Pharmaceutical composition for preventing or treating fatty liver

Abstract

To provide a composition for treating fatty liver, for reducing liver fat content, or for ameliorating liver diseases or other associated disorders caused by fatty liver.SOLUTION: A composition comprises (i) as an active ingredient, sucralose, or a combination of sucralose and one or more compounds selected from the group consisting of eriodictyol, menthol, and saccharin; or (ii) as an active ingredient, mannitol, or a combination of mannitol and one or more compounds selected from the group consisting of eriodictyol, menthol, and saccharin; or (iii) a combination as an active ingredient selected from the group consisting of (1) a combination of sucralose and eriodictyol, (2) a combination of saccharin and mannitol, (3) a combination of eriodictyol and mannitol, (4) a combination of menthol and mannitol, and (5) a combination of menthol, mannitol, and eriodictyol.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to methods and compositions for preventing or treating fatty liver, protecting liver function, or ameliorating liver disease or other related disorders caused by fatty liver. [Background technology]

[0002] Background of the Invention The liver is part of the animal's digestive system and is the main organ responsible for producing and secreting many digestive juices. It also plays a key role in absorption, metabolism, detoxification, and immune defense. The liver is a key organ for fat metabolism, playing a crucial role in the digestion, absorption, breakdown, synthesis, and transport of high-fat diets. Free fatty acids (FFA) taken up by the liver from the blood are ultimately synthesized into triglycerides (TG), which are then stored in the liver or transported from the liver into the blood circulation in the form of very low-density lipoproteins (VLDL). Therefore, when the liver is damaged, lipids (especially TG) are abnormally metabolized and accumulate in hepatocytes.

[0003] Under normal circumstances, fat constitutes 3% of the liver by weight. Clinically, "fatty liver disease (FLD)" refers to intrahepatic fat exceeding 5% of the liver by weight or to greater than 10% of hepatocytes exhibiting vesicular fatty change in liver tissue sections. 2 (Non-Patent Document 1). Depending on the cause of the disease, fatty liver can be divided into alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), or other fatty liver diseases caused by other factors such as drugs. Fatty liver disease is pathologically characterized by the appearance of steatosis or steatohepatitis. Based on the percentage of hepatocytes affected by fatty liver, fatty liver is classified as mild (<33%), moderate (33-66%), and severe (>66%). 3,9,21(Non-Patent Document 2, Non-Patent Document 3, Non-Patent Document 4). Previously, fatty liver was considered a benign and reversible condition and therefore not taken seriously, but recent studies have shown that it can lead to severe liver fibrosis and cirrhosis and liver cancer. As the obese population increases, the prevalence of FLD also increases.

[0004] The primary cause of liver disease in Western countries is chronic excessive alcohol consumption, and therefore, the majority of liver disease is caused by alcohol-related lesions. However, over the past 15–20 years, NAFLD has become the primary cause of liver dysfunction to be considered in Western countries. 2 (Non-Patent Document 1). Thaler described NAFLD in 1962. In 1980, Ludwig proposed the term "non-alcoholic steatohepatitis (NASH)" based on the concomitant NAFLD observed in a group of obese female patients with diabetes and hyperlipidemia. Then, in 1986, Schaffner again emphasized that NASH plays an important role in the mechanism of fibrosis induction in the progression of NAFLD. 21 (Non-Patent Document 4). By 1998, Day discovered that 15-50% of patients with NASH suffered from various degrees of induced fibrosis. 4 (Non-Patent Document 5), therefore, clinicians have begun to pay attention to NAFLD. Currently, in addition to AFLD, NASH is not just one stage in the natural progression of NAFLD in clinical practice; due to the presence of NASH, NAFLD is no longer considered a benign liver disease.

[0005] Currently, studies of FLD in North and South America, Japan, Northern and Southern Europe, Australia, and the Middle East have found that the prevalence of NAFLD is at least 10–39%. Postmortem histological examinations have shown that the prevalence of NAFLD is approximately 20%, with the incidence of concomitant NASH ranging from approximately 3–18%. The prevalence of NAFLD in obese individuals is up to 57–74% (4.6 times higher than in healthy individuals), with 20–25% of these individuals suffering from NASH lesions and 2–3% suffering from cirrhosis. In Taiwan, NAFLD prevalence has increased annually over the past 30 years due to improvements in the economic environment and dietary habits. In recent years, the prevalence of NAFLD in Taiwan has risen to 12–37%, similar to that in Japan (9–13%). While the prevalence of NAFLD in non-obese individuals is approximately 10%, the prevalence of NAFLD in morbidly obese individuals (BMI > 30) is as high as 80%. 15,23 (Non-patent document 6, Non-patent document 7).

[0006] In the UK, Day and James proposed the two-hit hypothesis regarding the mechanism of NAFLD based on numerous clinical and animal studies. Fatty liver is caused by the first hit, and steatohepatitis is caused by the second hit. The first hit is precipitated by excessive accumulation of fat in the liver caused by obesity, hyperlipidemia, etc. The second hit is caused by oxidative stress and the effects of reactive oxygen species (ROS) in mitochondria, leading to lipid peroxidation of the hepatocyte membrane, the release of pro-inflammatory cytokines and free radicals, and fibrosis due to stellate cell activation, leading to hepatocyte necrosis. 4,5,19 (Non-patent Documents 5, 8, and 9). The mechanism of NASH involves triglyceride peroxidation in hepatocytes, oxidative stress, ROS response, increased lipid peroxidation, or increased cytokines and liver enzymes, leading to a series of autoimmune interactions. 12 (Non-patent document 10).

[0007] Fatty liver disease is primarily caused by long-term excessive intake of animal fats, proteins, and carbohydrates. The excess calories are converted into fat and stored in the body, leading to obesity and fatty liver. Patients with fatty liver may have normal serum GOT / GPT levels. Therefore, accurate diagnosis of fatty liver disease should be performed using abdominal ultrasound, which currently provides an accuracy rate of over 97%.

