States and Europe. Metabolic fatty liver disease is not liver damage caused by alcohol, but begins with hepatic steatosis, in which fatty acids are deposited in the form of neutral fat in more than 5% of the liver parenchymal cells. When the accumulated fat becomes toxic through various mechanisms, hepatocytes show damage (ballooning degeneration) and can progress to metabolic dysfunction-associated steatohepatitis (formerly nonalcoholic steatohepatitis, NASH) accompanied by fibrosis. Metabolic steatohepatitis is a disease that occurs in the worsening process of the above metabolic fatty liver disease. As fat accumulates in hepatocytes, hepatocyte degeneration / necrosis occurs, and the resulting inflammation and liver fibrosis can develop into cirrhosis and liver cancer (Ong JP et al., Obesity Surgery volume 15, pages 310-315, 2005), so it is recognized as a serious disease worldwide.Metabolic steatohepatitis (MSL) is divided into primary and secondary causes. Primary causes are caused by hyperlipidemia, diabetes, or obesity, which are characteristics of metabolic syndrome (Szczepaniak LS et al., 2005). Secondary causes are known to be caused by nutritional factors (rapid weight loss, starvation, intestinal bypass surgery), various drugs, toxic substances (poisonous mushrooms, bacterial toxins), metabolic factors, and other factors. The prevalence of metabolic fatty liver disease is reported to be 32.4% worldwide and 34.6% in Korea, and it can approximately fourfold increase the risk of developing type 2 diabetes and significantly increase the risk of developing cardiovascular disease. Furthermore, unlike other liver diseases, the incidence of hepatocellular carcinoma increases in the early inflammatory state before liver fibrosis has progressed. Therefore, prompt treatment is necessary at the least metabolic steatohepatitis stage among metabolic fatty liver diseases. However, despite the increasing trend of new drug development and clinical trials, only one drug has received FDA approval to date. Therefore, it is essential to develop and study various therapeutic candidates for metabolic fatty liver disease.

[0004] The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic liver disease.

[0005] In addition, it is an object of the present invention to provide a food composition for preventing or improving metabolic liver disease.

[0006] In addition, it is an object of the present invention to provide a use for preventing or treating metabolic liver disease.

[0007] In addition, it is an object of the present invention to provide a method for treating metabolic liver disease, which comprises administering to a subject suffering from metabolic liver disease.

[0008] To achieve the above purpose, the present invention provides a pharmaceutical composition for preventing or treating metabolic liver disease, comprising oenothein B, an analog thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] In addition, the present invention provides a food composition for preventing or improving metabolic liver disease, comprising oenothein B or an analog thereof as an active ingredient.

[0010] In addition, the present invention provides a use of oenothein B or an analog thereof for the prevention or treatment of metabolic liver disease.

[0011] In addition, the present invention provides a method for treating metabolic liver disease, comprising administering oenothein B or an analog thereof to a subject suffering from metabolic liver disease.

[0012] According to the present invention, oenothein B reduced increased liver values ​​in an animal model of metabolic fatty liver disease, improved hepatic steatosis by reducing body weight, liver weight, and white adipose tissue, reduced inflammation, and inhibited hepatic fibrosis, and therefore has an effect that can be usefully utilized for the prevention or treatment of metabolic liver diseases including hepatic steatosis, metabolic steatohepatitis, and hepatic fibrosis.

[0013] Figure 1 is a diagram confirming changes in liver function in a mouse model of metabolic fatty liver disease caused by administration of oenothein B:

[0014] Before Inj: Before administration of PBS or oenothene B;

[0015] 4th Inj: 4 doses of PBS or oenothein B;

[0016] 10th Inj: 10 doses of PBS or oenothein B;

[0017] Severe: A group in which the disease progression of metabolic fatty liver disease is severe;

[0018] moderate: Group with moderate progression of metabolic fatty liver disease;

[0019] Normal liver mouse group: Normal diet-fed liver mouse group;

[0020] GAN diet: A group of mice fed a diet that induces metabolic abnormalities in fatty liver disease for 28 weeks and then administered PBS; and

[0021] GAN diet + oenothein B: Group administered oenothein B to mice with metabolic fatty liver disease.

