WO2023101316A1 - Composition pour la prévention ou le traitement de la stéatose, comprenant axl - Google Patents

Composition pour la prévention ou le traitement de la stéatose, comprenant axl Download PDF

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Publication number
WO2023101316A1
WO2023101316A1 PCT/KR2022/018680 KR2022018680W WO2023101316A1 WO 2023101316 A1 WO2023101316 A1 WO 2023101316A1 KR 2022018680 W KR2022018680 W KR 2022018680W WO 2023101316 A1 WO2023101316 A1 WO 2023101316A1
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axl
protein
composition
gene
metabolic diseases
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PCT/KR2022/018680
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English (en)
Korean (ko)
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박종선
이현지
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충남대학교산학협력단
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Publication of WO2023101316A1 publication Critical patent/WO2023101316A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/08—Hepato-biliairy disorders other than hepatitis
    • G01N2800/085—Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin

Definitions

  • the present invention relates to a composition for preventing or treating fatty liver comprising an AXL protein or gene as an active ingredient.
  • Fatty liver refers to a state in which fat is accumulated in hepatocytes, and the proportion of fat in a normal liver is about 5%.
  • fatty liver gets worse and the fat mass inside the liver cells grows, the important components of the cells, including the nucleus, are pushed to one side and the function of the liver cells deteriorates. As a result, the circulation of blood and lymph in the liver is impaired. When this happens, liver cells cannot receive oxygen and nutrients properly, and liver function deteriorates.
  • Fatty liver can be divided into alcoholic fatty liver and non-alcoholic fatty liver.
  • Alcoholic fatty liver is caused by alcohol. The more alcohol you drink, the more likely it occurs, and if you continue to drink alcohol, the ability of the liver to metabolize alcohol decreases, making fatty liver more severe. It also occurs in cases of poor nutritional status. Some alcoholic fatty livers can progress to alcoholic hepatitis and cirrhosis, leading to death.
  • Non-alcoholic fatty liver is a case of increased fat accumulation in the liver (exceeding 5% of hepatocytes), regardless of alcohol or viral infection, and is caused by increased fat synthesis and excretion in the liver. About 59% of non-alcoholic fatty liver patients caused by an imbalance between input and output of free fatty acids are caused by increased absorption of free fatty acids from the outside, and about 26% of patients are intrahepatic. It is known to be caused by an increase in the input of free fatty acids due to an increase in fat biosynthesis.
  • AXL is a receptor tyrosine kinase (RTX), whose name is derived from the Greek word meaning 'uncontrolled'.
  • RTX receptor tyrosine kinase
  • AXL protein regulates biological processes such as intracellular signal transduction, cytoskeletal function and gene expression, and is known to be expressed in platelets, monocytes, liver, hippocampus and cerebellum. or its mechanism is unknown.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases comprising an AXL protein or a polynucleotide encoding the AXL protein.
  • Another object of the present invention is to provide a method for inhibiting fat biosynthesis in the liver by administering an AXL protein or a vector containing a polynucleotide encoding the AXL protein to a non-human animal.
  • Another object of the present invention is to provide a method for treating metabolic diseases comprising administering the pharmaceutical composition described above to a subject.
  • Another object of the present invention is to provide a composition for diagnosing metabolic diseases comprising a substance for measuring the level of AXL gene or AXL protein.
  • Another object of the present invention is to provide an information providing method for diagnosing a metabolic disease comprising measuring the level of AXL gene or AXL protein.
  • Another object of the present invention relates to a method for screening a therapeutic agent for metabolic diseases, comprising the step of selecting a substance that increases the expression or activity level of AXL in a subject.
  • the present inventors confirmed that the expression of a gene related to fat synthesis in liver tissue increases when a high-fat diet is performed in an animal model in which AXL expression is suppressed.
  • the present invention relates to a pharmaceutical composition for preventing or treating a metabolic disease comprising an AXL protein or a polynucleotide encoding the AXL protein, and a composition for diagnosing a metabolic disease comprising an agent for measuring the level of AXL.
  • One aspect of the present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases, comprising an AXL protein or a vector containing a polynucleotide encoding the AXL protein as an active ingredient.
  • prevention refers to any action that suppresses or delays the onset of metabolic diseases by administration of the pharmaceutical composition according to the present invention.
  • treatment refers to all activities in which symptoms of metabolic diseases are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