[0008] Currently, there is no ideal drug with a specific therapeutic effect for FLD, and treatment guidelines aim to improve underlying risk factors or control the progression of chronic disease through the use of medication. Symptomatic treatment is recommended depending on the cause of fatty liver disease. For example, those with fatty liver disease caused by overweight should lose weight moderately. Anyone with alcoholic fatty liver disease should stop drinking alcohol and eat a balanced diet to improve their condition. Chemicals or drugs that damage the liver and lead to fatty liver disease through long-term exposure should be immediately discontinued. Fatty liver disease caused by diseases such as hepatitis C or high blood lipids should be treated by treating the underlying disease, such as hepatitis C treatment or blood lipid management. If excess triglycerides are caused by physical factors, fatty liver disease cannot be improved by weight loss. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Clark JM and Diehl AM. (2003) Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 289: 300-304 [Non-patent document 2] Carlisle R, Galambos JT, Warren WD. (1979) The relationship between conventional liver tests, quantitative function tests, and histopathology in cirrhosis. Deg Dis Sci 24:358–362

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[0010] However, drugs commonly used clinically to lower serum triglycerides and cholesterol often have side effects, such as hepatotoxicity, myalgia, myositis, and myopathies such as rhabdomyolysis. Myotoxicity is the most prominent side effect of lipid-lowering drugs. Statins, in particular, show the highest incidence of myotoxicity, followed by fibric acids. Furthermore, lipid-lowering drugs have a "fat transport" effect, transporting blood lipids to the liver. Since the liver already has accumulated fat, it becomes difficult to process the large amount of lipids that flow in, leading to excessive fat accumulation in the liver and exacerbating fatty liver disease. Lipid-lowering drugs are therefore not suitable for treating FLD.

[0011] Therefore, there remains a need to find ingredients that are effective in preventing and treating fatty liver and liver diseases caused by fatty liver, protecting liver function, and ameliorating related disorders. [Means for solving the problem]

[0012] The present invention provides one or more excipients (including flavonoid compounds) effective in preventing or treating fatty liver, protecting liver function, or ameliorating liver disease or other related disorders caused by fatty liver, wherein the compound is selected from the group consisting of sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol, saccharin, glycerin, sodium benzoate, iron oxide red, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, citric acid, butylated hydroxyanisole, poncirin, isovitexin, eriodictyol, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, siadopitisin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, xylitol, luteolin, sweltiamarin, and any combination thereof.

[0013] Thus, in one aspect, the present invention provides use of a compound described herein for the manufacture of a composition for preventing or treating fatty liver, protecting liver function, or ameliorating liver disease or other related disorders caused by fatty liver. The present invention also provides a method for preventing or treating fatty liver, protecting liver function, or ameliorating liver disease or other related disorders caused by fatty liver, comprising administering the compound.

[0014] In some embodiments, the compound is selected from the group consisting of sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol, saccharin, glycerin, sodium benzoate, red iron oxide, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, citric acid, butylated hydroxyanisole, and any combination thereof.

[0015] In some embodiments, the compound is selected from the group consisting of poncirin, isovitexin, eriodictyol, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, siadopitisin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, xylitol, luteolin, sweltiamarin, and any combination thereof.

[0016] In some embodiments, the compound is selected from the group consisting of eriodictyol, mannitol, menthol, sucralose, saccharin, and any combination thereof.

[0017] In some embodiments, the compound is selected from the group consisting of: (1) a combination of saccharin and mannitol, (2) a combination of menthol and mannitol, (3) a combination of sucralose and mannitol, (4) a combination of eriodictyol and mannitol, (5) a combination of eriodictyol and sucralose, (6) a combination of menthol, mannitol, and eriodictyol, and (7) a combination of sucralose, mannitol, and eriodictyol.

[0018] In some embodiments, one or more compounds described herein are administered in combination with one or more compounds selected from the group consisting of puerarin, phlorizin, sinensetin, (-)-epigallocatechin, kaempferol, ursolic acid, silymarin, (+)-limonene, hesperidin, (-)-epicatechin-3-gallate, silybin, formononetin, myristate ethyl ester, eicosapentaenoic acid (EPA), wogonin, povidone K-30, protocatechuic acid, umbelliferone, hesperitin, nordihydroguaiaretic acid, neohesperidin, naringin, (-)-epicatechin, glycyrrhizin, baicalin, quercitrin, and baicalein.

[0019] In some embodiments, the compounds of the present invention can reduce liver fat content in a subject.

[0020] In some embodiments, the compounds of the present invention can reduce fat content in liver cells of a subject.

[0021] In some embodiments, the compounds of the present invention can reduce liver damage, such as liver tissue damage or liver dysfunction, in a subject.

[0022] In some embodiments, the compounds of the present invention are capable of enhancing liver antioxidant activity in a subject.

[0023] In some embodiments, the compounds of the present invention can be used to ameliorate various types of liver fat accumulation-related disorders, including but not limited to fatty liver disease, acute and chronic alcoholic fatty liver disease, acute and chronic non-alcoholic fatty liver disease, acute and chronic alcoholic hepatitis, acute and chronic non-alcoholic steatohepatitis, non-alcoholic cirrhosis and alcoholic cirrhosis (ICD-9-CM diagnosis codes: 571.8, 571.0, 571.1, 571.2, 571.3, 571.4, 571.5, 571.9).

[0024] In some embodiments, subjects suitable for receiving the compounds of the present invention are those with fatty liver disease or obese people.

[0025] In some embodiments, the compounds of the present invention can be formulated into drugs, food additives, or health foods.

[0026] In another aspect, the present invention provides a composition comprising two or more compounds selected from the compounds described above.

[0027] In some embodiments, the compositions of the present invention comprise two or more compounds selected from the group consisting of eriodictyol, mannitol, menthol, sucralose, and saccharin.

[0028] In some embodiments, the compositions of the present invention comprise a combination selected from the group consisting of: (1) a combination of saccharin and mannitol, (2) a combination of menthol and mannitol, (3) a combination of sucralose and mannitol, (4) a combination of eriodictyol and mannitol, (5) a combination of eriodictyol and sucralose, (6) a combination of menthol, mannitol, and eriodictyol, and (7) a combination of sucralose, mannitol, and eriodictyol.

[0029] Without further elaboration, it is believed that the present invention can be utilized to the fullest extent by one skilled in the art based on the preceding description, and it is therefore to be understood that the following description is illustrative only and not limitative of the remainder of the disclosure in any way. [Brief explanation of the drawings]

[0030] In order to illustrate the invention, the following embodiments are shown, however, it should be understood that the invention is not limited to the preferred embodiments shown.

[0031] [Figure 1] FIG. 1 shows liver tissue sections taken from mice in which fatty liver was induced and then treated with different test substances for 4 weeks in groups. DETAILED DESCRIPTION OF THE INVENTION

[0032] Detailed Description of the Invention Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0033] As used herein, the terms "a" or "an" mean at least one (one or more than one) in terms of number, unless otherwise indicated.

[0034] The present invention discloses that one or more of the above compounds are effective in reducing liver fat content and alleviating related disorders. Thus, the present invention provides the use of the compounds described herein for the manufacture of a composition for preventing or treating fatty liver, protecting liver function, or alleviating liver disease or other related disorders caused by fatty liver. The present invention also provides a method for preventing or treating fatty liver, protecting liver function, or alleviating liver disease or other related disorders caused by fatty liver. The method comprises administering an effective amount of a compound described herein to a subject in need thereof. The present invention also provides a composition for preventing or treating fatty liver, protecting liver function, or alleviating liver disease or other related disorders caused by fatty liver.