[0022] Figure 2 is a diagram analyzing the changes in body weight, liver, epididymal white adipose tissue (eWAT), and retroperitoneal white adipose tissue (rWAT) weight in a mouse model of metabolic fatty liver disease caused by administration of oenothein B:

[0023] Severe: A group in which the disease progression of metabolic fatty liver disease is severe;

[0024] moderate: Group with moderate progression of metabolic fatty liver disease;

[0025] Normal liver mouse group: Normal diet-fed liver mouse group;

[0026] GAN diet: A group of mice fed a diet that induces metabolic abnormalities in fatty liver disease for 28 weeks and then administered PBS; and

[0027] GAN diet + oenothein B: Group administered oenothein B to mice with metabolic fatty liver disease.

[0028] Figure 3 is a histological analysis of the effect of improving hepatic steatosis in a mouse model of metabolic fatty liver disease by administration of oenothein B:

[0029] Normal liver mouse group: Normal diet-fed liver mouse group;

[0030] GAN diet: A group of mice fed a diet that induces metabolic abnormalities in fatty liver disease for 20 weeks and then administered PBS; and

[0031] GAN diet + oenothein B: Group administered oenothein B to mice with metabolic fatty liver disease.

[0032] Figure 4 is a histological analysis of the effect of improving liver fibrosis in a mouse model of metabolic fatty liver disease by administration of oenothein B:

[0033] Normal liver mouse group: Normal diet-fed liver mouse group;

[0034] GAN diet: A group of mice fed a diet that induces metabolic abnormalities in fatty liver disease for 28 weeks and then administered PBS; and

[0035] Oenothein B 5mg / kg: Group administered oenothein B to mice with metabolic fatty liver disease.

[0036] Hereinafter, the present invention will be described in detail with reference to the attached drawings and embodiments thereof. However, the following embodiments are provided as examples of the present invention. If a detailed description of a technology or configuration well known to those skilled in the art is judged to unnecessarily obscure the gist of the present invention, such detailed description may be omitted, and the present invention is not limited thereby. The present invention is capable of various modifications and applications within the scope of the following claims and equivalents interpreted therefrom.

[0037] Additionally, the terminology used in this specification is intended to appropriately express preferred embodiments of the present invention, and may vary depending on the intent of the user or operator, or the customs of the field to which the present invention pertains. Therefore, the definitions of these terms should be determined based on the contents throughout this specification. Throughout this specification, when a part is said to "include" a certain component, unless specifically stated otherwise, this does not mean that other components are excluded, but rather that other components may be included.

[0038] Unless otherwise defined, all technical terms used in this invention have the same meaning as commonly understood by those skilled in the art. While preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. The contents of all publications cited as references herein are incorporated herein by reference.

[0039]

[0040] In one aspect, the present invention relates to a pharmaceutical composition for preventing or treating metabolic liver disease, comprising oenothein B, an analog thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0041] In one embodiment, oenothene B may be a compound represented by the following chemical formula 1:

[0042]

[0043] The present invention includes not only oenothene B represented by Chemical Formula 1, but also pharmaceutically acceptable salts thereof, and all possible stereoisomers, geometric isomers, racemates, tautomers, N-oxides, hydrates or solvates that can be prepared therefrom.

[0044] In one embodiment, the analogue of oenothein B can be oenothein A, oenothein C, oenothein D, oenothein F or oenothein G.

[0045] In one embodiment, the pharmaceutically acceptable salt may be selected from the group consisting of alkali metal salts, alkaline earth metal salts, salts with inorganic acids, salts with organic acids, and salts with acidic amino acids.

[0046] In one embodiment, the metabolic liver disease may be metabolic dysfunction-associated steatotic liver disease (MASLD), and the disease progression may be moderate or severe metabolic fatty liver disease.

[0047] In one embodiment, the metabolic fatty liver disease may be steatosis, metabolic dysfunction-associated steatohepatitis, metabolic hepatitis, non-alcoholic fatty liver (NAFL), liver fibrosis, liver cirrhosis, steatosis, or hepatocellular carcinoma.

[0048] In one embodiment, the metabolic fatty liver disease may be liver fibrosis due to metabolic steatohepatitis, cirrhosis due to metabolic steatohepatitis, liver failure due to metabolic steatohepatitis, cardiovascular disease due to metabolic steatohepatitis, or hepatocellular carcinoma due to metabolic steatohepatitis.