  • Metabolic diseases which are diseases to be prevented or treated by the composition of the present invention, are obesity, type 2 diabetes, dyslipidemia, insulin resistance, hepatic steatosis and/or fatty liver, specifically non-alcoholic fatty liver disease. Hepatic steatosis or non-alcoholic fatty liver, specifically, non-alcoholic fatty liver induced by a high fat diet is more preferable, but is not limited thereto.
  • composition of the present invention provides a therapeutic agent for metabolic diseases targeting AXL as part of gene-targeted therapy.
  • the AXL gene is a receptor tyrosine kinase (RTX), and its name is derived from the Greek word meaning 'uncontrolled'.
  • the AXL protein is a protein encoded by the AXL gene and is also called AXL receptor tyrosine kinase.
  • the AXL protein described above regulates biological processes such as intracellular signal transduction, cytoskeletal function, and gene expression, and is known to be expressed in platelets, monocytes, liver, hippocampus, and cerebellum, but treatment of fatty liver through promotion of AXL expression or activity. None has been reported about it yet.
  • the nucleotide sequence of the AXL gene is shown in SEQ ID NO: 1 or 2.
  • the nucleotide sequence of the gene is registered in the gene bank (Gene ID: BC058230.1), those skilled in the art will be able to easily obtain it.
  • amino acid sequence of the AXL protein may be represented by SEQ ID NO: 3 or 4, but is not limited thereto.
  • AXL protein according to the present invention includes a protein having the amino acid sequence of SEQ ID NO: 3 or 4 and functional equivalents of the protein.
  • “Functional equivalent” means at least 70% or more, preferably 80% or more, more preferably 90% or more, even more preferably, the amino acid sequence of SEQ ID NO: 3 or 4 as a result of addition, substitution or deletion of amino acids. has a sequence homology of 95% or more, and refers to a protein exhibiting substantially the same physiological activity as the protein having the amino acid sequence of SEQ ID NO: 3 or 4.
  • “Substantially homogeneous physiological activity” means preventive or therapeutic activity of metabolic diseases.
  • the vector containing the polynucleotide encoding the AXL protein may be a recombinant viral vector, a plasmid vector, a cosmid vector or a bacteriophage vector, preferably a recombinant viral vector, but is not limited thereto.
  • the recombinant virus may be adenovirus, adeno-associated virus, retrovirus, herpes simplex virus, and/or lentivirus, preferably adenovirus, but is not limited thereto.
  • the AXL protein or the polynucleotide encoding the AXL protein has an effect of inhibiting fat biosynthesis in the liver.
  • the pharmaceutical composition according to the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient.
  • the pharmaceutically acceptable carrier is one commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto.
  • lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like may be further included.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) depending on the desired method, and the dosage is the patient's condition and weight, the degree of disease , Depending on the drug form, administration route and time, it can be appropriately selected by those skilled in the art.
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and an effective amount is a patient's disease type, severity, drug activity, drug sensitivity, time of administration, route of administration and excretion rate, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, body weight, absorption rate, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and concomitant drugs, and in general, body weight 0.001 to 150 mg per 1 kg, preferably 0.01 to 100 mg may be administered daily or every other day, or divided into 1 to 3 times a day.
  • body weight 0.001 to 150 mg per 1 kg, preferably 0.01 to 100 mg may be administered daily or every other day, or divided into 1 to 3 times a day.
  • the dosage is not limited to the scope of the present invention in any way.
  • Another aspect of the present invention relates to a method of inhibiting fat biosynthesis in the liver by administering an AXL protein or a vector containing a polynucleotide encoding the AXL protein to a non-human animal.
  • the method of the present invention uses the above-described AXL protein or a vector containing the polynucleotide encoding the AXL protein, descriptions of overlapping contents with those described above are omitted to avoid excessive complexity in the present specification.
  • Another aspect of the present invention relates to a method for treating a metabolic disease comprising administering the aforementioned pharmaceutical composition to a subject.
  • the "individual” means a subject in need of treatment of a disease, and more specifically, means a mammal such as a human or non-human primate, mouse, dog, cat, horse, and cow.
  • Another aspect of the present invention relates to a composition for diagnosing metabolic diseases, including a substance for measuring the level of AXL gene or AXL protein.
  • diagnosis means the action of confirming the presence or characteristics of a pathological state, that is, a metabolic disease, by administration of the composition according to the present invention.
  • the material for measuring the level of the AXL gene may be a primer or probe capable of amplifying the AXL gene, and the material for measuring the level of the AXL protein may be an antibody that specifically recognizes the AXL protein, Any agent capable of measuring the expression or activity level of a gene may be included without limitation.
