Application of corosolic acid in preparation of medicine for preventing or treating non-alcoholic fatty liver disease

Abstract

The invention discloses an application of corosolic acid in preparation of a medicine for preventing or treating a non-alcoholic fatty liver disease, and relates to the technical field of medicines. The research finds that corosolic acid improves the treatment mechanism of the non-alcoholic fatty liver disease from the perspective of dynamic balance of intestinal flora, and in addition, corosolic acid has the effects of reducing the in-vivo lipid level and protecting the liver at the same time; the corosolic acid is used for improving the non-alcoholic fatty liver disease by playing a role through the hepatic intestinal axis, balancing the relative expression abundance of intestinal flora and regulating a metabolic pathway, so that the intestinal injury is reduced, the effect of protecting the liver is played, and a foundation is laid for later development of medicines for treating the non-alcoholic fatty liver disease by corosolic acid.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to application of corosolic acid in preparing a medicine for preventing or treating non-alcoholic fatty liver disease. Background Art

[0002] In my country, nearly half of chronic liver disease patients suffer from non-alcoholic fatty liver disease, among which non-alcoholic fatty liver disease accounts for about 45%-50% of non-alcoholic fatty liver disease. However, at present, there is only one drug, resmetiro, which was recently approved by the FDA for the treatment of non-alcoholic fatty liver disease, and it has not been popularized. There is a serious shortage of drugs that can be used to treat non-alcoholic fatty liver disease, and the number of deaths from non-alcoholic fatty liver disease is increasing year by year worldwide. Therefore, it is of great significance to find a drug that can be used to treat non-alcoholic fatty liver disease, and this drug is a traditional Chinese medicine that can both reduce lipid levels in the body and protect the liver.

[0003] In view of this, the present invention is proposed. Summary of the invention

[0004] The purpose of the present invention is to provide an application of corosolic acid in the preparation of a medicament for preventing or treating non-alcoholic fatty liver disease, so as to solve the above technical problems.

[0005] The present invention is achieved in that:

[0006] In a first aspect, an embodiment of the present invention provides a use of corosolic acid in the preparation of a medicament for preventing or treating non-alcoholic fatty liver disease.

[0007] In a second aspect, an embodiment of the present invention provides a use of corosolic acid in the preparation of a drug for preventing or treating lipid-lowering and liver-protecting diseases.

[0008] In a third aspect, an embodiment of the present invention provides a use of corosolic acid in the preparation of an anti-liver cancer drug.

[0009] The present invention has the following beneficial effects:

[0010] The application of corosolic acid provided in the embodiment of the present invention in the preparation of a drug for preventing or treating non-alcoholic fatty liver disease shows that corosolic acid improves the therapeutic mechanism of non-alcoholic fatty liver disease from the perspective of the dynamic balance of intestinal flora. In addition, the corosolic acid has the effect of reducing lipid levels in the body while protecting the liver; it acts through the liver-gut axis, upregulating the relative expression abundance of Prevotellaceae UCG-001, Bacteroides and Lachnospiraceae NK4A136_group bacteria, downregulating the relative expression abundance of Lachnoclostridium bacteria, Lleibacterium bacteria and Colidextribacter bacteria, and regulating metabolic pathways to improve non-alcoholic fatty liver disease, thereby reducing intestinal damage and playing a role in protecting the liver. It has great potential in the treatment of non-alcoholic fatty liver disease, laying the foundation for the later development of corosolic acid for the treatment of non-alcoholic fatty liver disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0012] Figure 1 Results of mouse serum test: TC( Figure 1 A) TG( Figure 1 B) AST( Figure 1 C) and ALT( Figure 1 D)

[0013] Figure 2 Mouse weight changes: Mouse weight measurement results ( Figure 2 A), Final weight of mice ( Figure 2 B), Mouse body weight changes ( Figure 2 C);

[0014] Figure 3 Observation of the weight change and color of mouse liver;

[0015] Figure 4 Results of temperature changes and body fat distribution in living mice: Temperature changes in mice ( Figure 4 A), fat distribution in mice ( Figure 4 B);

[0016] Figure 5 Mouse liver pathology section and mouse white fat pathology section results: Mouse liver pathology section results ( Figure 5A), mouse liver oil red section (5B), mouse white fat pathological section ( Figure 5 C), HE pathological section of mouse small intestine (5D);

[0017] Figure 6 The overall structural changes of the intestinal flora of mice;