[0049] In one embodiment, the composition of the present invention may exhibit any one or more of the following effects (a) to (e):

[0050] (a) decreased blood ALT, AST, or ALP levels;

[0051] (b) reduction in liver weight or white adipose tissue;

[0052] (c) Inhibition of fat accumulation in liver tissue (reduction of accumulated fat);

[0053] (d) reduced immune cell infiltration; and

[0054] (e) Reduction of liver fibrosis.

[0055] Oenothein B of the present invention is a compound of the ellagitannin series among antioxidant plant polyphenols, and was first isolated from evening primrose (Oenothera erythrosepala). Oenothein B is known to exist not only in the Onagraceae family to which Oenothera belongs, but also in other plants belonging to the Myrtaceae and Lythraceae families, such as eucalyptus (Eucalyptus globulus) (Yoshida, T, Molecules, 2018).

[0056] The oenothene B of the present invention can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, or phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, and alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, Contains phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

[0057] The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving torsemide or cromolyn in an excess aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Alternatively, the salt can be prepared by evaporating the solvent or excess acid from the mixture and drying it, or by suction filtration of the precipitated salt. In addition, a pharmaceutically acceptable metal salt can be prepared using a base. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. In addition, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0058] The pharmaceutical composition of the present invention may additionally include a known therapeutic agent for metabolic liver disease in addition to oenothein B, an analog thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, and may be used in combination with other known treatments for the treatment of these diseases.

[0059] In the present invention, the term "prevention" means any action that inhibits or delays the occurrence, spread, and recurrence of metabolic liver disease by administering the pharmaceutical composition according to the present invention, and "treatment" means any action that improves or beneficially changes the symptoms of metabolic liver disease by administering the composition of the present invention. Those of ordinary skill in the art to which the present invention pertains will be able to know the exact criteria for diseases to which the composition of the present invention is effective and determine the degree of improvement, enhancement, and treatment by referring to materials presented by the Korean Medical Association, etc.

[0060] The term "therapeutically effective amount" used in combination with the active ingredient in the present invention means an amount effective in preventing or treating a target disease, and the therapeutically effective amount of the composition of the present invention may vary depending on various factors, such as the administration method, target site, and patient condition. Therefore, the dosage for use in humans should be determined as an appropriate amount by taking both safety and efficacy into consideration. It is also possible to estimate the amount used in humans from the effective amount determined through animal testing. Such considerations in determining the effective amount are described, for example, in Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed.(2001), Pergamon Press; and E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed.(1990), Mack Publishing Co.

[0061] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects. The effective dosage level may be determined based on factors including the patient's health condition, the type of metabolic liver disease, the cause of the metabolic liver disease, the severity, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the excretion rate, the duration of treatment, the drugs used in combination or simultaneously, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by those skilled in the art.

[0062] The pharmaceutical composition of the present invention may include a carrier, diluent, excipient, or a combination of two or more thereof commonly used in biological preparations. The term "pharmaceutically acceptable" as used herein means that the composition exhibits a characteristic of not being toxic to cells or humans exposed to the composition. The carrier is not particularly limited as long as it is suitable for delivering the composition in vivo, and for example, compounds described in Merck Index, 13th ed., Merck & Co. Inc., saline solution, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components may be mixed and used. If necessary, other common additives such as antioxidants, buffers, and bacteriostatic agents may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate the composition into a main use form such as an aqueous solution, suspension, or emulsion, pills, capsules, granules, or tablets. Furthermore, it can be preferably formulated according to each disease or ingredient using an appropriate method in the field or the method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).

[0063] In one embodiment, the pharmaceutical composition may be in one or more dosage forms selected from the group consisting of oral dosage forms, topical preparations, suppositories, sterile injectable solutions and sprays, with oral or injectable dosage forms being more preferred.

