WO2023240376A1 - Utilisation de répresseur de récepteurs nucléaires de cellules épithéliales intestinales ncor comme cibles pour le criblage de médicaments - Google Patents

Utilisation de répresseur de récepteurs nucléaires de cellules épithéliales intestinales ncor comme cibles pour le criblage de médicaments Download PDF

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WO2023240376A1
WO2023240376A1 PCT/CN2022/098294 CN2022098294W WO2023240376A1 WO 2023240376 A1 WO2023240376 A1 WO 2023240376A1 CN 2022098294 W CN2022098294 W CN 2022098294W WO 2023240376 A1 WO2023240376 A1 WO 2023240376A1
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ncor
intestinal epithelial
insulin
mice
nuclear receptor
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PCT/CN2022/098294
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Chinese (zh)
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李平平
侯少聪
于恒彩
崔冰
柳星峰
姜茜
孔丽娟
马春晓
赵其锦
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中国医学科学院药物研究所
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells

Definitions

  • the invention belongs to the field of medical technology, relates to the field of genetic engineering technology, and particularly relates to the application of a new target intestinal epithelial cell nuclear receptor inhibitor NCoR for preventing and treating insulin resistance and obesity-related diseases.
  • Diabetes and obesity have become one of the major chronic diseases that threaten the health of urban and rural residents in my country. Their incidence rates are increasing year by year in China and around the world, and they have become a major public health problem. Diabetes is mainly divided into type 1 and type 2 diabetes. Type 1 diabetes is an autoimmune disease. The main reason is the necrosis of pancreatic beta cells and the absolute lack of insulin secretion. The pathogenesis and pathophysiological process of type 2 diabetes are complex and involve polygenic and multi-organ abnormalities. Insulin resistance is the most important pathophysiological defect during the pathogenesis, and obesity and related chronic inflammation are the main causes of insulin resistance. , studies in recent years have shown that intestinal flora is also one of the important influencing factors.
  • TZD insulin sensitizer thiazolidinedione
  • the nuclear receptor inhibitor NCoR is one of the nuclear receptor corepressor proteins.
  • the nuclear receptor superfamily includes peroxisome proliferator receptor PPAR ⁇ , PPAR ⁇ / ⁇ , PPAR ⁇ , farnesoid X receptor FXR and liver X receptor. LXR, etc., are all involved in the regulation of lipid metabolism and inflammatory pathways, and the target of TZD is PPAR ⁇ .
  • corepressor proteins such as NCoR bind to the upstream promoter region of nuclear receptors and inhibit their activity; when ligands bind to the ligand-binding domain LBD, nuclear receptors dissociate from NCoR, etc. , recruiting coactivators to exert their transcriptional regulatory effects.
  • NCoR is widely expressed in many tissues, and its systemic knockout can be fatal. Studies on conditional knockout of NCoR in different tissues have found that although NCoR can interact with a variety of nuclear receptors, in different cells, NCoR knockout will specifically activate certain nuclear receptors to regulate gene transcription. The functions are not the same in different cells.
  • NCoR In adipose tissue [5] , knockout of NCoR can significantly reduce macrophage infiltration and inflammation in adipose tissue of high-fat fed mice through activation of PPAR ⁇ , and improve insulin resistance in insulin target tissues; NCoR in macrophages [7] Conditional knockout of LXR can relieve the inhibition of LXR, activate gene expression of fatty acid synthesis pathway, increase the synthesis of anti-inflammatory fatty acids, inhibit NF- ⁇ B-dependent inflammatory response, thereby improving the overall inflammatory state and increasing insulin sensitivity; while in muscle Tissue [11] , the main effect of NCoR knockout is the activation of PPAR ⁇ and so on.
  • NCoR will also show activation of a specific nuclear receptor after being knocked out in intestinal epithelial cells, and further regulate the absorption and metabolism of nutrients such as lipids, the metabolism of bile acids, and the incretin GLP-1 secretion and composition of intestinal flora, thereby regulating overall insulin sensitivity.
  • the technical problem solved by the present invention is to provide the application of the intestinal epithelial cell nuclear receptor inhibitor NCoR as a target in screening or preparing drugs or biological preparations for preventing, alleviating or treating insulin resistance, obesity and related diseases, thereby providing new solutions for diabetes and obesity. Treatments such as these provide an effective solution.
