Medicine for treating metabolism-related fatty liver disease by taking JOSD2 gene or protein as target spot

Abstract

The invention discloses a medicine for treating metabolism-related fatty liver diseases by taking a JOSD2 gene or protein as a target spot, and belongs to the technical field of biological medicines. The medicine contains a substance for up-regulating JOSD2 gene expression or enhancing a JOSD2 protein function. The new functions of the JOSD2 gene and the encoded protein thereof in MAFLD are confirmed through in-vivo and in-vitro experiments for the first time, it is determined that JOSD2 is a protection factor in MAFLD, MAFLD can be treated by increasing JOSD2 expression or enhancing the activity of JOSD2, and MAFLD treatment drugs are developed by taking JOSD2 as a drug action target. The invention provides a brand new target for clinical treatment of MAFLD, and provides a new thought and a new view for innovative drug research and development of MAFLD.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to the use of JOSD2 gene or JOSD2 protein as a drug target in the preparation of a drug for treating metabolism-related fatty liver disease. Background Art

[0002] Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disease in the world. As of now, about 38% of adults worldwide are suffering from MAFLD, and its prevalence is expected to increase further in the next decade. MAFLD refers to a disease induced by factors other than alcohol and other factors that clearly induce liver damage. Its typical pathological feature is the excessive accumulation of lipids, mainly cholesterol (Total cholesterol, TC) and triglycerides (Triglyceride, TG) in hepatocytes. As the disease progresses, MAFLD will further develop into metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis (Liver fibrosis) and liver cirrhosis (Liver cirrhosis).

[0003] Due to the extremely complex pathogenesis and pathological process of MAFLD, the current clinical treatment methods for MAFLD are very limited. The symptoms are mainly improved by changing dietary habits, increasing physical exercise and supplementing with symptomatic drugs. There is no effective and specific drug for the treatment of MAFLD.

[0004] Therefore, in-depth research on the pathogenesis of MAFLD and revealing the key functional proteins that play a vital role in it are expected to provide new targets for the clinical treatment of MAFLD, and also provide new ideas for the development of innovative anti-MAFLD drugs.

[0005] Josephin domain containing 2 (JOSD2) belongs to the Machado-Joseph Deubiquitinase (MJDs) family of deubiquitinases. In addition to JOSD2, the family also includes JOSD1, ATXN3 (Ataxin3), and ATXN3L (Ataxin 3-like). So far, there are few studies on the biological functions of JOSD2, mainly focusing on the fields of tumors and cardiovascular. Studies have reported that JOSD2 can promote the abnormal growth of intrahepatic cholangiocarcinoma by regulating the key effector YAP / TAZ of the Hippo signaling pathway through deubiquitination (ActaPharmaceutica Sinica B, 2021, 11 (12): 4008-4019.), and can also inhibit LKB1 activity by removing the K6 type ubiquitin chain of LKB1 protein, thereby promoting the malignant proliferation of non-small cell lung cancer (Signal Transduction and Targeted Therapy volume, 2024, 9: 11). In addition, some studies have pointed out that JOSD2 can inhibit the ubiquitination degradation of SERCA2a protein by mediating its deubiquitination regulation, thereby improving calcium handling in cardiomyocytes and reducing cardiac hypertrophy and dysfunction (Nature Cardiovascular Research volume, 2023, 2: 764-777.).

[0006] It can be seen that JOSD2 plays a key role in the progression of tumors, cardiovascular diseases, etc., but its role in chronic liver diseases such as MAFLD and MASH has not been reported at home and abroad. Therefore, clarifying the role of JOSD2 in MAFLD is expected to provide experimental basis for the development of JOSD2 as a drug target for the treatment of MAFLD. Summary of the invention

[0007] The purpose of the present invention is to explore the genes / proteins related to the occurrence and development of metabolic-related fatty liver disease, use them as targets for the prevention and treatment of metabolic-related fatty liver disease, and screen drugs for the treatment of metabolic-related fatty liver disease.

[0008] To achieve the above object, the present invention adopts the following technical solution:

[0009] The present invention provides the use of JOSD2 gene or the protein encoded by it as a target in the preparation of a drug for treating metabolism-related fatty liver disease, wherein the drug comprises a substance that upregulates JOSD2 gene expression or enhances JOSD2 protein function.