  • a "primer” is a nucleic acid sequence having a short free 3-terminal hydroxyl group, which can form base pairs with a complementary template and refers to a short nucleic acid sequence that functions as a starting point for template strand copying.
  • a primer can initiate DNA synthesis in the presence of a reagent for polymerization (i.e., DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates in an appropriate buffer and temperature.
  • probe refers to a nucleic acid fragment such as RNA or DNA corresponding to a few bases to several hundred bases in length that can form a specific binding with mRNA, and is labeled to detect the presence or absence of a specific mRNA. You can check.
  • the probe may be manufactured in the form of an oligonucleotide probe, a single stranded DNA probe, a double stranded DNA probe, an RNA probe, or the like. Selection of suitable probes and hybridization conditions can be modified based on those known in the art.
  • antibody means a specific protein molecule directed against an antigenic site.
  • an antibody means an antibody that specifically binds to a marker protein, and includes both polyclonal antibodies, monoclonal antibodies and recombinant antibodies.
  • nucleic acid sequences of the genes of the present invention are registered in the gene bank, those skilled in the art can design antisense oligonucleotides, primer pairs, or probes that specifically amplify specific regions of these genes based on the sequences.
  • Antisense oligonucleotides, primers or probes of the present invention can be chemically synthesized using the phosphoramidite solid support method, or other well-known methods. Such nucleic acid sequences can also be modified using a number of means known in the art. Non-limiting examples of such modifications include methylation, capping, substitution of one or more natural nucleotides with homologues, and modifications between nucleotides, such as uncharged linkages such as methyl phosphonates, phosphotriesters, phosphoro amidates, carbamates, etc.) or to charged linkages (eg phosphorothioates, phosphorodithioates, etc.).
  • Another aspect of the present invention relates to an information providing method for diagnosing a metabolic disease comprising the following steps.
  • the expression level or the amount of protein of the AXL gene is decreased compared to the expression level or protein level of the normal control group, it can be determined that a metabolic disease, specifically, fatty liver has progressed.
  • the method includes mammals, particularly humans.
  • the human includes a person suspected or not suspected of having a metabolic disease and a person in need of a diagnosis of a metabolic disease.
  • the “biological sample” may consist of tissues, cells, blood, serum, plasma, saliva and urine, but is not limited thereto.
  • the sample may be pretreated before being used for detection, and may include, for example, filtration, distillation, extraction, concentration, inactivation of interfering components, addition of reagents, and the like.
  • nucleic acids and proteins may be separated from the sample and used for detection.
  • RT-PCR reverse transcription polymerase reaction
  • Competitive RTPCR competitive reverse transcription polymerase reaction
  • Realtime RT-PCR real-time reverse transcription polymerase reaction
  • RPA RNase protection assay
  • measurement of protein expression level is a process of confirming the presence and expression level of the protein expressed from the gene of the present invention in liver tissue cells in order to confirm the progress of metabolic disease, and is performed by measuring the amount of protein.
  • Analysis methods for this include Western blot, enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA), radioimmunodiffusion, Ouchterlony immunodiffusion method, rocket immunoelectrophoresis , tissue immunostaining, immunoprecipitation assay, complement fixation assay, flow cytometry (Fluorescence Activated Cell Sorter, FACS), protein chip, etc., but are not limited thereto.
  • Another aspect of the present invention relates to a method for screening a therapeutic agent for metabolic diseases, comprising the step of selecting a substance that increases the expression or activity level of an AXL protein or a gene encoding the AXL protein in a subject.
  • the expression or activity level of the AXL protein or the gene encoding the same when the expression or activity level of the AXL protein or the gene encoding the same is measured in the subject and the candidate for treatment of metabolic disease is administered, the expression or activity level of the AXL protein or the gene encoding the same is increased compared to the previous candidate.
  • the substance can be used as a therapeutic agent for metabolic diseases.
  • the method may measure the expression or activity level of the AXL protein or the gene encoding the AXL protein in the individual before treating the subject with the target material and measure and compare it after the treatment, or treat some of the subjects with the target material to compare the target material to the control group. The degree of expression or activity can also be compared.