[0018] Figure 7 Mouse intestinal bacteria Figure 7 A) and genus ( Figure 7 B) horizontal structural changes;

[0019] Figure 8 potential altered metabolic pathways in mice;

[0020] Fig. 9 This is a heat map analysis of the correlation between mouse intestinal flora and drug efficacy indicators (Pearson). DETAILED DESCRIPTION

[0021] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0022] Non-alcoholic fatty liver disease refers to diseases closely related to insulin resistance and metabolic syndrome, except for liver diseases caused by alcohol and other clear factors (such as viral hepatitis, drug-induced fatty liver, etc.), including simple fatty liver and its evolutionary non-alcoholic fatty liver disease, liver fibrosis, cirrhosis and liver cancer. In addition to alcoholic liver disease caused by heavy drinking, there is another type of fatty liver, called non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease refers to a clinical pathological syndrome characterized by excessive fat deposition in liver cells, excluding alcohol and other clear liver-damaging factors.

[0023] Considering that non-alcoholic fatty liver disease can cause serious liver damage in patients, when screening drugs for treating non-alcoholic fatty liver disease, the present invention shifts the focus of drug screening to traditional Chinese medicine that can both reduce lipid levels in the body and protect the liver. Studies have shown that corosolic acid has the effect of protecting liver damage caused by alcohol, however, some studies have reported that corosolic acid is not ideally absorbed in the body. Based on this, the present invention is proposed.

[0024] Corosolic acid is a natural product, also known as 2α-hydroxyursolic acid, with the molecular formula: C 30 H 48O4 is a pentacyclic triterpenoid compound of the α-amyrin type or ursane type. Its basic skeleton is the pentacyclic mother nucleus of polyhydropinene. It is mainly derived from Chinese medicines such as Lagerstroemia indica, loquat leaves and hawthorn. Currently, this natural product has been marketed in the United States as a nutritional supplement and is also a phase III clinical trial drug for the treatment of diabetes. It will be certified by the FDA in the near future.

[0025] In recent years, studies have found that corosolic acid has attracted widespread attention as a new plant drug for the treatment of non-alcoholic fatty liver disease, prevention and treatment of obesity and type 2 diabetes, and a functional natural health food raw material. In addition, corosolic acid also has pharmacological effects such as anti-diabetes and its induced kidney damage, anti-tumor, anti-inflammatory, anti-myocardial damage, anti-hypertensive, anti-bacterial, inhibition of osteoclastogenesis and osteolysis, showing its potential in the treatment of various diseases. With the continuous deepening of research, this product will have a very broad market prospect. However, some studies have reported that the absorption of corosolic acid in the body is not ideal (Liu Q., Zhao D., Chen X., et al. Determination of corosolic acid, a natural potential anti-diabetes compound, in rat plasma by high-performance liquid chromatography-mass spectrometry and its application to pharmacokinetic and bioavailability studies. Planta medica, 2011, 77 (15), 1707–1711.). Therefore, it is of great significance to find a drug that can be used to treat non-alcoholic fatty liver disease, and this drug is a traditional Chinese medicine that can both lower lipid levels in the body and protect the liver.

[0026] In a first aspect, an embodiment of the present invention provides a use of corosolic acid in the preparation of a medicament for preventing or treating non-alcoholic fatty liver disease.

[0027] It should be noted that corosolic acid is a Chinese patent medicine that has the effect of lowering lipid levels in the body while protecting the liver. Corosolic acid improves the therapeutic mechanism of non-alcoholic fatty liver disease from the perspective of the dynamic balance of intestinal flora and regulating metabolic pathways. It has great potential in the treatment of non-alcoholic fatty liver disease and lays the foundation for the later development of corosolic acid for the treatment of non-alcoholic fatty liver disease.

[0028] It should be noted that corosolic acid has the effect of protecting liver damage caused by alcohol; it has many important functions in the human body, including intestinal health, metabolic regulation, immune regulation, anti-inflammatory and anti-tumor effects, and has potential value in the treatment of metabolic diseases by affecting the physiological functions of the whole body. They can regulate the metabolism of glucose and fat, and further affect the body's energy balance and weight management.

[0029] The dosage of corosolic acid applied to the subject can be reduced or increased according to actual needs.

[0030] In an optional embodiment of the present invention, the solvent for preparing the drug is: sodium carboxymethyl cellulose with a mass concentration of 0.5%.