[0010] The present invention found that the JOSD2 gene or its encoded protein plays a key role in the progression of metabolic-related fatty liver disease. Specifically, it was found that the expression of JOSD2 protein in the liver tissue of the MAFLD model induced by a high-fat and high-cholesterol diet was significantly downregulated, and liver-specific knockout of JOSD2 can accelerate the progression of MAFLD induced by a high-fat and high-cholesterol diet, mainly manifested as aggravated lipid accumulation in the liver, increased body weight and liver weight, increased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), TC and low-density lipoprotein cholesterol (LDLC) content, and increased TC and TG content in liver tissue and promoted the occurrence of inflammation; in addition, the study also found that exogenous overexpression of JOSD2 can alleviate the accumulation of hepatocyte lipids induced by palmitic acid / oleic acid (PAOA).

[0011] The above studies indicate that JOSD2 expression has a negative regulatory effect on the progression of MAFLD. Taking JOSD2 as a target and using drugs that increase JOSD2 expression or enhance its activity can be used to treat MAFLD.

[0012] Furthermore, the metabolism-related fatty liver disease is induced by a high-fat and high-cholesterol diet.

[0013] Furthermore, the manifestations of the metabolic-related fatty liver disease include liver enlargement and excessive accumulation of lipids in the liver.

[0014] Furthermore, the metabolism-related fatty liver disease includes one or more of metabolism-related fatty liver hepatitis, liver fibrosis, cirrhosis and other chronic liver diseases.

[0015] Furthermore, the coding sequence of the human JOSD2 gene is shown in SEQ ID NO. 1, and the amino acid sequence of the encoded protein is shown in SEQ ID NO. 2; the coding sequence of the mouse Josd2 gene is shown in SEQ ID NO. 3, and the amino acid sequence of the encoded protein is shown in SEQ ID NO. 4. The applicable objects of the present invention are not limited to humans or mice.

[0016] The present invention develops a corresponding pharmaceutical preparation for up-regulating protein expression or enhancing protein activity for JOSD2 gene or JOSD2 protein. The drug achieves the purpose of treating metabolism-related fatty liver disease by increasing JOSD2 expression or enhancing its activity.

[0017] Furthermore, the substance that upregulates JOSD2 gene expression is an adenovirus recombinant vector (Adeno-associated virus-JOSD2, AAV-JOSD2) that overexpresses JOSD2. The substance that enhances the function of JOSD2 protein is a JOSD2 purified protein or active polypeptide. The present invention is not limited to this, and any related JOSD2 product that can obtain biological safety and target JOSD2 at the biological level is applicable.

[0018] Furthermore, substances that upregulate JOSD2 gene expression or enhance JOSD2 protein function can regulate JOSD2 expression or enhance its activity, including but not limited to compound preparations and Chinese herbal medicines. Chinese herbal medicines or other drugs that can upregulate JOSD2 expression or enhance its activity all fall within the scope of protection of the present invention.

[0019] Furthermore, the drug also includes a pharmaceutically acceptable carrier. The carrier is any preparation or carrier medium that can deliver an effective dose of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or the subject.

[0020] Furthermore, the dosage form of the drug is any one of tablets, granules, solutions, emulsions, suspensions, and capsules. The drug is prepared according to a preparation method described in pharmacy.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The present invention confirms the important role of JOSD2 gene and its encoded protein in MAFLD disease for the first time through in vitro and in vivo experiments. The present invention adopts the recognized high-fat and high-cholesterol diet to induce MAFLD model, and finds that JOSD2 is significantly downregulated in the liver tissue of MAFLD model; and liver-specific knockout of JOSD2 can promote lipid accumulation in the liver, increase body weight and liver weight, increase ALT, AST, TC, LDLC in serum and TC and TG content in liver tissue, and promote inflammatory response in liver tissue, thereby aggravating the disease process of MAFLD induced by high-fat and high-cholesterol diet; and exogenous overexpression of JOSD2 can improve MAFLD symptoms. The above studies confirm that JOSD2 is a protective factor in MAFLD, and increasing JOSD2 expression or enhancing its activity can treat MAFLD. Therefore, drugs for treating MAFLD can be developed using this as a drug target.

[0023] The present invention provides a new target for the clinical treatment of MAFLD and provides new ideas and new perspectives for the development of innovative drugs for MAFLD. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1JOSD2 was significantly downregulated in the liver tissue of MAFLD model mice induced by a high-fat and high-cholesterol diet; (A) Anatomical diagram of mice in the normal control (NC) and high-fat and high-cholesterol (HFHC) diet groups; (B) Liver images of mice in the NC and HFHC groups; (C) Protein immunoblotting to detect the expression of JOSD2 protein in the liver tissue of mice in the NC and HFHC groups.