[0035] As used herein, the term "liver fat content" refers to the fat content that accumulates in the liver of an object, where the fat comprises lipids generally defined as triglycerides (TG) and cholesterol.As used herein, the term "liver fat content reduction" generally refers to the reduction of abnormal liver fat content in an object, that is, the reduction of abnormal liver fat content, more specifically, the reduction of abnormal liver fat content to normal level.For example, under normal circumstances, fat accounts for 3% by weight of liver.When the fat in liver exceeds 5% by weight of liver, it is judged as abnormal fat accumulation (above liver fat content is a relative percentage for illustrative purposes, and may vary according to ethnicity and other factors).In certain embodiments, the term "liver fat content reduction" used herein can refer to the reduction of abnormal liver fat content in an object, for example, from 5% by weight or more of liver to 3% by weight of liver. Liver fat content can be assessed by standard analytical methods, including but not limited to ultrasound analysis, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), computed tomography (CT), and liver biopsy.

[0036] As used herein, the term "liver function" refers to one or more physiological functions performed by the liver.Liver function can be analyzed by many common assays, such as alanine aminotransferase (ALT) assay or aspartate aminotransferase (AST) assay.According to the present invention, the compounds described herein can be used to protect liver function, including improving liver function and preventing liver damage.

[0037] As used herein, the term "liver disease" refers to hepatocyte injury or damage caused by certain factors, which may lead to liver dysfunction. According to the present invention, the compounds described herein can be used to ameliorate liver disease caused by fatty liver. More specifically, the term "liver damage" as used herein refers to a liver with histological or biochemical dysfunction compared to a normal liver. In certain embodiments, the term "liver damage" as used herein refers to liver lesions caused by alcoholic or non-alcoholic factors, such as high-fat diets or obesity. In certain embodiments, the term "liver damage" can refer to liver tissue damage with one or more characteristics selected from fatty liver, lobular inflammation, hepatocyte hypertrophy, and vesicular lipid droplets produced by hepatocytes. In certain embodiments, the term "liver damage" can refer to liver biochemical dysfunction, which can be determined from the activity of alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Higher ALT or AST activity indicates more severe liver biochemical dysfunction.

[0038] As used herein, the term "liver antioxidant activity" refers to the activity or ability to combat oxidative stress.The enhancement of the liver antioxidant activity of a subject by the compound of the present invention includes, but is not limited to, reducing oxidative stress or enhancing the enzyme activity or content of members of antioxidant system.Members of antioxidant system can be glutathione peroxidase (GPx), glutathione (GSH), glutathione reductase (GRd) and / or superoxide dismutase (SOD).

[0039] According to the present invention, the compounds described herein include common excipients and bioflavonoids that can be used to reduce liver fat content and alleviate related disorders.The term "related disorders" described herein includes disorders caused by abnormal accumulation of liver fat, including but not limited to fatty liver disease, acute and chronic alcoholic fatty liver disease, acute and chronic non-alcoholic fatty liver disease, acute and chronic alcoholic hepatitis, acute and chronic non-alcoholic steatohepatitis, non-alcoholic cirrhosis and alcoholic cirrhosis (ICD-9-CM diagnosis code: 571.8, 571.0, 571.1, 571.2, 571.3, 571.4, 571.5, 571.9).

[0040] As used herein, the term "prevention" refers to preventative measures for a disease or a symptom or condition of a disease, including but not limited to the application or administration of one or more active agents to a subject who has not yet been diagnosed as suffering from the disease or symptom or condition of the disease, but who may be susceptible or prone to the disease. The purpose of preventative measures is to avoid, prevent, or delay the onset of the disease or symptom or condition of the disease.

[0041] As used herein, the term "treatment" refers to a therapeutic approach to a disease or a symptom or condition of a disease, including, but not limited to, the application or administration of one or more active agents to a subject suffering from the disease or a symptom or condition of a disease or a disease exacerbation. The purpose of a therapeutic approach is to treat, cure, alleviate, relieve, alter, treat, ameliorate, improve, or affect the disease, the symptom or condition of a disease, the disorder caused by the disease, or a disease exacerbation.

[0042] As used herein, the term "individual" or "subject" includes a human or non-human animal, particularly a mammal, such as a companion animal (e.g., dog, cat, etc.), livestock (e.g., cow, sheep, pig, horse, etc.), or laboratory animal (e.g., rat, mouse, guinea pig, etc.).

[0043] As used herein, the term "effective amount" refers to the amount of an active ingredient that achieves a desired biological efficacy or therapeutic effect in a treated subject, e.g., the amount of an active ingredient that reduces liver fat content or ameliorate an associated disorder in a subject.

[0044] For purposes of delivery and uptake, an effective amount of the active ingredient of the present invention can be formulated with a pharmaceutically acceptable carrier to form a pharmaceutical composition in a suitable dosage form. Depending on the route of administration, the pharmaceutical composition of the present invention preferably contains about 0.1% to about 100% by weight of the active ingredient based on the total weight of the composition.

[0045] As used herein, the term "pharmaceutically acceptable" means that the carrier is compatible with the active ingredient of the composition (and does not affect the effectiveness of the active ingredient), and preferably, the carrier can stabilize the active ingredient and is safe for the subject being treated. A carrier can be a diluent, vehicle, excipient, or medium for the active ingredient. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The composition can further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents. After administration to a patient, the compositions of the invention may effect quick, sustained or delayed release of the active ingredient.

[0046] According to the present invention, the compositions may be in any dosage form, such as tablets, pills, powders, lozenges, capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and packaged powders.

[0047] The compositions of the present invention can be administered by any physiologically acceptable route, including oral, parenteral (e.g., intramuscular, intravenous, subcutaneous, and intraperitoneal), transdermal, suppository, and intranasal administration. Parenteral administration preferably uses a sterile aqueous solution, which may contain sufficient salts or other substances, such as glucose, to make the solution isotonic with blood. The aqueous solution may be suitably buffered, if necessary (preferably having a pH of 3 to 9). Those skilled in the art can prepare suitable parenteral compositions using known standard pharmacological techniques under sterile conditions.

[0048] The present invention is also illustrated by the following specific examples, which are provided for illustrative purposes and not for limiting the invention. It will be apparent to those skilled in the art that various modifications can be made to the specific examples disclosed by the present invention and still obtain the same or similar results without departing from the spirit and scope of the invention. [Example]

[0049] 1. Materials and Methods 1.1 Cell lines and cell culture media The human hepatoma cell line HepG2 was used to analyze the activity of various compounds of the present invention in reducing fat content.