[0064] The term "administration" used in the present invention means providing a predetermined substance to an individual or patient by any appropriate method, and may be administered parenterally (for example, intravenously, subcutaneously, intraperitoneally, or locally in the form of an injection) or orally depending on the intended method, and the dosage range varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. Liquid preparations for oral administration of the composition of the present invention include suspensions, oral solutions, emulsions, syrups, etc., and may include various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, etc. The pharmaceutical composition of the present invention may be administered by any device that allows the active substance to move to target cells. Preferred administration methods and formulations include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and drip injection. Injections can be manufactured using aqueous solvents such as saline solution and Ringer's solution, non-aqueous solvents such as vegetable oil, higher fatty acid ester (e.g., ethyl oleate, etc.), alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.), and pharmaceutical carriers such as stabilizers to prevent deterioration (e.g., ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers to adjust pH, and preservatives to inhibit microbial growth (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

[0065] The term "subject" used in the present invention means any animal, including humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, that has developed or may develop the above metabolic liver disease, and the above diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to the subject. The pharmaceutical composition of the present invention can be administered in combination with existing therapeutic agents.

[0066] The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive. At this time, the pharmaceutically acceptable additive may include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, mannitol, maltose, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, sucrose, dextrose, sorbitol, and talc. The pharmaceutically acceptable additive according to the present invention is preferably included in the composition in an amount of 0.1 to 90 parts by weight, but is not limited thereto.

[0067] In one aspect, the present invention relates to a food composition for preventing or improving metabolic liver disease, comprising oenothein B or an analog thereof as an active ingredient.

[0068] In one embodiment, the metabolic liver disease may be metabolic dysfunction-associated steatotic liver disease (MASLD), and the disease progression may be moderate or severe metabolic fatty liver disease.

[0069] In one embodiment, the metabolic fatty liver disease may be steatosis, metabolic dysfunction-associated steatohepatitis, metabolic hepatitis, non-alcoholic fatty liver (NAFL), liver fibrosis, liver cirrhosis, steatosis, or hepatocellular carcinoma.

[0070] In one embodiment, the metabolic fatty liver disease may be liver fibrosis due to metabolic steatohepatitis, cirrhosis due to metabolic steatohepatitis, liver failure due to metabolic steatohepatitis, cardiovascular disease due to metabolic steatohepatitis, or hepatocellular carcinoma due to metabolic steatohepatitis.

[0071] In one embodiment, the composition of the present invention may exhibit any one or more of the following effects (a) to (e):

[0072] (a) decreased blood ALT, AST, or ALP levels;

[0073] (b) reduction in liver weight or white adipose tissue;

[0074] (c) Inhibition of fat accumulation in liver tissue;

[0075] (d) reduced immune cell infiltration; and

[0076] (e) Reduction of liver fibrosis.

[0077] When the composition of the present invention is used as a food composition, the composition may be added as is or used in combination with other foods or food ingredients, and may be used appropriately according to conventional methods. In addition to the active ingredient, the composition may include a food-related acceptable food additive, and the amount of the active ingredient mixed may be appropriately determined depending on the intended use (prevention, health, or therapeutic treatment).

[0078] The term "food supplement additive" used in the present invention means a component that can be added to food as an auxiliary, and can be appropriately selected and used by those skilled in the art as added in the manufacture of health functional foods of each formulation. Examples of food supplement additives include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc., but the types of food supplement additives of the present invention are not limited by the above examples.

[0079] The food composition of the present invention may include a health functional food. The term "health functional food" as used herein refers to a food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients with useful functionality for the human body. Here, "functionality" means obtaining a beneficial effect for health purposes, such as regulating nutrients for the structure and function of the human body or physiological functions. The health functional food of the present invention can be manufactured by methods commonly used in the art, and during the manufacturing process, raw materials and ingredients commonly added in the art can be added. In addition, the formulation of the health functional food can be manufactured without limitation as long as it is a formulation recognized as a health functional food. The food composition of the present invention can be manufactured in various forms, and unlike general drugs, it has the advantage of not causing side effects that may occur with long-term administration of drugs using food as a raw material, and is highly portable, so the health functional food of the present invention can be consumed as a supplement to enhance the effectiveness of a treatment for metabolic liver disease.

[0080] In addition, there is no limitation on the type of health food in which the composition of the present invention can be used. In addition, a composition containing the composition of the present invention as an active ingredient can be prepared by mixing other appropriate auxiliary ingredients that can be included in health functional foods and known additives according to the selection of a person skilled in the art. Examples of foods to which the composition can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and the like can be prepared by adding the extract according to the present invention to juice, tea, jelly, and juice made with the extract as a main ingredient.

[0081] In one aspect, the present invention relates to the use of oenothene B, an analog thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of metabolic liver diseases.