  • Another technical problem solved by the present invention is to provide an application of an intestinal epithelial cell nuclear receptor inhibitor NCoR in preparing insulin-sensitizing or lipid-lowering mouse models, which is specifically verified at the animal level by knocking out mouse intestinal epithelial cells.
  • NCoR can increase glucose tolerance and clearance, reduce lipid absorption, and promote lipid metabolism and clearance.
  • the first aspect of the technical solution of the present invention is to provide an application of the intestinal epithelial cell nuclear receptor inhibitor NCoR as a target in screening or preparing drugs or biological agents for preventing, alleviating or treating insulin resistance, obesity and related diseases.
  • the insulin resistance, obesity and related diseases are diabetes, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, obesity and glucose intolerance.
  • the biological agent or the drug is used to inhibit the interaction between the nuclear receptor NCoR of intestinal epithelial cells and the nuclear receptor, change the content and composition of bile acids, and reduce the content of lipids such as intestinal triglycerides and cholesterol. Absorption, increase its excretion; promote oxidative metabolism heat production and energy consumption; promote the secretion of incretin GLP-1, regulate insulin secretion and glucose and lipid metabolism pathways.
  • the above-mentioned effects of the biological agent or the drug do not depend on changes in intestinal flora.
  • the nuclear receptors include Lxr, Ppar ⁇ or Fxr.
  • the second aspect of the technical solution of the present invention is to provide the application of an intestinal epithelial cell nuclear receptor inhibitor NCoR in preparing insulin-sensitizing or lipid-lowering mouse models.
  • the inhibition of NCoR includes, but is not limited to, knocking out the gene by genetic recombination through the Cre-LoxP system to obtain an insulin-sensitizing or lipid-lowering mouse model with tissue-specific knockout of NCoR.
  • the insulin-sensitizing or lipid-lowering mouse model with tissue-specific knockout of NCoR can increase glucose tolerance and clearance capacity, reduce lipid absorption capacity, and promote lipid metabolism and clearance capacity.
  • the tissue is selected from intestinal epithelial cells.
  • the third aspect of the technical solution of the present invention is the application of an intestinal epithelial cell nuclear receptor inhibitor NCoR in the preparation of kits for screening drugs or biological agents for preventing, alleviating or treating insulin resistance, obesity and related diseases.
  • the insulin resistance, obesity and related diseases are diabetes, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, obesity and glucose intolerance.
  • the biological agent or the drug is used to inhibit the interaction between the nuclear receptor NCoR of intestinal epithelial cells and the nuclear receptor, change the content and composition of bile acids, and reduce the content of lipids such as intestinal triglycerides and cholesterol. Absorption, increase its excretion; promote oxidative metabolism heat production and energy consumption; promote the secretion of incretin GLP-1, regulate insulin secretion and glucose and lipid metabolism pathways.
  • the above-mentioned effects of the biological agent or the drug do not depend on changes in intestinal flora. Beneficial technical effects:
  • the present invention found that conditionally knocking out the NCoR gene of intestinal epithelial cells in mice to obtain NCoR tissue-specific knockout mice, and then feeding them with a high-fat diet, can significantly reverse the obesity and insulin resistance of the mice. type, reduce body weight, reduce liver and abdominal fat weight, improve oral glucose tolerance and insulin sensitivity, and use the gold standard hyperinsulinemic euglycemic clamp test to evaluate, further accurately proving the overall and target organs such as liver and adipose tissue. Insulin sensitivity was significantly improved.
  • conditional knockout of NCoR in intestinal epithelial cells of mice can also significantly improve hyperinsulinemia and liver lipid accumulation in obese mice, change the content and composition of bile acids, reduce intestinal lipid absorption, and stimulate active pancreatic Secretion of glucagon-like peptide (GLP-1).
  • GLP-1 glucagon-like peptide
  • conditional intestinal epithelial cell NCoR knockout mice by co-raising wild-type mice with conditional intestinal epithelial cell NCoR knockout mice, it was proven that the phenotypic improvement effect of conditional intestinal epithelial cell NCoR knockout is not mediated by intestinal flora. .
  • the inventors discovered for the first time that conditional knockout of NCoR in intestinal epithelial cells can improve overall insulin sensitivity and reduce body weight, indicating that it can be used as a target.
  • By inhibiting the NCoR of intestinal epithelial cells it increases the secretion of the incretin hormone GLP-1, changes the content and composition of bile acids, inhibits intestinal lipid absorption, increases energy metabolic rate, etc., thereby improving lipid metabolism, insulin resistance and obesity. , helps to change the current situation of lack of clinical insulin sensitizers, and has positive significance for the prevention and treatment of type 2 diabetes and obesity.