[0050] Using Dulbecco's modified Eagle's medium (DMEM), DMEM medium Nos. A to F shown in Table 1 were prepared for the following experiments.

[0051] [Table 1] DMEM medium Nos. A to F were stored at 2 to 8°C and warmed in a 37°C water bath before the experiment.

[0052] 1.2 Cell count and viability test Dead cells take up 0.4% trypan blue and show color; on the other hand, live cells, due to their intact cell membranes, do not take up the dye and show a transparent color. 100 μL of the cell suspension and an equal volume of 0.4% trypan blue were mixed uniformly to obtain a mixture. A portion of the mixture (approximately 20 μL) was added to the groove on the chamber of a hemocytometer and then covered with a cover slip for observation under an optical microscope. Live cells were not stained, and dead cells were blue.

[0053] 1.3 Oleic acid-induced fatty liver cell formation from HepG2 cells HepG2 cell line (15 × 10 6 The HepG2 cells were cultured in DMEM medium No. B, incubated at 37°C in a 5% CO2 incubator for 24 hours, cultured in DMEM medium No. C (serum-free medium) for 24 hours, and finally cultured in DMEM medium No. D (containing oleate / albumin complex) for another 48 hours to induce HepG2 cell line and obtain fatty liver cells.

[0054] 1.4 Treatment of fatty liver cells in each group The HepG2 cell line was divided into six groups: (1) blank: no treatment; (2) DMSO group: cells from the blank were treated with dimethyl sulfoxide (DMSO); (3) control: the formation of fatty liver cells was induced with oleic acid; (4) vehicle group: fatty liver cells obtained by induction with oleic acid were treated with DMSO; (5) positive control: fatty liver cells were treated with silymarin; and (6) test group: fatty liver cells were treated with various compounds of the present invention.

[0055] 1.5 Measurement of TG in cells After 72 hours of incubation, treated cells from each group were washed twice with PBS and then incubated with 0.5 ml of trypsin / EDTA for 3 minutes. Cells were then scraped with 2 ml of PBS, transferred to a centrifuge tube, and disrupted by sonication. 20 μL of cell extract was removed and the protein content was measured. TG measurements were performed using a commercially available reagent combination (Randox). The TG content obtained above was divided by the protein content to obtain a ratio representing the relative TG content in the cells.

[0056] 1.6 Laboratory animals B6 mice were selected for animal testing, as recommended in the "Method for Evaluating the Liver Protection and Health Management Efficacy of Health Foods" published by the Ministry of Health. At least four mice were used for the preliminary test in each group, and at least 12 mice were used for the confirmatory test in each group. Male mice weighing 18–23 g were purchased from BioLASCO (Taipei) and housed at the Laboratory Animal Center of the National Defense Medical Academy under a normal light / dark cycle (lights on: 7:00 AM–7:00 PM, lights off: 7:00 PM–7:00 AM) at 23±2°C with a relative humidity of 55±15%. Animal experiments were conducted in accordance with the guidelines for animal experiments of the National Institutes of Health. Mice were fed 3–5 g of normal chow per day and water ad libitum for 1–2 weeks, and their health was monitored. Mouse weights were recorded weekly.

[0057] 1.7 Animal Grouping The test animals were randomly divided into blank, high-fat diet control (HFD), positive control (PS), and test group. Blank animals were fed normal chow. HFD animals were fed high-fat chow. PS animals were fed high-fat chow and supplemented with silymarin (5 mg / kg / day) by gavage. Test group animals were fed high-fat chow and force-fed with the test compound by gavage.

[0058] 1.8 Test Method The blank animals were fed a normal diet for 12 weeks, while the HFD, PS, and test group animals were fed a high-fat diet for 12 weeks. After 8 weeks of feeding, the blank and HFD animals were gavaged with deionized water once daily; the PS animals were gavaged with silymarin once daily; and the test group animals were given the test compound once daily for 4 or 8 weeks.

[0059] Blood samples were collected from the cheek or heart before the study and at weeks 8, 12, and 16 afterward. At the end of the study, all mice were weighed and then sacrificed, with simultaneous collection of blood samples from the cheek or heart. Blood samples were left at room temperature for 1 hour to clot, then centrifuged at 15,700 × g for 5 minutes at 4°C in a refrigerated centrifuge to separate serum. Biochemical indices of liver function, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides (TG), total cholesterol (TCHO / TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), were then measured using an automated blood chemistry analyzer.

[0060] In addition, abdominal fat and liver specimens were collected from the abdomen of sacrificed mice and weighed to compare the weights of the fat and liver, and obtain liver weight to body weight ratios. 3Two tissue blocks were cut and fixed in 10% neutral formalin solution, then embedded in paraffin for sectioning and H&E staining for histopathological observation. The remaining liver was then frozen for storage and detection of hepatic triglyceride and total cholesterol levels. Furthermore, the liver function of each group of animals was analyzed using the Galactose Single Point Method, which is recognized and recommended by the US FDA and the Taiwan Ministry of Health and Welfare for quantifying residual liver function in clinical practice. At the end of the study, animals were intravenously administered 0.5 g of galactose (GSP® 0.4 g / mL) per kg. One hour after administration, approximately 0.5 mL of whole blood was collected using filter paper to assess the liver function of the mice. The higher the GSP value, the worse the residual liver function (FDA: “Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic Function—Study Design, Data Analysis and Impact on Dosing and Labeling. 2003”).

[0061] 1.9 Histopathological tissue sectioning At the end of the study, all mice were sacrificed. A volume of approximately 1 cm was removed from the largest right lobe of the liver. 3 A single tissue block was cut and fixed in 10% neutral formalin, then dehydrated and hyalinized in various concentrations of ethanol (30%, 50%, 70%, 95%, 99.5%) and xylene. The xylene was then replaced with hot paraffin solution. Finally, the tissue was embedded in paraffin solution. The completed paraffin specimen was cut into 5 μm-thick paraffin sections using a microtome. The sections were mounted on clean slides, dried at 37°C, and then stained using H&E staining.

[0062] 1.10 Hematoxylin and Eosin Staining (H&E) Liver tissue sections were deparaffinized in xylene for 30 minutes and then rehydrated sequentially in 99.5%, 95%, 70%, 50%, and 30% ethanol for 30 minutes each. After immersion in distilled water for 10 minutes, the sections were ready for staining. The sections were first immersed in hematoxylin for 30 seconds to stain the cell nuclei, then washed in distilled water for several minutes, stained with eosin for 2–5 minutes, and washed again in distilled water for several minutes. After the staining process, the sections were dehydrated twice in 50%, 70%, 95%, and 100% aqueous ethanol for 30 seconds each, hyalinized twice in xylene, and finally mounted in mounting medium for storage.

