Application of liver metabolism regulator in preparation of medicine for treating metabolism-related fatty liver disease

Abstract

The invention belongs to the field of pharmacy, and particularly discloses an application of a liver metabolism regulator in preparation of a medicine for treating metabolism-related fatty liver diseases, and the liver metabolism regulator is a free compound with a structural formula of 1 # imgabs0 # and a derivative of the free compound. Innovative research shows that the compound represented by the formula 1 can be used as an active component, participates in liver metabolism, and can inhibit the progress of metabolism-related fatty liver diseases by reducing the content of triglyceride, glutamic-pyruvic transaminase and glutamic oxalacetic transaminase and improving lipid accumulation and liver injury. The invention can be used for non-therapeutic scientific research and pharmaceutical purposes based on the special effect of the formula 1.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, in particular to the field of metabolism-related fatty liver disease drugs. Background Art

[0002] Metabolic fatty liver disease (formerly known as non-alcoholic fatty liver disease) is a chronic liver disease characterized by liver fat deposition (>5% hepatocyte steatosis) and combined with metabolic dysfunction (such as obesity, type 2 diabetes, hypertension or dyslipidemia). It has become a major public health problem facing society today.

[0003] For metabolic-related fatty liver disease, the US patent document with publication number US 7,723,295 B2 discloses a treatment method of pioglitazone. The patent document with publication number WO 2018 / 035795 A1 discloses a treatment method of a GLP-1 receptor agonist such as semaglutide. The patent document with publication number US 9,180,868 B2 discloses a scheme using a fatty acid synthase (FASN) inhibitor as a therapeutic agent.

[0004] In summary, although the prior art has disclosed some treatment strategies, there is currently only one drug approved for the treatment of patients with metabolic-related fatty liver hepatitis with moderate or severe liver fibrosis. Most patients still do not have safe and reliable drugs available. Therefore, it is of great significance to develop new drugs for the treatment of metabolic-related fatty liver disease. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides an application of a liver metabolism regulator in the preparation of a drug for treating metabolism-related fatty liver disease, aiming to improve the therapeutic effect and safety of metabolism-related fatty liver disease based on the innovative use of safe and effective liver metabolism regulators.

[0006] The second object of the present invention is to provide a drug for treating metabolism-related fatty liver disease comprising the liver metabolism regulator.

[0007] A use of a liver metabolism regulator in the preparation of a drug for treating metabolism-related fatty liver disease, wherein the liver metabolism regulator is a free compound having a structural formula 1 and a derivative thereof;

[0008]

[0009] The innovative research of the present invention shows that the formula 1 can be used as an active ingredient to participate in liver metabolism, and can inhibit the progression of metabolic-related fatty liver disease by reducing triglyceride, alanine aminotransferase and aspartate aminotransferase content, improving lipid accumulation and liver damage. In the present invention, based on the special effects of formula 1, it can be used for non-therapeutic scientific research purposes and pharmaceutical purposes.

[0010] In the application of the present invention, the derivative is at least one of the ester and glycoside derived from Formula 1.

[0011] The application of the present invention is to combine the formula 1 with other active ingredients to prepare a drug for treating metabolism-related fatty liver disease.

[0012] The application of the present invention is to combine the liver metabolism regulator and a pharmaceutically acceptable excipient to prepare a pharmaceutically acceptable drug dosage form.

[0013] In the application of the present invention, the drug dosage form includes at least one of an oral preparation and an injection preparation.

[0014] The present invention also provides a drug for treating metabolism-related fatty liver disease, comprising a pharmaceutically effective amount of a liver metabolism regulator.

[0015] The drug for treating metabolism-related fatty liver disease of the present invention also includes pharmaceutically acceptable excipients.

[0016] The drug for treating metabolism-related fatty liver disease has a pharmaceutically acceptable dosage form.

[0017] The drug for treating metabolism-related fatty liver disease has a dosage form comprising at least one of granules, tablets, capsules, pills or oral liquid preparations.

[0018] Beneficial Effects

[0019] The present invention discovers for the first time that Formula 1 can reduce lipid accumulation in fatty liver cells in vitro, improve insulin resistance and glucose tolerance in mice with metabolic-related fatty liver disease, reduce lipid accumulation in the blood and liver, and improve liver function. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 These are the results of Oil Red O staining of primary hepatocytes and the detection of intracellular triglycerides.

[0021] Figure 2 These are the test results and statistical analysis of glucose tolerance and insulin tolerance tests in each group of mice.

[0022] Figure 3 These are the statistical results of the detection of triglyceride and cholesterol levels in the serum and liver of each group of mice.

[0023] Figure 4 These are the statistical results of the detection of serum alanine aminotransferase and aspartate aminotransferase in each group of mice. DETAILED DESCRIPTION

[0024] The technical solution of the present invention is further described below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto. The reagents and materials involved in the embodiments are all common commercially available products unless otherwise specified.

[0025] C57 mice were purchased from Hunan Slake Jingda Experimental Animal Co., Ltd., and the high-fat, high-sugar, high-cholesterol feed used to establish the metabolic-related fatty liver disease model was purchased from Research Diets. Palmitic acid and oleic acid used to establish fatty liver cells were purchased from Sigma.