[0025] Figure 2 PAOA reduces JOSD2 protein expression in hepatocytes in a concentration-dependent and time-dependent manner; wherein: (A) Protein immunoblotting detected the effect of different concentrations of PAOA on JOSD2 protein expression in hepatocytes HL7702; (B) Protein immunoblotting detected the effect of different concentrations of PAOA on JOSD2 protein expression in primary mouse hepatocytes; (C) Protein immunoblotting detected the effect of PAOA on JOSD2 protein expression in hepatocytes HL7702 at different time points.

[0026] Figure 3 Liver-specific knockout of JOSD2 exacerbates the disease progression of the MAFLD model induced by a high-fat, high-cholesterol diet; wherein: (A) Real-time quantitative PCR technology was used to detect the expression of the Josd2 gene in different organs of normal mice (Wild type, WT) and liver-specific JOSD2 knockout mice (Hepatocyte specific knockout, HKO); (B) An electronic balance was used to regularly monitor the body weight of mice in each group; (C) Liver images and liver weights of mice in each group.

[0027] Figure 4 The liver-specific knockout of JOSD2 increased the levels of ALT, AST, TC, LDLC in the serum of mice and TC and TG in the liver tissue; wherein: (AD) the blood biochemical analyzer was used to detect the levels of ALT, AST, TC, and LDLC in the serum of each group of mice; (EF) the kit was used to detect the levels of TC and TG in the liver tissue of each group of mice.

[0028] Figure 5Liver-specific knockout of JOSD2 exacerbates lipid accumulation in liver tissue, promotes the synthesis and uptake of cholesterol and fatty acids, and inhibits fatty acid β-oxidation; (A) Hematoxylin and eosin (H&E), Oil red O, and Sirius red staining of liver tissue sections of mice in each group; (B) Real-time quantitative PCR technology was used to detect the expression of cholesterol synthesis and metabolism genes, as well as fatty acid synthesis, uptake, and β-oxidation genes in liver tissues of normal mice and liver-specific knockout JOSD2 mice fed a high-fat and high-cholesterol diet.

[0029] Figure 6 Liver-specific knockout of JOSD2 promotes inflammatory response in mouse liver tissue; wherein: (A) protein immunoblotting was used to detect the activation of the inflammatory signaling pathway IKKβ / NF-κB in the liver tissue of each group of mice; (B) real-time quantitative PCR technology was used to detect the expression of inflammatory-related genes in the liver tissue of normal mice and liver-specific knockout JOSD2 mice fed a high-fat and high-cholesterol diet.

[0030] Figure 7 Overexpression of JOSD2 can alleviate the lipid accumulation in hepatocytes induced by PAOA. Oil red O staining was used to detect the triglyceride content in hepatocytes of the normal group and the JOSD2 overexpression group after PAOA treatment. DETAILED DESCRIPTION

[0031] The present invention will be further described below in conjunction with specific embodiments. The following embodiments are only used to illustrate the present invention and are not intended to limit the scope of application of the present invention. Without departing from the spirit and essence of the present invention, modifications or replacements made to the inventive method, steps or conditions all belong to the scope of the present invention.

[0032] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the materials and reagents used are reagents and materials that can be obtained from commercial channels unless otherwise specified.

[0033] Mice: C57BL / 6 male mice were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd., ALB-cre mice were purchased from Shanghai South Model Organisms Technology Co., Ltd., JOSD2 conditional knockout mice were provided by Beijing Biocytogen Biotechnology Co., Ltd., and liver-specific knockout JOSD2 mice were obtained by hybridization of JOSD2 conditional knockout mice and ALB-cre mice. High-fat and high-cholesterol diets were purchased from Research Diet, USA (Cat. No.: D09100310). Mice were fed with normal diet and high-fat and high-cholesterol diet starting at 8 weeks of age for 18 weeks.

[0034] Cells: Hepatocytes HL7702 were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences, and mouse primary liver cells were isolated and obtained by collagenase digestion.

[0035] Inducers: Palmitic acid (PA, catalog number: P5585) and oleic acid (OA, catalog number: O1008) were purchased from Sigma-Aldrich. Preparation method: Weigh a certain amount of oleic acid and palmitic acid, dissolve in 0.1M sodium hydroxide solution (heated in a water bath at 75°C), prepare 0.1M PA stock solution and OA stock solution respectively, mix the PA stock solution and OA stock solution in a volume ratio of 1:2 to prepare a 0.1M PAOA stock solution.