  • the step of measuring the level of expression or activity of the AXL protein or the gene encoding it is polymerase reaction (PCR), reverse transcription polymerase reaction (RT-PCR), competitive reverse transcription polymerase reaction (Competitive RT-PCR), real-time reverse transcription polymerization Enzyme reaction (Realtime RT-PCR), RNase protection assay (RPA; Northern blotting), DNA chip, Western blotting, ELISA (enzyme linked immunosorbent assay), radioimmunoassay (Radioimmunoassay, RIA), radioimmunodiffusion, Ouchterlony immunodiffusion, rocket immunoelectrophoresis, immunoprecipitation assay, complement fixation assay, protein chip , and can be measured by one or more methods selected from the group consisting of in vitro kinase assay (IKKB), but is not limited thereto.
  • IKKB in vitro kinase assay
  • a method of treating the target substance to the subject is not particularly limited, and for example, a biological sample obtained from the subject may be treated.
  • the biological sample may be any of the samples described above.
  • target substance means an unknown substance used in screening to examine whether or not it affects the expression or activity level of AXL of the present invention.
  • the target substance includes, but is not limited to, chemicals, nucleotides, antisense-RNA, siRNA (small interference RNA) and natural product extracts.
  • the present invention relates to a composition for preventing or treating fatty liver, a composition for diagnosis, and a method for providing information for diagnosis.
  • a composition for preventing or treating fatty liver a composition for diagnosis
  • a method for providing information for diagnosis By regulating the expression and activity of AXL, the marker of the present invention, it is expected to be useful for the development of a therapeutic agent for fatty liver.
  • FIG. 1a shows the size (FIG. 1a), body weight (FIG. 1b) and food intake of AXL knockout mice when fed with a high-fat diet (HFD) or normal diet (NCD) according to an embodiment of the present invention.
  • Figure 2 is a diagram confirming the effect of AXL knockout on the size and mass of the liver of mice when fed a high-fat diet (HFD) or normal diet (NCD) according to an embodiment of the present invention.
  • HFD high-fat diet
  • NCD normal diet
  • Figure 3 is a diagram confirming the effect of AXL knockout on the size and mass of subcutaneous white adipose tissue of mice when fed with a high-fat diet (HFD) or normal diet (NCD) according to an embodiment of the present invention.
  • HFD high-fat diet
  • NCD normal diet
  • FIG. 4a to 4c are glucose tolerance (FIG. 4a), insulin tolerance (FIG. 4b) and fasting blood glucose/serum insulin levels of AXL knockout mice when fed a high-fat diet (HFD) according to an embodiment of the present invention.
  • FIGs 5a and 5b show, according to an embodiment of the present invention, AXL knockout during high-fat diet (HFD) feeding the liver (Fig. 5a) and subcutaneous white adipose tissue (Fig. 5b) of fat biosynthesis-related proteins ( It is a diagram confirming the effect on ACC, FAS, PPARr and SREBP1c) levels.
  • the present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases, including an AXL protein or a vector containing a polynucleotide encoding the AXL protein.
  • Example 1 High fat diet Axl Determination of the possibility of developing obesity and/or hepatic steatosis in knockout mice
  • Axl wild type mice and Axl knockout (KO) mice (Axl -/- ) mice (C57BL/6) were provided and used by Professor Jeon Tae-hoon's lab at Korea University. Mice were housed in a controlled environment (12/12h light/dark cycle; humidity 50-60%; ambient temperature 22 °C). All mouse experiments were performed in a facility in accordance with institutional guidelines, and the experimental protocols were conducted by Korea Research Institute of Bioscience and Biotechnology and Chungnam. It was approved by the University Institutional Review Board.
  • mice fed the high-fat diet (HFD) or normal diet (NCD) were sacrificed at the 17th week of feeding, and the liver (FIG. 2) and subcutaneous white adipose tissue (SWAT) ( The size and mass of Fig. 3) were confirmed.
  • HFD high-fat diet
  • NCD normal diet
  • SWAT subcutaneous white adipose tissue
  • Axl KO mice fed a normal diet showed similar body weight compared to WT mice (littermates) fed the same diet.
  • WT mice littermates
  • HFD high-fat diet
  • HFD high-fat diet
  • HFD high-fat diet
  • mice Seven-week-old WT and Axl KO mice (C57BL/6) were fed a high-fat diet (HFD) with 60% of calories from fat (D12492) and sacrificed at 26 weeks of feeding.
  • HFD high-fat diet
  • ACC, FAS, PPARr and SREBP1c in liver and subcutaneous white adipose tissue (sWAT) were confirmed using Western blot.
  • Anti-pACC(S79), anti-ACC, anti-FAS, anti-PPAR ⁇ , anti-SREBP1c antibody or anti-GAPDH antibody were used as primary antibodies, and HRP conjugated anti-mouse IgG antibodies were used as secondary antibodies.
  • GAPDH was selected as a control group for comparing protein expression.
  • anti-pACC S79
  • anti-ACC anti-FAS and anti-GAPDH antibodies
  • anti-PPAR ⁇ and anti-SREBP1c antibodies were obtained from Santa Cruz Biotechnology (USA)
  • HRP Conjugated anti-mouse IgG antibodies were obtained from Koma biotech (Korea).
  • liver and subcutaneous white adipose tissue were collected and fixed in 4% paraformaldehyde overnight at 4°C. Fixed samples were embedded in paraffin, cut into 5 m sections and mounted on slides to create a series of 6 slides with similar adjacent sections. One slide of each series was stained with H&E (hematoxylin & eosin).
  • the present invention relates to a composition for preventing or treating fatty liver comprising an AXL protein or gene as an active ingredient.