[0031] It should be noted that corosolic acid has low solubility in water and poor absorption in the body. Therefore, in the present invention, sodium carboxymethyl cellulose is used as a solvent when preparing corosolic acid. As a suspending solvent, sodium carboxymethyl cellulose can ensure uniform dispersion of corosolic acid.

[0032] The dosage form of the relevant drug is selected from any one of tablets, capsules, pellets, oral liquids and granules, wherein the oral liquids include any one of solutions, suspensions and emulsions.

[0033] Furthermore, the drug also includes pharmaceutically acceptable excipients.

[0034] In an optional embodiment of the present invention, the drug has at least one of the following uses:

[0035] (1) Inhibit the weight gain of the subject;

[0036] (2) reduce the levels of total cholesterol, triglycerides, alanine aminotransferase and aspartate aminotransferase in the serum of the subjects;

[0037] (3) Raise the temperature of the subject and increase energy consumption;

[0038] (4) Change the size of the subject's fat cells and reduce the subject's fat distribution;

[0039] (5) upregulating the relative abundance of Firmicutes and Verrucomicrobia in the intestinal flora of the subjects;

[0040] (6) Down-regulate the relative abundance of Bacteroidetes in the intestinal flora of the subjects.

[0041] In an optional embodiment of the present invention, the upregulated intestinal flora includes at least one of Prevotella UCG-001, Bacteroides and Lachnospira NK4A136_group.

[0042] Furthermore, the upregulated intestinal flora includes at least one of Prevotellaceae UCG-001 bacteria, Bacteroides bacteria and Lachnospiraceae NK4A136_group bacteria.

[0043] In an optional embodiment of the present invention, the downregulated intestinal flora includes at least one of Lachnoclostridium bacteria, Lleibacterium bacteria and Colidextribacter bacteria.

[0044] In an optional embodiment of the present invention, the use of the drug also includes: participating in regulating at least one metabolic process of amino acid metabolism, cell proliferation and apoptosis, carbohydrate metabolism, lipid metabolism and energy metabolism in non-alcoholic fatty liver disease.

[0045] In an optional embodiment of the present invention, the use of the drug also includes: protecting intestinal damage caused by non-alcoholic fatty liver disease.

[0046] In an optional embodiment of the present invention, non-alcoholic fatty liver disease is at least one of simple fatty liver, steatohepatitis and fatty liver fibrosis.

[0047] In a second aspect, an embodiment of the present invention provides a use of corosolic acid in the preparation of a drug for preventing or treating lipid-lowering and liver-protecting diseases.

[0048] In a third aspect, an embodiment of the present invention provides a use of corosolic acid in the preparation of an anti-liver cancer drug.

[0049] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0050] Example 1

[0051] This example establishes an animal model of non-alcoholic fatty liver disease, conducts drug intervention, sample collection, drug efficacy evaluation, and mechanism exploration. The details are as follows:

[0052] 1.1 Animals and main materials

[0053] SPF grade C57BL / 6 mice, male, weighing 18g-22g, were provided by Guangdong Medical Experimental Animal Center; high-fat feed was provided by Nantong Trofi Feed Technology Co., Ltd.; metformin (Met) was purchased from a pharmacy; corosolic acid (CRA, 98%) was purchased from Chengdu Purifa Technology Development Co., Ltd.; 0.5% sodium carboxymethylcellulose solution was purchased from Sinopharm Chemical Reagent Co., Ltd.

[0054] 1.2 Preparation of corosolic acid

[0055] Preparation of CRA-H: Take 40 mg of corosolic acid, put it in a 50 mL beaker, add 20 mL of 0.5% sodium carboxymethyl cellulose solution, stir with a glass rod to make it evenly dispersed, and prepare CRA-H with a mass concentration of 2 mg / mL.

[0056] Preparation of CRA-L: The preparation method is based on CRA-H by gradient dilution to obtain CRA-L with a mass concentration of 1 mg / mL.

[0057] 1.3 Establishment of animal model

[0058] After 7 days of adaptive feeding, 60 male C57BL / 6J mice were randomly divided into 12 normal control groups (Control), 12 model groups (Model), 12 positive drug groups (Met, 400mg / kg), and 12 corosolic acid high and low groups (CRA-L, CRA-H) each; except for the control group, which was given a normal diet and feed, the other 4 groups were given a high-fat diet (i.e., HFD diet) to construct a non-alcoholic fatty liver disease model (i.e., model group), and the modeling lasted for 8 weeks. At the 8th week, the model can be successfully constructed by observing indicators such as mouse weight, blood cholesterol, and liver fat changes, and corresponding adjustments can be made.