[0063] 1.11 Histopathological observations In cases of ongoing liver injury, the degree of hepatic fat accumulation was assessed by H&E staining of liver tissue to observe hepatocellular lesions, fat accumulation, necrosis, or fibrosis. All histopathological sections were cut from the same location in the largest right lobe of the liver to eliminate bias in subjective observations, and then subjected to pathological staining. Regarding the evaluation of semiquantitative analysis of pathology, all sections were scored (NAS score) without knowledge of the study design. 16 The results had to be confirmed by a physician or veterinary pathologist who performed the double-blind comparative analysis. Finally, differential analyses of each group were performed using statistical methods.

[0064] 1.12 Analysis of liver antioxidant capacity Approximately 0.1 g of liver tissue was collected from sacrificed animals and homogenized by centrifugation in a biomasher for 10 minutes. Nine weight-fold (w / w) buffer (pH 7.4, 50 mmol / L Tris-HCl, 180 mmol / L KCl) was added to the homogenized tissue and then thoroughly mixed using a vortex mixer for subsequent use. The resulting liver tissue homogenization solution samples were used to analyze various members of the hepatic antioxidant system, including glutathione peroxidase (GPx), glutathione (GSH), glutathione reductase (Grd), and superoxide dismutase (SOD). Related analytical methods can be found in public literature, such as the draft "Methods for Evaluating the Hepatoprotective and Healthcare Efficacy of Health Foods" published by the Taiwan Ministry of Health and Welfare.

[0065] 1.13 Statistical analysis All data were expressed as mean ± standard deviation (SD). Statistical significance of test results was determined by one-way ANOVA calculation using the Statistical Package for Social Science program (version 13, SPSS Inc.). Multiple comparisons were then performed using the least significant difference method in post-hoc tests to confirm significant differences between groups. Mean differences between groups were considered significant when p<0.05.

[0066] 2.Results 2.1 Cell experiments In the cell experiments, the results of the reduction in TG levels in HepG2 cells measured in the positive control (silymarin) are shown in Table 2.

[0067] [Table 2]

[0068] The results of the reduction in TG content in HepG2 adipocytes measured using a constant concentration of test compound are shown in Table 3. The results indicate that the test compounds exhibited varying degrees of TG content reduction effects in fatty liver cells formed from induced HepG2 cells under the condition of a constant test concentration, compared to the control. The TG reduction rate (%) was calculated as follows: [1 - (TG content of test group - TG content of blank) / (TG content of oleic acid-induced group - TG content of blank)] × 100%.

[0069] [Table 3-1] [Table 3-2]

[0070] [Table 4]

[0071] [Table 5]

[0072] [Table 6]

[0073] 2.2 Animal experiments In animal experiments, all animals were treated to induce fatty liver, except for the blank group, which was fed a normal diet. After 8 weeks, animals in each group were given various treatments in addition to their initial diet for 4 or 8 weeks. The blank and HFD animals were given deionized water; the PS animals were given silymarin; and the test group animals were given different test compounds, including puerarin, phlorizin, eriodictyol, sucralose, mannitol, saccharin, hesperitin, menthol, and combinations of these compounds.

[0074] 2.2.1 Effects on Animal Body Weight, Liver Weight, and Body Fat Weight and Safety Assessment of Test Compounds From the results of the animal experiments, the liver weight, body fat weight, and body weight gain of the animals in each group are shown in Tables 4-1 and 4-2.

[0075] [Table 7]

[0076] [Table 8]

[0077] The results showed that abdominal fat weight increased in animals with induced fatty liver. Administration of the test compound, mannitol, menthol and sucralose each significantly reduced abdominal fat weight in the animals.

[0078] Furthermore, after administering the test compound, no abnormal condition was observed in the animals of the test group.No animals died during the test.No disease or clinical symptoms caused by the test compound were observed in the autopsy of the animals sacrificed after the test.Therefore, the test compound was safe.

[0079] 2.2.2 The test compound is effective in reducing lipid content in the liver Figure 1 shows that fatty liver was induced in mice, and hepatocytes near the hepatic portal region (including the bile duct, portal vein, and hepatic artery) were covered with many large vesicular lipid droplets, and hepatocyte hypertrophy was observed. This indicates that an animal model of fatty liver was successfully established through induction.

[0080] The results of the animal experiments show that several test compounds exhibit lipid-reducing effects in animal livers after 4 or 8 weeks of administration. The results are shown in Tables 5-1 and 5-2.

[0081] [Table 9]

[0082] [Table 10]

[0083] The results show that TG and TC increased in the liver of mice with induced fatty liver. Administration of test compounds, hesperitin, puerarin, eriodictyol, phlorizin, mannitol, menthol and sucralose each significantly reduced TG in the liver, and in particular, 4-week treatment with eriodictyol reduced liver TG content by approximately 67% (p<0.005). Furthermore, administration of test compounds, hesperitin, eriodictyol, phlorizin, mannitol, menthol, sucralose and saccharin each significantly reduced TC in the liver, and in particular, 4-week treatment with saccharin reduced liver TC content by approximately 56% (p<0.005).

[0084] With regard to the administration of combinations of two test compounds, the combination of saccharin and mannitol, the combination of menthol and mannitol, the combination of sucralose and mannitol, the combination of eriodictyol and mannitol, or the combination of eriodictyol and sucralose could effectively reduce liver TGs. In particular, 4 weeks of treatment with the combination of menthol and mannitol had a significant effect of reducing liver TG content by about 77% (p<0.005); 8 weeks of treatment with the combination of eriodictyol and sucralose had a significant effect of reducing liver TG content by about 78% (p<0.005). Furthermore, the combination of sucralose and mannitol, the combination of eriodictyol and mannitol, or the combination of eriodictyol and sucralose significantly reduced liver TC content (p<0.005), and in particular, 8 weeks of treatment with the combination of eriodictyol and sucralose had a significant effect of reducing liver TC content by approximately 77% (p<0.005).

[0085] Regarding the administration of the combination of the three test compounds, the combination of menthol, mannitol, and eriodictyol or the combination of sucralose, mannitol, and eriodictyol can effectively reduce liver TG, and in particular, the combination of sucralose, mannitol, and eriodictyol for 8 weeks has a remarkable effect of reducing liver TG content by about 79% (p<0.005).In addition, the combination of sucralose, mannitol, and eriodictyol can significantly reduce liver TC.