[0082] In one aspect, the present invention relates to a method for treating metabolic liver disease, comprising administering to a subject suffering from metabolic liver disease a pharmaceutically effective amount of oenothein B, an analog thereof, or a pharmaceutically acceptable salt thereof of the present invention.

[0083] The present invention is described in more detail through the following examples. However, the following examples are intended only to concretize the content of the present invention and are not intended to limit the present invention.

[0084]

[0085] Example 1. Preparation of an animal model of fatty liver disease with metabolic abnormalities

[0086] To develop an animal model of metabolic fatty liver disease, C57BL / 6 male mice were fed a GAN diet (40% total fat, 20% fructose, 2% cholesterol; Research Diets #D09100310) in their diet and 4.2% sugar water (fructose + glucose) in their drinking water for 20 to 28 weeks to induce metabolic fatty liver disease. The animal model developed hepatic steatosis from the 12th week of dietary intake of the metabolic fatty liver diet, metabolic steatohepatitis from the 20th week, and liver fibrosis from the 26th week.

[0087]

[0088] Example 2. Analysis of the therapeutic effect of oenothein B on fatty liver disease caused by metabolic disorders.

[0089] 2-1. Liver function recovery effect

[0090] In order to confirm the effect of oenothein B on the recovery of liver function, mice (fed for 28 weeks) in which metabolic fatty liver disease was induced in Example 1 were divided into Severe and Moderate groups based on the results of ALT, AST, and ALP analysis according to the degree of disease progression (Severe group: ALT standard 500 U / L or more; and Moderate group: ALT standard 300 U / L or more and less than 500 U / L), placed in a mouse holder, and 100 μl to 150 μl of blood was collected from the tail, placed in a capillary blood collection tube (serum separating tube, BD bioscience), left at room temperature for 30 minutes, and then centrifuged at 1500 × g at 4°C for 15 minutes. After centrifugation, the plasma (supernatant) was collected in an Eppendorf tube and the levels of ALT, AST and ALP in the plasma were analyzed. Mice showing similar levels were administered PBS to the control group and oenothein B to the experimental group intraperitoneally every two days. After the 4th and 10th injections, the plasma was separated and analyzed for ALT, AST and ALP. At this time, oenothein B was prepared at a concentration of 10 mg / ml in DW and filtered through a 0.2 μm pore filter. In the same way, it was mixed with PBS at 5 mg / kg and administered intraperitoneally to mice every two days.

[0091] As a result, it was confirmed that the plasma ALT, AST, and ALP levels of the animal model of metabolic abnormality fatty liver disease (GAN diet), which were significantly increased compared to normal mice fed a normal diet (Normal standard diet), were significantly reduced by administration of oenothein B (10 administrations) (GAN diet + oenothein B) and recovered to a level similar to the liver levels of normal mice (Fig. 1).

[0092]

[0093] 2-2. Effect of treatment on fatty liver disease due to metabolic abnormalities

[0094] The body weights of the normal liver mouse group (Normal standard diet), the group injected with PBS to mice with severe or moderate metabolic fatty liver disease (fed for 28 weeks) (GAN diet), and the group injected with 5 mg / kg (200 μl) of oenothein B intraperitoneally 10 times at 2-day intervals to mice with severe or moderate metabolic fatty liver disease (GAN diet+oenothein B) were checked, and after administration, the mice were euthanized, and the liver, epididymal white adipose tissue (eWAT), and retroperitoneal white adipose tissue (rWAT) were collected and weighed.

[0095] Observation of body weight during administration revealed that both severe and moderate metabolic fatty liver disease mice showed a decrease in body weight to the level of the normal liver control group when administered oenothein B (Fig. 2). In addition, the livers of mice with induced metabolic fatty liver disease were approximately three times larger than those of normal livers, and the liver weight and white adipose tissue of the group administered oenothein B were significantly reduced compared to the normal liver mouse group (Fig. 2).

[0096]

[0097] 2-3. Effect of treating hepatic steatosis

[0098] The livers of mice with normal liver function (Normal standard diet), mice with metabolic fatty liver disease induced by hepatic steatosis but no fibrosis by administering GAN diet + sugar water for 20 weeks, mice injected with PBS (GAN diet), and mice injected intraperitoneally with 5 mg / kg of oenothein B 10 times at 2-day intervals (GAN diet + oenothein B) were removed and fixed in 10% formalin solution. The fixed liver tissues were embedded in paraffin, sectioned into 4 μm thick sections, attached to glass slides, stained with hematoxylin & eosin, and then observed in cross-section under a microscope (×100).