[0059] 1.4 Medication intervention

[0060] The normal control group and the model group were given 0.5% sodium carboxymethyl cellulose by gavage at a volume of 0.1 mL / kg, the positive drug group (Met, 400 mg / kg), and the corosolic acid group (CRA-L, 20 mg / kg; CRA-H, 40 mg / kg). The model mice were treated for 8 weeks, and high-fat diet was continued during the treatment period. The mental state of the mice was observed every day and the weight changes were recorded. Each group was given ordinary feed and pure water, and they were free to eat.

[0061] 1.5 Collecting samples

[0062] It should be noted that the methods of collecting samples vary for different testing items, which are explained in detail in the corresponding testing items.

[0063] In addition, prepare the materials, write the labels, and assign the personnel to collect the samples a few days before the collection. On the day of collection or the next day, contact the sample delivery company to test 16S rRNA and make pathological sections.

[0064] 1.6 Efficacy evaluation and results

[0065] 1.6.1 Mouse serum testing

[0066] The specific operation of collecting samples is as follows: fast for 12 hours after the last administration, remove all animal feed 12 hours in advance, but supply drinking water normally, weigh the body weight, and collect the feces of each group of mice. Anesthetize the animals, obtain blood samples from the venous plexus of the mouse fundus after anesthesia, and then take the mouse blood sample into a 2mL EP tube, centrifuge (3000rpm, 4℃) for 10min, extract the upper serum, put it into EP tubes, divide it into tubes, and store it in a -80℃ low-temperature refrigerator.

[0067] Before the modeling was completed, two model mice were randomly selected to measure the levels of TG (triglycerides), TC (total cholesterol), ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in their bodies using Nanjing Jiancheng kits, and the degree of model construction was evaluated based on these indicators.

[0068] Related results can be found in Figure 1 , where TC( Figure 1 A) TG( Figure 1 B) AST( Figure 1 C) and ALT( Figure 1 D).

[0069] from Figure 1 It can be seen that the TC( Figure 1 A) TG( Figure 1 B) AST( Figure 1 C) and ALT( Figure 1 D) were significantly higher than those of the normal control group (P<0.05), indicating that the non-alcoholic fatty liver disease model was successfully constructed; after drug intervention, TC, TG, AST and ALT were significantly decreased in the positive drug group (Met group) and corosolic acid group (CRA-L, CRA-H) (P<0.05).

[0070] 1.6.2 Changes in mouse weight

[0071] The specific operation of collecting samples is as follows: fast for 12 hours after the last administration, remove all feeds of animals 12 hours in advance, supply drinking water normally, and weigh the body weight. Figure 2 , among which, the mouse weight measurement results ( Figure 2 A), Final weight of mice ( Figure 2 B), Mouse body weight changes ( Figure 2 C).

[0072] from Figure 2 It can be seen that compared with the normal control group, the body weight of mice in the model group increased significantly (P<0.05), further indicating that the non-alcoholic fatty liver disease model was successfully constructed.

[0073] In contrast, after drug intervention, the weight gain of mice fed a high-fat diet was effectively inhibited.

[0074] It should be noted that compared with the model group, *P<0.05, **P<0.01, ***P<0.001.

[0075] 1.6.3 Observation of mouse liver weight and color

[0076] The specific operation of collecting samples is as follows: the mouse liver is quickly removed on an ice table, weighed, and filmed and summarized. The relevant results are shown in Figure 3 .

[0077] from Figure 3 It can be seen that by dissecting mice and taking out the liver for ordinary photography, it was observed that compared with the normal control group, the liver of the model group mice was larger in size and had a larger distribution of fat droplets, resulting in the entire liver being pink and white. After drug intervention, the above conditions were well reversed.

[0078] It should be noted that compared with the model group, *P<0.05, **P<0.01, ***P<0.001.

[0079] 1.6.4 Temperature changes and body fat distribution in mice

[0080] The results of temperature changes and body fat distribution in living mice are shown in Figure 4 , among which, the temperature change of mice ( Figure 4 A), fat distribution in mice ( Figure 4 B).