[0036] Western blotting: JOSD2 antibody (catalog number: SAB2103354) was purchased from Sigma-Aldrich, GAPDH antibody (catalog number: db106) and β-Actin (catalog number: db7283) were purchased from Hangzhou Daige Biotechnology Co., Ltd., p-IKKβ (Tyr188) antibody (catalog number: 347345), IKKβ antibody (catalog number: R24676), and IKBα antibody (catalog number: R23322) were purchased from Chengdu Zhengneng Biotechnology Co., Ltd., p-P65 (S529) antibody (catalog number: ET1604-27), P65 antibody (catalog number: ER0815), and p-IKBα (S32) antibody (catalog number: ET1609-78) were purchased from Hangzhou Huaan Biotechnology Co., Ltd.

[0037] Fluorescence quantitative PCR primers are shown in Table 1:

[0038] Table 1

[0039]

[0040]

[0041] Serum ALT, AST, TC and LDL-C content detection: ALT detection kit (ab282882), AST detection kit (ab263882), LDL-C detection kit (ab65390) were purchased from abcam, TC detection kit (A111-2-1) and TG detection kit (A110-2-1) were purchased from Nanjing Jiancheng Bioengineering Institute. The test method was carried out according to the kit instructions.

[0042] H&E staining: H&E staining solution (C0107) was purchased from Bio-Tech Biotech Co., Ltd. The test method was carried out according to the instructions of the kit.

[0043] Oil Red O staining: Oil Red O staining kit (C0157M) was purchased from Bio-Tech Biotech Co., Ltd. The test method was carried out according to the kit instructions.

[0044] Sirius red staining: The modified Sirius red staining kit (G1472) was purchased from Solebao Biotechnology Co., Ltd. The test method was carried out according to the kit instructions.

[0045] Example 1: Downregulation of JOSD2 expression in liver tissue of MAFLD model mice

[0046] 1. Select 8-week-old C57BL / 6 male mice and feed them with normal feed and high-fat and high-cholesterol feed for 18 weeks respectively. Dissect the mice to obtain the mouse liver and take pictures.

[0047] like Figure 1 As shown in A and B, compared with the normal feed group, a large amount of white fat was observed in the abdominal cavity of mice in the high-fat and high-cholesterol diet group, and the liver was enlarged, soft, yellowish brown, and greasy, indicating that the MAFLD model was successfully constructed.

[0048] 2. The expression of JOSD2 protein in the liver tissue of mice in the normal diet group and the high-fat and high-cholesterol diet group was examined by protein immunoblotting.

[0049] like Figure 1 As shown in Figure C, compared with the normal diet group, JOSD2 was significantly downregulated in the liver tissue of mice in the high-fat and high-cholesterol diet group.

[0050] Example 2: PAOA downregulates JOSD2 protein expression in hepatocytes

[0051] 1. PAOA is a classic in vitro MAFLD model inducer. Normal hepatocytes HL7702 were treated with different concentrations of PAOA (0, 0.5, 0.75, 1.0 mM) for 24 h, and the expression of JOSD2 protein was investigated by western blotting.

[0052] The results are as follows Figure 2 As shown in A, PAOA can down-regulate JOSD2 protein expression in a concentration-dependent manner.

[0053] 2. Mouse primary hepatocytes were isolated from mouse liver tissue by collagenase digestion method and treated with different concentrations (0, 0.5, 0.75, 1.0 mM) of PAOA for 24 h. Protein immunoblotting was used to investigate the expression of JOSD2 protein.

[0054] The results are as follows Figure 2 As shown in B, PAOA can also down-regulate the expression of JOSD2 protein in mouse primary hepatocytes in a concentration-dependent manner.

[0055] 3. Normal hepatocytes HL7702 were treated with 1.0 mM PAOA, and the expression of JOSD2 protein was investigated by western blotting at 0 h, 6 h, 12 h and 24 h.

[0056] The results are as follows Figure 2 As shown in Figure C, PAOA can downregulate JOSD2 protein expression in a time-dependent manner. Example 3: Liver-specific knockout of JOSD2 exacerbates the disease progression of the MAFLD model induced by a high-fat, high-cholesterol diet

[0057] 1. JOSD2 conditional knockout mice and ALB-cre mice were hybridized to obtain JOSD2 liver-specific knockout mice. Fluorescence quantitative PCR technology was used to compare the expression of Josd2 gene in different organs and tissues of normal mice and JOSD2 liver-specific knockout mice.