[0099] As a result, it was confirmed that the liver steatosis of mice administered with oenothein B was improved to a level similar to that of mice with normal livers, and that immune cell infiltration was also reduced (Fig. 3).

[0100]

[0101] 2-4. Effects of treating liver fibrosis

[0102] Livers were removed from the following groups: a group of mice with normal liver function (Standard diet), a group of mice with metabolic fatty liver disease that developed fibrosis by administering GAN diet + sugar water for 28 weeks and injected with PBS (GAN diet), and a group of mice with metabolic fatty liver disease that received intraperitoneal injections of 5 mg / kg of oenothein B 10 times at 2-day intervals (Oenothein B 5 mg / kg). After staining with Sirius red, 15 randomly selected areas were photographed under a microscope (×100). Collagen (red) Area (%) relative to the total area was calculated from the tissue photographs taken using Image J.

[0103] As a result, liver fibrosis was significantly increased in the GAN diet group compared to the normal liver mouse group, and liver fibrosis in the group administered oenothein B was significantly improved compared to the GAN diet group (n=6) (*p<0.05 and **p<0.01) (Fig. 4).

Claims

1. A pharmaceutical composition for the prevention or treatment of metabolic liver disease, comprising oenothein B, an analogue thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

2. A pharmaceutical composition for the prevention or treatment of metabolic liver disease, wherein the metabolic liver disease in claim 1 is metabolic dysfunction-associated steatotic liver disease (MASLD).

3. A pharmaceutical composition for the prevention or treatment of metabolic liver disease, wherein the metabolic fatty liver disease in paragraph 2 is steatosis, metabolic dysfunction-associated steatohepatitis, metabolic dysfunction hepatitis, non-alcoholic fatty liver (NAFL), liver fibrosis, liver cirrhosis, or hepatocellular carcinoma.

4. A pharmaceutical composition for the prevention or treatment of metabolic liver disease, wherein the metabolic fatty liver disease in paragraph 2 is liver fibrosis due to metabolic steatohepatitis, cirrhosis due to metabolic steatohepatitis, liver failure due to metabolic steatohepatitis, cardiovascular disease due to metabolic steatohepatitis, or hepatocellular carcinoma due to metabolic steatohepatitis.

5. A pharmaceutical composition for preventing or treating metabolic liver disease, which exhibits any one or more of the following effects (a) to (e) in paragraph 1: (a) decreased blood ALT, AST, or ALP levels; (b) reduction in liver weight or white adipose tissue; (c) Inhibition or reduction of fat accumulation in liver tissue; (d) reduced immune cell infiltration; and (e) Reduction of liver fibrosis.

6. A food composition for preventing or improving metabolic liver disease, comprising oenothein B or an analog thereof as an active ingredient.

7. A food composition for preventing or improving metabolic liver disease, wherein the metabolic liver disease in paragraph 6 is metabolic dysfunction-associated steatotic liver disease (MASLD).

8. A food composition for preventing or improving metabolic liver disease, wherein the metabolic fatty liver disease in paragraph 7 is steatosis, metabolic dysfunction-associated steatohepatitis, metabolic dysfunction hepatitis, non-alcoholic fatty liver (NAFL), liver fibrosis, liver cirrhosis, steatosis, or hepatocellular carcinoma.

9. In paragraph 7, the metabolic fatty liver disease is liver fibrosis due to metabolic steatohepatitis, cirrhosis due to metabolic steatohepatitis, liver failure due to metabolic steatohepatitis, cardiovascular disease due to metabolic steatohepatitis, or hepatocellular carcinoma due to metabolic steatohepatitis, a food composition for preventing or improving metabolic liver disease.

10. Use of oenothein B, its analogues or its pharmaceutically acceptable salts for the prevention or treatment of metabolic liver diseases.

11. A method for treating metabolic liver disease, comprising administering to a subject suffering from metabolic liver disease a pharmaceutically effective amount of oenothein B, an analogue thereof, or a pharmaceutically acceptable salt thereof.

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