[0081] It should be noted that fat accumulation is accompanied by a decrease in energy expenditure. In order to verify whether corosolic acid reduces body fat distribution by regulating energy expenditure in the prevention and treatment of non-alcoholic fatty liver disease, temperature monitoring and in-body fat distribution detection were performed on living mice.

[0082] from Figure 4 It can be seen that compared with the normal control group, the temperature of the mice in the model group was lower, and after drug intervention, the temperature of the mice in the model group increased; the component analysis of conscious small animals found that compared with the normal control group, the model mice had enlarged body contours and a wider fat distribution area, and after the intervention of corosolic acid and MET, the temperature of the mice increased, energy consumption increased, and the fat distribution of the mice was effectively reduced.

[0083] 1.6.5 Observation of mouse liver pathological sections and mouse white fat pathological sections

[0084] The specific operation of collecting samples is as follows: the liver and small intestine of mice were quickly removed on an ice table and stored in 4% paraformaldehyde solution for pathological section observation and later for HE experiments; epididymal white fat (eWAT) was taken, photographed and frozen for later use. Figure 5 , Figure 5 A is the result of mouse liver pathological section. Figure 5 B is the oil red section of mouse liver. Figure 5 C is a pathological section of mouse white fat. Figure 5 D is the HE pathological section of mouse small intestine.

[0085] from Figure 5 The pathological sections showed that the liver cells in the normal control group were evenly distributed and neatly arranged. Compared with the normal control group, the liver of the model group was severely damaged, and the liver cell structure was filled with lipid droplets, which were porous after being dissolved by the solvent. After drug intervention, the pathological changes in the liver were reversed ( Figure 5 A-5B), corosolic acid showed good effects in protecting the liver and reducing fat. Mouse white fat pathological section ( Figure 5 C) The results showed that compared with the normal control group, the volume of white fat cells in the model group mice increased. Corosolic acid can change the volume of fat cells and reduce fat distribution. The results of mouse small intestine HE showed that the intestinal villi structure of the normal control group mice were intact and tight. In contrast, the intestinal mucosal barrier of the model group mice was severely damaged, and the length of the small intestinal villi was significantly shortened or completely lost, resulting in a reduction in the absorption area. After the mucosal barrier was severely damaged, the integrity of the villus epithelial cells was lost, resulting in partial exposure of the basement membrane. After CRA administration, the small intestinal structure of mice with non-alcoholic fatty liver disease was well restored ( Figure 5 D).

[0086] 1.6.6 Changes in intestinal flora of mice

[0087] The 16S rRNA technology was used to determine the changes in the intestinal flora of each group of mice. The specific results are shown in Figure 6-Figure 7 .

[0088] The specific operation of collecting samples is as follows: Feces of the normal control group and the model group were collected a few days before the last administration for intestinal flora testing. Feces of the administration group were collected on the day of the last administration, as much as possible, and a part of them was used for metabolomics and intestinal flora testing. The collected intestinal content samples were stored in a -80℃ low-temperature refrigerator for future use.

[0089] Depend on Figure 6 As can be seen from A, the three groups can be clearly separated, indicating that the intestinal flora of mice in the three groups are significantly different. Figure 6 B and Figure 6 It can be concluded that compared with normal mice, the species diversity of the intestinal flora of model mice ( Figure 6 B) and bacterial abundance ( Figure 6 C) decreased significantly, and this phenomenon was reversed in model mice after drug intervention, indicating that CRA can fight non-alcoholic fatty liver disease by regulating the abundance and diversity of intestinal flora.

[0090] from Figure 7 It can be seen that compared with the intestinal flora of normal control group mice, the flora in the model mice was disordered, mainly at the phylum level, among which Bacteroidetes was downregulated, and Firmicutes and Verrucomicrobiota were increased. After the administration of corosolic acid, the flora structure at the above phylum level in the model mice was adjusted towards the direction of the normal control group.

[0091] The sequencing depth was detected to the genus level, and it was found that after administration of corosolic acid, the relative abundance of PrevotellaceaeUCG-001, Bacteroides and LachnospiraceaeNK4A136_group was mainly upregulated, while the relative abundance of Lachnoclostridium, Lleibacterium and Colidextribacter was mainly downregulated. Figure 7 B), suggesting that corosolic acid may play a role in treating NAFLD by upregulating the ratio of these potential probiotics and downregulating the ratio of these harmful bacteria, thereby regulating the liver-gut axis.