[0058] like Figure 3 As shown in A, the Josd2 gene was specifically knocked out only in mouse liver tissue, indicating that the JOSD2 liver-specific knockout model was successfully constructed.

[0059] 2. Select 8-week-old normal mice and JOSD2 liver-specific knockout mice, feed them with normal diet and high-fat and high-cholesterol diet for 18 weeks, and monitor the weight of mice regularly during this period. At the end of the experiment, the mice were bled from the orbits, dissected, and the livers were obtained and photographed.

[0060] The results are as follows Figure 3 As shown in B and C, liver-specific knockout of JOSD2 can aggravate the disease progression of MAFLD induced by a high-fat, high-cholesterol diet, mainly manifested by excessive accumulation of lipids in the liver, increased body and liver weight, soft liver texture, and earthy yellow color.

[0061] Example 4: Liver-specific knockout of JOSD2 increases ALT, AST, TC, LDLC in mouse serum and TC and TG levels in liver tissue

[0062] 1. The blood of the mice in Example 3 was placed at room temperature for 30 minutes, and serum was obtained by centrifugation. Then, the ALT, AST, TC and LDLC levels in the serum of mice in each group were detected using a kit.

[0063] The results are as follows Figure 4 As shown in AD, liver-specific knockout of JOSD2 significantly increased the levels of ALT, AST, TC and LDLC in the serum of mice.

[0064] 2. Use the kit to detect the TC and TG contents in the liver tissue of each group of mice.

[0065] The results are as follows Figure 4As shown in E and F, liver-specific knockout of JOSD2 can significantly increase the TC and TG contents in mouse liver tissue.

[0066] Example 5: Liver-specific knockout of JOSD2 exacerbates lipid accumulation in liver tissue, promotes the synthesis and uptake of cholesterol and fatty acids, and inhibits fatty acid β-oxidation

[0067] 1. The mouse liver tissue sections in Example 3 were stained with H&E, Oil red O and Sirius red, respectively.

[0068] The results are as follows Figure 5 As shown in A, the liver tissue of the HFHC group mice with liver-specific knockout of JOSD2 showed more obvious vacuoles, increased lipid droplet size and number, and increased collagen content, proving that liver-specific knockout of JOSD2 aggravated the progression of MAFLD induced by a high-fat, high-cholesterol diet.

[0069] 2. The genes related to cholesterol and fatty acid metabolism in the liver tissues of mice in each group were detected by fluorescent quantitative PCR technology.

[0070] The results are as follows Figure 5 As shown in B, liver-specific knockout of JOSD2 significantly downregulated the Cyp7a1 (Cholesterol 7α-hydroxylase) gene and upregulated the Hmgcr (3-Hydroxy-3-methylglutaryl-coenzyme A reductase) gene. The Cyp7a1 gene encodes the rate-limiting enzyme that catalyzes the decomposition of cholesterol into bile acid in the liver, while the Hmgcr gene mediates the synthesis of cholesterol. This indicates that liver-specific knockout of JOSD2 can promote cholesterol synthesis in liver tissue and inhibit its metabolism.

[0071] In addition, liver-specific knockout of JOSD2 increased the expression of fatty acid synthesis genes Fasn (Fatty acidsynthase), Scd1 (stearoyl-CoA desaturase-1), Accα (Acetyl-CoAcarboxylase alpha), Ppar-γ (Peroxisome proliferator-activated receptors gamma), and fatty acid uptake genes Fatp1 (Fatty acid transport protein1), Fabp1 (Fatty acid binding protein 1), Cd36 (Fatty acid translocase CD36) in liver tissue, and inhibited the expression of fatty acid β-oxidation genes Acox1 (Acyl-coenzymeA oxidase 1), Mcad (Medium-chain acyl-coenzyme A dehydrogenase), Cpt-1α (Carnitine palmitoyl transferase 1alpha), indicating that liver-specific knockout of JOSD2 can promote the synthesis and uptake of fatty acids in liver tissue and inhibit fatty acid β-oxidation.

[0072] Example 6: Liver-specific knockout of JOSD2 promotes inflammatory response in mouse liver tissue

[0073] 1. Western blotting was used to detect the activation of the inflammatory signaling pathway IKKβ / NF-κB in the liver tissues of the mice in each group in Example 3.

[0074] The results are as follows Figure 6 As shown in A, liver-specific knockout of JOSD2 significantly increased the expression of p-IKKβ (phosphorylated-IkappaB kinase beta), p-P65 (phosphorylated-NFkappaB subunitp65) and p-IKBα (phosphorylated-NF-kappaB inhibitor alpha) proteins in liver tissue.