[0086] 2.2.3 The test compound is effective in reducing liver damage 2.2.3.1 Effect on reducing hepatic fat and liver damage in liver tissue The results of animal experiments showed that several test compounds were effective in reducing hepatic fat and liver damage in liver tissue over a 4-week study period. Figure 1 shows that animals with fatty liver had liver tissue damage, including many large vesicular lipid droplets covering hepatocytes near the hepatic portal region (including the bile duct, portal vein, and hepatic artery) and hepatocyte hypertrophy. In contrast, after 4 weeks of treatment with silymarin, menthol, eriodictyol, or mannitol, large vesicular lipid droplets within hepatocytes in liver tissue sections were significantly reduced. While some small, broken droplets were still observed in mice treated with silymarin, the morphology of liver tissue in mice treated with menthol, eriodictyol, or mannitol was similar to that of animals in the blank group, indicating milder fatty liver disease. Furthermore, the results of NAS scoring are shown in Table 6.

[0087] [Table 11]

[0088] NAS (Nonalcoholic Fatty Liver Disease Activity Score) indicates the activity score of nonalcoholic fatty liver disease [Hepatology. 2005 Jun;41(6):1313-21], which involves a comprehensive assessment of the degree of steatosis, lobular inflammation, and hepatocellular hypertrophy. The score table is shown in Table 7. A higher score indicates more severe liver damage.

[0089] [Table 12]

[0090] The results show that mice with fatty liver have liver tissue damage (increased NAS).The administration of the test compounds, eriodictyol and mannitol, can each significantly reduce liver damage.It is noteworthy that the administration of the combination of the two test compounds, menthol and mannitol, has an excellent effect, i.e., there is almost no liver damage and NAS is the same as that of the blank.

[0091] 2.2.3.2 Effect on reducing liver dysfunction The results of animal studies indicate that several test compounds can reduce liver dysfunction in animals over a 4-week or 8-week treatment period. The results are shown in Tables 8-1 and 8-2.

[0092] [Table 13]

[0093] [Table 14]

[0094] ALT and AST are the most commonly used enzyme indicators of liver biochemical dysfunction. Under normal circumstances, these enzymes are present in hepatocytes. However, when liver cells are damaged, they leak. Increased serum ALT and AST levels generally reflect liver inflammation and liver dysfunction.

[0095] The results show that animals with fatty liver suffer from liver dysfunction (ALT and AST levels are elevated).The administration of test compounds, hesperitin, puerarin, eriodictyol, phloridzin, mannitol, menthol, sucralose and saccharin can significantly reduce ALT and AST levels, respectively, and in particular, mannitol treatment for 4 weeks has a significant effect of reducing ALT levels by about 64% (p<0.005) and AST levels by about 60% (p<0.005).

[0096] Regarding the administration of the combination of two test compounds, the combination of menthol and mannitol or the combination of eriodictyol and sucralose can significantly reduce ALT levels; the combination of menthol and mannitol, the combination of sucralose and mannitol, or the combination of saccharin and mannitol can significantly reduce AST levels. In particular, 4 weeks of treatment with the combination of menthol and mannitol has a significant effect of reducing ALT levels by about 76% (p<0.005) and AST levels by about 62% (p<0.005).

[0097] Regarding the administration of the combination of the three test compounds, the combination of sucralose, mannitol and eriodictyol can significantly reduce the ALT level (p<0.005).

[0098] 2.2.4 Test compounds can enhance hepatic antioxidant activity The results of the animal studies indicate that several test compounds are effective in enhancing liver antioxidant activity in animals over a 4-week study period. The results are shown in Tables 9-1 and 9-2.

[0099] [Table 15]

[0100] [Table 16]

[0101] Gpx, GSH, Grd, and SOD are common components of the hepatic antioxidant system, which can reduce oxidative stress in the liver and protect the liver from damage caused by oxidative stress. Increased Gpx, GSH, Grd, and SOD levels indicate that the liver maintains better antioxidant activity.

[0102] The results show that mice with fatty liver have reduced antioxidant activity. Administration of the test compounds hesperitin, puerarin, eriodictyol, phloridzin, and mannitol can each significantly enhance antioxidant activity, and in particular, mannitol treatment for 4 weeks has a significant effect of substantially increasing Gpx, GSH, Grd, and SOD levels (p<0.005).