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Abstract

La présente invention concerne une composition pour prévenir ou traiter la stéatose, une composition de diagnostic, et un procédé de fourniture d'informations pour le diagnostic. L'expression et l'activité d'AXL, qui est un marqueur de la présente invention, sont régulées, et il est ainsi attendu qu'AXL soit efficacement utilisé dans le développement d'un agent thérapeutique contre la stéatose.
PCT/KR2022/018680 2021-11-30 2022-11-24 Composition pour la prévention ou le traitement de la stéatose, comprenant axl WO2023101316A1 (fr)

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KR1020210167877A KR20230080560A (ko) 2021-11-30 2021-11-30 Axl을 포함하는 지방간 예방 또는 치료용 조성물
KR10-2021-0167877 2021-11-30

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030157573A1 (en) * 2002-02-12 2003-08-21 Orna Mor Use of Axl receptor for diagnosis and treatment of renal disease
KR20170134641A (ko) * 2015-04-10 2017-12-06 샤카이후쿠시호진 온시자이단사이세이카이 간 질환의 병태를 판별하는 방법

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Publication number Priority date Publication date Assignee Title
KR101925020B1 (ko) 2017-04-21 2018-12-04 연세대학교 산학협력단 Mkrn1의 발현 또는 활성 억제제를 유효성분으로 함유하는, 대사성 질환의 예방 및 치료용 약학적 조성물

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030157573A1 (en) * 2002-02-12 2003-08-21 Orna Mor Use of Axl receptor for diagnosis and treatment of renal disease
KR20170134641A (ko) * 2015-04-10 2017-12-06 샤카이후쿠시호진 온시자이단사이세이카이 간 질환의 병태를 판별하는 방법

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BHAVE SAYALI, HO HAN KIAT: "Exploring the Gamut of Receptor Tyrosine Kinases for Their Promise in the Management of Non-Alcoholic Fatty Liver Disease", BIOMEDICINES, vol. 9, no. 12, pages 1776, XP093070510, DOI: 10.3390/biomedicines9121776 *
LEE HYUN-JI: "The role and function ofAXL, a new target of obese fatty liver", CHUNGNAM NATIONAL UNIVERSITY HOSPITAL NEWSLETTER - HAPPY KEEPER, 1 January 2021 (2021-01-01), XP093070508, Retrieved from the Internet <URL:http://webzine.cnuh.co.kr/2021/07/sec3/study> *
TUTUSAUS ANNA, DE GREGORIO ESTEFANÍA, CUCARULL BLANCA, CRISTÓBAL HELENA, ARESTÉ CRISTINA, GRAUPERA ISABEL, COLL MAR, COLELL ANNA, : "A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target", CMGH CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, vol. 9, no. 3, 1 January 2020 (2020-01-01), pages 349 - 368, XP093070513, ISSN: 2352-345X, DOI: 10.1016/j.jcmgh.2019.10.010 *
ZHU CHENJING, WEI YUQUAN, WEI XIAWEI: "AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications", MOLECULAR CANCER, BMC, vol. 18, no. 1, 1 December 2019 (2019-12-01), pages 153, XP093013311, DOI: 10.1186/s12943-019-1090-3 *

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