[0075] 2. Fluorescence quantitative PCR was used to detect the expression of inflammatory-related genes in the liver tissues of mice in each group.

[0076] The results are as follows Figure 6As shown in B, liver-specific knockout of JOSD2 upregulated the expression of pro-inflammatory genes Il-1β (Interleukin-1beta), Tnfr1 (Tumor necrosis factor receptor-1), Ikkα (IkappaB kinase alpha), Il6 (Interleukin-6), and Tnfα (Tumor necrosis factor alpha), and downregulated the expression of anti-inflammatory gene Il10 (Interleukin-10), indicating that liver-specific knockout of JOSD2 promotes inflammatory response in mouse liver tissue.

[0077] Example 7: Overexpression of JOSD2 can alleviate PAOA-induced hepatocyte lipid accumulation

[0078] Vector and JOSD2 were overexpressed in HL7702 hepatocytes by lentiviral infection, and the overexpression efficiency of JOSD2 was detected by Western blotting. Cells in the Vector group and the JOSD2 overexpression group were treated with 1.0 mM PAOA for 12 h, and then stained with Oil red O.

[0079] The results are as follows Figure 7 As shown, overexpression of JOSD2 can alleviate PAOA-induced lipid accumulation in hepatocytes to a certain extent.

[0080] In summary, the present invention has confirmed the new function of the JOSD2 gene and its encoded protein in MAFLD for the first time through in vitro and in vivo experiments. By constructing a recognized high-fat, high-cholesterol diet-induced MAFLD model, it was found that JOSD2 was significantly downregulated in the liver tissue of MAFLD model mice. It was also found that liver-specific knockout of JOSD2 can increase the accumulation of lipids such as triglycerides in the liver, activate inflammatory pathways in liver tissue, thereby aggravating the process of the MAFLD model induced by high fat and high cholesterol, and overexpression of JOSD2 can alleviate the accumulation of hepatocyte lipids induced by PAOA. The present invention confirms that JOSD2 is a protective factor in MAFLD, and drugs that upregulate JOSD2 expression or enhance its activity can be used to treat MAFLD, providing new targets and new ideas for the treatment of clinical MAFLD and related drug development.

[0081] The above description of the embodiments is a preferred implementation of the present invention, which is to facilitate the understanding and use of the present invention by those skilled in the art, and is not intended to limit the present invention. It is easy for those skilled in the art to make various modifications to these embodiments, and therefore, the present invention is not limited to the above embodiments. Any modifications and improvements made without departing from the scope and principle of the present invention should be within the protection scope of the present invention.

Claims

1. Use of the JOSD2 gene or the protein encoded by it as a target in the preparation of a drug for treating metabolic-related fatty liver disease, characterized in that: The medicine comprises a substance that upregulates JOSD2 gene expression or enhances JOSD2 protein function.

2. The use according to claim 1, characterized in that The metabolic-related fatty liver disease is induced by a high-fat and high-cholesterol diet.

3. The use according to claim 1 or 2, characterized in that: The manifestations of the metabolic-related fatty liver disease include liver enlargement and excessive accumulation of lipids in the liver.

4. The use according to claim 1, characterized in that The metabolism-related fatty liver disease includes one or more of metabolism-related fatty liver hepatitis, liver fibrosis, and liver cirrhosis.

5. The use according to claim 1, characterized in that The coding sequence of the human JOSD2 gene is shown in SEQ ID NO.1, and the amino acid sequence of the encoded protein is shown in SEQ ID NO.2; the coding sequence of the mouse Josd2 gene is shown in SEQ ID NO.3, and the amino acid sequence of the encoded protein is shown in SEQ ID NO.

4.

6. The use according to claim 1, characterized in that The substance that upregulates the expression of the JOSD2 gene is an adenovirus recombinant vector that overexpresses JOSD2, or a compound preparation or Chinese herbal medicine that upregulates the expression of the JOSD2 gene.

7. The use according to claim 1, characterized in that The substance that enhances the function of JOSD2 protein is JOSD2 purified protein or active polypeptide, or a compound preparation or Chinese herbal medicine that enhances the activity of JOSD2 protein.

8. The use according to claim 1, characterized in that The medicament further includes a pharmaceutically acceptable carrier.

9. The use according to claim 8, characterized in that The dosage form of the drug is any one of tablets, granules, solutions, emulsions, suspensions and capsules.

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