[0103] In view of the above, the compounds provided in the present invention can reduce liver fat content, reduce liver damage, and enhance liver antioxidant activity. These compounds belong to low-molecular-weight natural plant phenolic compounds and are widely distributed in fruits and vegetables, grains, roots, flowers, tea, red wine, etc. In addition, these compounds have been confirmed to be safe in animal experiments and have been found to have the potential to be developed into health foods or drugs for reducing liver fat and ameliorating related disorders such as fatty liver disease, acute and chronic alcoholic fatty liver disease, acute and chronic nonalcoholic fatty liver disease (NAFLD), acute and chronic alcoholic hepatitis, acute and chronic nonalcoholic steatohepatitis, nonalcoholic cirrhosis, and alcoholic cirrhosis (ICD-9-CM diagnosis codes: 571.8, 571.0, 571.1, 571.2, 571.3, 571.4, 571.5, 571.9). The present application also includes the following aspects. [Aspect 1] 1. Use of a compound for the manufacture of a composition for preventing or treating fatty liver, protecting liver function, or ameliorating liver disease or other related disorders caused by fatty liver, wherein the compound is selected from the group consisting of sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol, saccharin, glycerin, sodium benzoate, red iron oxide, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, citric acid, butylated hydroxyanisole, poncirin, isovitexin, eriodictyol, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, siadopitisin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, xylitol, luteolin, sweltiamarin, and any combination thereof. [Aspect 2] 2. The use of embodiment 1, wherein the compound is selected from the group consisting of sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol, saccharin, glycerin, sodium benzoate, red iron oxide, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, citric acid, butylated hydroxyanisole, and any combination thereof. [Aspect 3] 2. The use of embodiment 1, wherein the compound is selected from the group consisting of poncirin, isovitexin, eriodictyol, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, siadopitisin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, xylitol, luteolin, sweltiamarin, and any combination thereof. [Aspect 4] 2. The use of embodiment 1, wherein the compound is selected from the group consisting of eriodictyol, mannitol, menthol, sucralose, saccharin, and any combination thereof. [Aspect 5] The use of embodiment 1, wherein the compound is selected from the group consisting of: (1) a combination of saccharin and mannitol, (2) a combination of menthol and mannitol, (3) a combination of sucralose and mannitol, (4) a combination of eriodictyol and mannitol, (5) a combination of eriodictyol and sucralose, (6) a combination of menthol, mannitol, and eriodictyol, and (7) a combination of sucralose, mannitol, and eriodictyol. [Aspect 6] 6. The use of any one of Aspects 1 to 5, wherein the compound further comprises puerarin, phlorizin, sinensetin, (-)-epigallocatechin, kaempferol, ursolic acid, silymarin, (+)-limonene, hesperidin, (-)-epicatechin-3-gallate, silybin, formononetin, myristate ethyl ester, eicosapentaenoic acid (EPA), wogonin, povidone K-30, protocatechuic acid, umbelliferone, hesperitin, nordihydroguaiaretic acid, neohesperidin, naringin, (-)-epicatechin, glycyrrhizin, baicalin, quercitrin, and / or baicalein. [Aspect 7] The use of embodiment 6, wherein the composition is used to reduce liver fat content in a subject. [Aspect 8] The use of embodiment 6, wherein the composition is used to reduce fat content in liver cells of a subject. [Aspect 9] The use of embodiment 6, wherein the composition is used to reduce liver damage in a subject. [Aspect 10] The use of embodiment 9, wherein said liver damage comprises liver tissue damage or liver dysfunction. [Aspect 11] The use according to embodiment 6, wherein the composition is used to enhance liver antioxidant activity. [Aspect 12] The use of embodiment 6, wherein the liver disease or other related disorder is selected from the group consisting of acute and chronic alcoholic fatty liver, acute and chronic non-alcoholic fatty liver, acute and chronic alcoholic hepatitis, acute and chronic non-alcoholic steatohepatitis, non-alcoholic cirrhosis, and alcoholic cirrhosis. [Aspect 13] The use according to any one of embodiments 1 to 5, wherein the composition can be administered to a patient with non-alcoholic fatty liver disease or an obese individual. [Aspect 14] The use according to any one of Aspects 1 to 5, wherein the composition is a drug, a food additive, or a health food. [Aspect 15] A composition comprising two or more compounds selected from the group consisting of sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol, saccharin, glycerin, sodium benzoate, red iron oxide, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, citric acid, butylated hydroxyanisole, poncirin, isovitexin, eriodictyol, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, cyadopiticin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, homoorientin, xylitol, luteolin, and sweltiamarin. [Aspect 16] 16. The composition of embodiment 15, comprising two or more compounds selected from the group consisting of sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol, saccharin, glycerin, sodium benzoate, red iron oxide, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, citric acid, and butylated hydroxyanisole. [Aspect 17] 16. The composition of embodiment 15, comprising two or more compounds selected from the group consisting of poncirin, isovitexin, eriodictyol, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, siadopitisin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, xylitol, luteolin, and sweltiamarin. [Aspect 18] 16. The composition of embodiment 15, comprising two or more compounds selected from the group consisting of eriodictyol, mannitol, menthol, sucralose, and saccharin. [Aspect 19] 16. The composition of embodiment 15, comprising a combination selected from the group consisting of: (1) a combination of saccharin and mannitol, (2) a combination of menthol and mannitol, (3) a combination of sucralose and mannitol, (4) a combination of eriodictyol and mannitol, (5) a combination of eriodictyol and sucralose, (6) a combination of menthol, mannitol, and eriodictyol, and (7) a combination of sucralose, mannitol, and eriodictyol. [Aspect 20] 20. The composition of any one of aspects 15 to 19, further comprising puerarin, phlorizin, sinensetin, (-)-epigallocatechin, kaempferol, ursolic acid, silymarin, (+)-limonene, hesperidin, (-)-epicatechin-3-gallate, silybin, formononetin, myristate ethyl ester, eicosapentaenoic acid (EPA), wogonin, povidone K-30, protocatechuic acid, umbelliferone, hesperitin, nordihydroguaiaretic acid, neohesperidin, naringin, (-)-epicatechin, glycyrrhizin, baicalin, quercitrin, and / or baicalein. [Aspect 21] The composition of embodiment 20, wherein the compounds, each or combined, are present in the composition in an amount effective to reduce liver fat content or ameliorate an associated disorder in a subject. [Aspect 22] The composition of embodiment 20, wherein the compounds, each or combined, are present in the composition in an amount effective to reduce liver fat content in hepatocytes of a subject. [Aspect 23] The composition of embodiment 20, wherein the compounds, each or combined, are present in the composition in an amount effective to reduce liver damage in a subject. [Aspect 24] 24. The composition of embodiment 23, wherein said liver damage comprises liver tissue damage or liver dysfunction. [Aspect 25] 21. The composition of embodiment 20, wherein the compounds, each or combined, are present in the crude product in an amount effective to enhance hepatic antioxidant activity. [Aspect 26] 21. The composition of embodiment 20, wherein the compounds, each or combined, are present in the composition in an amount effective to treat or prevent fatty liver, acute and chronic alcoholic fatty liver, acute and chronic non-alcoholic fatty liver, acute and chronic alcoholic hepatitis, acute and chronic non-alcoholic steatohepatitis, non-alcoholic cirrhosis, and alcoholic cirrhosis. [Aspect 27] 21. The composition according to embodiment 20, wherein the composition is a drug, a food additive, or a health food. [Aspect 28] 1. A method for preventing or treating fatty liver, protecting liver function, or ameliorating liver disease or other related disorders caused by fatty liver in a subject in need thereof, comprising the step of: preventing or treating fatty liver, protecting liver function, or ameliorating liver disease or other related disorders caused by fatty liver, the method comprising the step of: using sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol, saccharin, glycerin, sodium benzoate, red iron oxide, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, kueh 20. A method for treating a skin condition comprising administering to said subject an effective amount of a compound selected from the group consisting of trans-cinnamic acid, butylated hydroxyanisole, poncirin, isovitexin, eriodictyol, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, siadopitisin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, homoorientin, xylitol, luteolin, sweltiamarin, and combinations thereof. [Aspect 29] 1. Use of a compound for the manufacture of a composition for reducing liver fat content or ameliorating an associated disorder, wherein the compound is selected from the group consisting of sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol, saccharin, glycerin, sodium benzoate, red iron oxide, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, citric acid, butylated hydroxyanisole, poncirin, isovitexin, eriodictyol, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, siadopitisin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, xylitol, luteolin, sweltiamarin, and any combination thereof. [Aspect 30] 30. The use of embodiment 29, wherein the compound is selected from the group consisting of sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol, saccharin, glycerin, sodium benzoate, red iron oxide, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, citric acid, butylated hydroxyanisole, and any combination thereof. [Aspect 31] 30. The use of embodiment 29, wherein the compound is selected from the group consisting of poncirin, isovitexin, eriodictyol, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, siadopitisin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, xylitol, luteolin, sweltiamarin, and any combination thereof. [Aspect 32] 30. The use of embodiment 29, wherein the compound is selected from the group consisting of liodictyol, mannitol, menthol, sucralose, saccharin, and any combination thereof. [Aspect 33] The compound is selected from the group consisting of (1) a combination of saccharin and mannitol, (2) a combination of menthol and mannitol, (3) a combination of sucralose and mannitol, (4) a combination of eriodictyol and mannitol, (5) a combination of eriodictyol and sucralose, (6) a combination of menthol, mannitol, and eriodictyol, and (7) a combination of sucralose, mannitol, and eriodictyol. [Aspect 34] 34. The use of any one of aspects 29 to 33, wherein the compound further comprises puerarin, phlorizin, sinensetin, (-)-epigallocatechin, kaempferol, ursolic acid, silymarin, (+)-limonene, hesperidin, (-)-epicatechin-3-gallate, silybin, formononetin, myristate ethyl ester, eicosapentaenoic acid (EPA), wogonin, povidone K-30, protocatechuic acid, umbelliferone, hesperitin, nordihydroguaiaretic acid, neohesperidin, naringin, (-)-epicatechin, glycyrrhizin, baicalin, quercitrin, and / or baicalein.