[0026] Embodiment 1:

[0027] The effect of formula 1 on intracellular lipid accumulation was detected using primary mouse hepatocytes. 6-8 week old C57BL / 6J male mice used to isolate mouse primary hepatocytes were purchased from Hunan Slake Jingda Experimental Animal Co., Ltd. The isolated mouse primary hepatocytes were cultured in MEMα medium containing 10% FBS. The primary hepatocytes were treated with a mixture of 0.2mM palmitic acid (PA) and 0.4mM oleic acid (OA) (PAOA), and a fatty liver cell model was successfully constructed in 24 hours. Formula 1 was dissolved in DMSO, diluted to 10um, and added to PAOA to treat primary hepatocytes for 24 hours. After culturing for 24 hours, the triglyceride content in the cells was determined according to the intracellular triglyceride detection kit. The intracellular lipid droplets were stained red by Oil Red O staining and observed under a microscope.

[0028] Embodiment 2:

[0029] After 16 weeks of diet feeding, mice with metabolic-related fatty liver disease model were constructed, and the mice were randomly divided into 2 groups, which were gavaged with solvent control and formula 1 respectively. The solvent of formula 1 is 10% DMSO and 90% glycerol. The gavage dose is 40 mg / kg, and the gavage duration is 8 weeks. After 8 weeks of gavage, the mice were subjected to a glucose tolerance test. The mouse feed was removed at 17:00 in the afternoon of the day before the glucose tolerance test and fasting began. The experiment started at 9:00 in the morning of the test day, and the weight and fasting blood glucose of the mice were recorded. 20% glucose solution was injected intraperitoneally into the mice, and the blood glucose values ​​were measured 15 / 30 / 60 / 90 / 120 minutes after the injection. After 3 days of recovery from the glucose tolerance test, an insulin tolerance test was performed. Fasting began at 8:00 in the morning on the test day, and the experiment started at 14:00 in the afternoon. The weight and fasting blood glucose of the mice were recorded, and 7.5U insulin was injected intraperitoneally into the mice, and the blood glucose values ​​were measured 15 / 30 / 60 / 90 / 120 minutes after the injection. After 3 days of recovery after the experiment, the mice were killed, blood was collected, liver weight was weighed and the liver was retained for subsequent testing. The lipid (triglyceride and cholesterol) content in the blood and liver of the mice and the liver function (alanine aminotransferase and aspartate aminotransferase) indicators were measured according to relevant kits.

[0030] Figure 1 Formula 1 can reduce lipid accumulation in fatty liver cells;

[0031] BSA: bovine serum albumin (control solvent); PAOA: Palmitic acid and oleic acid, a mixture of palmitic acid and oleic acid.

[0032] Figure 2 Formula 1 can improve the glucose tolerance and insulin sensitivity of mice with metabolic-related fatty liver disease; GTT: Glucose tolerance test; ITT: insulin tolerance test; AUC: area under curve; Control: solvent control group; Formula 1: Formula 1 group; *p<0.05, **p<0.01.

[0033] Figure 3 Formula 1 can reduce the lipid content in serum and liver of mice with metabolic-related fatty liver disease; TG: triglyceride; TC: total cholesterol; Control: solvent control group; Formula 1: Formula 1 group; *p<0.05, **p<0.01.

[0034] Figure 4 Formula 1 can reduce liver damage in mice with metabolic-related fatty liver disease; ALT: glutamic pyruvictransaminase; AST: glutamic oxaloacetic transaminase; Control: solvent control group; Formula 1: Formula 1 group; *p<0.05, ***p<0.001.

Claims

1. Use of a liver metabolism regulator in the preparation of a drug for treating metabolism-related fatty liver disease, characterized in that: The liver metabolism regulator is a free compound having the structural formula 1 and its derivatives; 2. Use of the liver metabolism regulator according to claim 1 in the preparation of a drug for treating metabolism-related fatty liver disease, characterized in that: The derivative is at least one of an ester and a glycoside derived from Formula 1.

3. Use of the liver metabolism regulator according to claim 1 in the preparation of a drug for treating metabolism-related fatty liver disease, characterized in that: The formula 1 and other active ingredients are combined to prepare a drug for treating metabolism-related fatty liver disease.

4. Use of the liver metabolism regulator according to claim 1 in the preparation of a drug for treating metabolism-related fatty liver disease, characterized in that: The liver metabolism regulator is combined with a pharmaceutically acceptable excipient to prepare a pharmaceutically acceptable drug dosage form.

5. Use of the liver metabolism regulator according to claim 4 in the preparation of a drug for treating metabolism-related fatty liver disease, characterized in that: The pharmaceutical dosage form includes at least one of an oral preparation and an injection preparation.

6. A drug for treating metabolic-related fatty liver disease, characterized in that: The invention comprises a pharmaceutically effective amount of the liver metabolism regulator described in any one of claims 1 to 5.

7. The drug for treating metabolic-related fatty liver disease according to claim 6, characterized in that: Pharmaceutically acceptable excipients are also included.

8. The drug for treating metabolic-related fatty liver disease according to claim 6 or 7, characterized in that: It has a pharmaceutically acceptable dosage form.

9. The drug for treating metabolic-related fatty liver disease according to claim 8, characterized in that: The dosage form includes at least one of granules, tablets, capsules, pills or oral liquid preparations.

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