[0092] 1.6.7 Potential metabolic function changes in mice

[0093] According to the changes in the intestinal flora structure of mice obtained in 1.6.6, the inventors performed PICRUSt function prediction on the potential metabolic function of corosolic acid on non-alcoholic fatty liver disease. The results are as follows Figure 8 shown.

[0094] from Figure 8 It can be concluded that corosolic acid may be involved in metabolic processes such as Amino acid metabolism, Cell growth and death, Carbohydrate metabolism, Lipid metabolism, and Energy metabolism.

[0095] 1.6.8 Potential relationship between mouse intestinal flora and drug efficacy indicators of non-alcoholic fatty liver disease

[0096] To further clarify the relationship between intestinal flora regulated by corosolic acid and non-alcoholic fatty liver disease, we used correlation analysis, and the relevant results are shown in Fig. 9 .

[0097] Depend on Fig. 9 It can be seen that Prevotellaceae UCG-001 (Prevotellaceae UCG-001), Bacteroides (Bacteroides) and Lachnospiraceae NK4A136_group (Lachnospiraceae NK4A136_group) were negatively correlated with TG, TC, AST and ALT, while Lachnoclostridium, Lleibacterium and Colidextribacter were positively correlated with TG, TC, AST and ALT, which further illustrates that corosolic acid is likely to exert its therapeutic effect by regulating these bacterial communities.

[0098] In summary, the preparation method of corosolic acid provided by the embodiment of the present invention is simple, and the raw material source is wide, which is conducive to universal promotion. Corosolic acid is dose-dependent in the application of preventing and treating non-alcoholic fatty liver disease. It improves the therapeutic mechanism of non-alcoholic fatty liver disease from the perspective of the dynamic balance of intestinal flora. In addition, the corosolic acid has the effect of reducing lipid levels in the body while protecting the liver; it works through the liver-gut axis, upregulating the relative expression abundance of Prevotellaceae UCG-001 bacteria, Bacteroides bacteria and Lachnospiraceae NK4A136_group bacteria, downregulating the relative expression abundance of Lachnoclostridium bacteria, Lleibacterium bacteria and Colidextribacter bacteria, and regulating metabolic pathways to improve non-alcoholic fatty liver disease, thereby reducing intestinal damage and playing a role in protecting the liver. The corosolic acid provided by the present invention has great potential in the treatment of non-alcoholic fatty liver disease, laying the foundation for the later drug development of corosolic acid for the treatment of non-alcoholic fatty liver disease.

[0099] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Use of corosolic acid in the preparation of a drug for preventing or treating non-alcoholic fatty liver disease.

2. The use according to claim 1, characterized in that: The drug has at least one of the following uses: (1) Inhibit the weight gain of the subject; (2) reduce the levels of total cholesterol, triglycerides, alanine aminotransferase and aspartate aminotransferase in the serum of the subjects; (3) Raise the temperature of the subject and increase energy consumption; (4) Change the size of the subject's fat cells and reduce the subject's fat distribution; (5) upregulating the relative abundance of Firmicutes and Verrucomicrobia in the intestinal flora of the subjects; (6) Down-regulate the relative abundance of Bacteroidetes in the intestinal flora of the subjects.

3. The use according to claim 2, characterized in that: The upregulated intestinal flora included at least one of Prevotella UCG-001, Bacteroides and Lachnospiraceae NK4A136_group.

4. The use according to claim 3, characterized in that: The upregulated intestinal flora includes at least one of PrevotellaceaeUCG-001 bacteria, Bacteroides bacteria and Lachnospiraceae NK4A136_group bacteria.

5. The use according to claim 2, characterized in that: The downregulated intestinal flora includes at least one of Lachnoclostridium bacteria, Lleibacterium bacteria and Colidextribacter bacteria.

6. The use according to claim 2, characterized in that: The use of the drug also includes: participating in regulating at least one metabolic process among amino acid metabolism, cell proliferation and apoptosis, carbohydrate metabolism, lipid metabolism and energy metabolism in non-alcoholic fatty liver disease.

7. The use according to claim 2, characterized in that: The use of the drug also includes: protecting intestinal damage caused by non-alcoholic fatty liver disease.

8. The use according to claim 1, characterized in that: The non-alcoholic fatty liver disease includes at least one of simple fatty liver, steatohepatitis and fatty liver fibrosis.

9. Use of corosolic acid in the preparation of drugs for preventing or treating lipid-lowering and liver-protecting diseases.

10. Use of corosolic acid in the preparation of anti-liver cancer drugs.

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