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Claims

1. 1. A composition for use in treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, comprising: (i) as an active ingredient, an effective amount of sucralose or a combination of sucralose with one or more compounds selected from the group consisting of eriodictyol, menthol, and saccharin; or (ii) an effective amount of, as an active ingredient, mannitol or a combination of mannitol with one or more compounds selected from the group consisting of eriodictyol, menthol, and saccharin; or (iii) an effective amount of a combination as an active ingredient selected from the group consisting of (1) a combination of sucralose and eriodictyol, (2) a combination of saccharin and mannitol, (3) a combination of eriodictyol and mannitol, (4) a combination of menthol and mannitol, and (5) a combination of menthol, mannitol, and eriodictyol. A composition comprising:

2. A composition for use in treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, the composition comprising an effective amount of sucralose as an active ingredient.

3. A composition for use in treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, the composition comprising an effective amount of a combination of sucralose and eriodictyol as active ingredients.

4. A composition for use in treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, the composition comprising an effective amount of mannitol as an active ingredient.

5. A composition for use in treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, the composition comprising an effective amount of a combination of mannitol and saccharin as active ingredients.

6. 1. A composition for use in treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, the composition comprising an effective amount of a combination of mannitol and menthol as active ingredients.

7. A composition for use in treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, the composition comprising an effective amount of a combination of mannitol and eriodictyol as active ingredients.

8. A composition for use in treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, the composition comprising an effective amount of a combination of mannitol, menthol, and eriodictyol as active ingredients.

9. Additionally, it contains sorbitol, glycerin, sodium benzoate, red iron oxide, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, citric acid, butylated hydroxyanisole, poncirin, isovitexin, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, siadopitisin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, xylitol, luteolin, sweltiamarin, puerarin, phloridzin, sinensetin, ( 9. The composition of claim 1, comprising (-)-epigallocatechin, kaempferol, ursolic acid, silymarin, (+)-limonene, hesperidin, (-)-epicatechin-3-gallate, silybin, formononetin, myristate ethyl ester, eicosapentaenoic acid (EPA), wogonin, povidone K-30, protocatechuic acid, umbelliferone, hesperitin, nordihydroguaiaretic acid, neohesperidin, naringin, (-)-epicatechin, glycyrrhizin, baicalin, quercitrin, and / or baicalein.

10. 10. The composition of any one of claims 1 to 9, wherein the liver disease or other related disorder is selected from the group consisting of acute and chronic alcoholic fatty liver, acute and chronic non-alcoholic fatty liver, acute and chronic alcoholic hepatitis, acute and chronic non-alcoholic steatohepatitis, non-alcoholic cirrhosis and alcoholic cirrhosis.

11. The composition according to any one of claims 1 to 10, wherein the subject is a patient with non-alcoholic fatty liver disease or an obese individual.

12. The composition according to any one of claims 1 to 11, which is a drug, a food additive or a health food.

13. 1. Use of a composition for the manufacture of a medicament for treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, the composition comprising: (i) as an active ingredient, an effective amount of sucralose or a combination of sucralose with one or more compounds selected from the group consisting of eriodictyol, menthol, and saccharin; or (ii) an effective amount of, as an active ingredient, mannitol or a combination of mannitol with one or more compounds selected from the group consisting of eriodictyol, menthol, and saccharin; or (iii) an effective amount of a combination as an active ingredient selected from the group consisting of (1) a combination of sucralose and eriodictyol, (2) a combination of saccharin and mannitol, (3) a combination of eriodictyol and mannitol, (4) a combination of menthol and mannitol, and (5) a combination of menthol, mannitol, and eriodictyol. Including, use.

14. Use of a composition for manufacturing a medicament for treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, wherein the composition comprises an effective amount of sucralose as an active ingredient.

15. Use of a composition for manufacturing a medicament for treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, wherein the composition comprises an effective amount of a combination of sucralose and eriodictyol as active ingredients.

16. Use of a composition for the manufacture of a medicament for treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, wherein the composition comprises an effective amount of mannitol as an active ingredient.

17. Use of a composition for manufacturing a medicament for treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, wherein the composition comprises an effective amount of a combination of mannitol and saccharin as active ingredients.

18. 1. Use of a composition for the manufacture of a medicament for treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, the composition comprising an effective amount of a combination of mannitol and menthol as active ingredients.

19. Use of a composition for manufacturing a medicament for treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, wherein the composition comprises an effective amount of a combination of mannitol and eriodictyol as active ingredients.

20. Use of a composition for manufacturing a medicament for treating fatty liver, reducing liver fat content, or ameliorating liver disease or other related disorders caused by fatty liver in a subject, the composition comprising an effective amount of a combination of mannitol, menthol, and eriodictyol as active ingredients.

21. The composition may further comprise sorbitol, glycerin, sodium benzoate, red iron oxide, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, citric acid, butylated hydroxyanisole, poncirin, isovitexin, ergosterol, β-myrcene, hyperoside, (+)-catechin, galangin, morin, siadopitisin, didymin, goscypin, luteolin-7-glucoside, (+)-taxifolin, trans-cinnamic acid, diosmin, linarin, xylitol, luteolin, sweltiamarin, puerarin, phloridzin, and sinensetin.

21. The use according to any one of claims 13 to 20, comprising an extract of a sesame oil-based compound, such as cereals containing ...

22. 22. The use according to any one of claims 13 to 21, wherein the liver disease or other related disorder is selected from the group consisting of acute and chronic alcoholic fatty liver, acute and chronic non-alcoholic fatty liver, acute and chronic alcoholic hepatitis, acute and chronic non-alcoholic steatohepatitis, non-alcoholic cirrhosis and alcoholic cirrhosis.

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