  • FIG 1 shows the effects of conditional intestinal epithelial cell NCoR knockout of the present invention on body weight and tissue weight
  • A shows wild-type mice (WT mice) and intestinal epithelial cell NCoR knockout mice ( IKO mice);
  • B is the average weekly food intake of WT and IKO mice during high-fat diet feeding;
  • C is the main organs liver and abdominal cavity of WT and IKO mice after high-fat diet feeding The wet weight of fat (WAT) and pancreas (Pancreas);
  • D is the proportion of liver, abdominal fat (WAT) and pancreas (Pancreas) in the body weight of the main organ of WT and IKO mice after feeding with high-fat diet.
  • Figure 2 shows the effect of NCoR knockout in conditional intestinal epithelial cells of the present invention on the insulin sensitivity phenotype of mice fed normal diet and high-fat diet;
  • FIG 3 shows the effects of NCoR knockout in conditional intestinal epithelial cells of the present invention on hormone secretion in high-fat diet-fed mice: A. Fasting insulin levels in WT and IKO mice after high-fat diet feeding and 15-minute blood insulin levels after sugar stimulation; B. Fasting glucose-insulin-stimulating hormone-1 (GLP-1) levels in WT and IKO mice after high-fat diet feeding; C. GLP-1 levels 10 minutes after glucose stimulation in WT and IKO mice after high-fat diet feeding.
  • GLP-1 glucose-insulin-stimulating hormone-1
  • Figure 4 shows the results of a hyperinsulinemic euglycemic clamp experiment to accurately evaluate insulin sensitivity in high-fat diet-fed mice after NCoR knockout in conditional intestinal epithelial cells of the present invention
  • a glucose infusion rate B glucose disposal rate
  • D Inhibition rate of hepatic glucose output by insulin at steady state compared with basal state
  • E Inhibition rate of blood free fatty acid levels by insulin at steady state compared with basal state
  • F Blood insulin levels at basal and steady state.
  • Figure 5 shows the effect of NCoR knockout in conditional intestinal epithelial cells of the present invention on lipid levels in mice fed a high-fat diet; A blood triglyceride level; B blood total cholesterol level; C blood free fatty acid level; D liver glycerol Triglyceride level; E total cholesterol level in liver; F free fatty acid level in liver; G triglyceride level in feces; H total cholesterol level in feces; I free fatty acid level in feces.
  • Figure 6 is a co-house experiment of conditional intestinal epithelial cell NCoR knockout mice and wild-type mice of the present invention
  • A the co-housed group (CO-WT and CO-IKO) after high-fat diet feeding Oral glucose tolerance of mice and mice in separate feeding groups (WT and IKO);
  • B Insulin of mice in co-raising group (CO-WT and CO-IKO) and mice in separate feeding group (WT and IKO) after high-fat diet feeding Tolerance;
  • C Body weight changes of mice in the co-feeding group (CO-WT and CO-IKO) and separate feeding groups (WT and IKO) during high-fat diet feeding;
  • D After high-fat diet feeding in the co-feeding group (CO- Fasting insulin levels and blood insulin levels 10 minutes after glucose stimulation in WT and CO-IKO) mice and in separate rearing groups (WT and IKO) mice.
  • Figure 7 shows the effect of NCoR knockout in conditional intestinal epithelial cells of the present invention on energy metabolism in mice fed a high-fat diet.
  • Figure 8 shows the effect of NCoR knockout in conditional intestinal epithelial cells of the present invention on the bile acid composition of mice fed a high-fat diet.
  • A The composition of bile acids in the blood of WT and IKO mice after feeding with a high-fat diet
  • B The composition of bile acids in the ileum of WT and IKO mice after feeding with a high-fat diet
  • C The composition of bile acids in the feces of WT and IKO mice after feeding with a high-fat diet
  • NCoR flox/flox mice were backcrossed with Villin Cre tool mice for several generations to obtain male homozygous mice (IKO) with conditional knockout of NCoR in intestinal epithelial cells.
  • IKO male homozygous mice
  • NCoR flox mice with corresponding birth dates and genders were selected.
  • /flox mice served as wild-type control mice (WT). There were 10-15 mice in each group of WT and IKO groups. They were fed a high-fat diet (60% of calories came from fat, purchased from Research Diets Company), and changes in body weight and food intake were monitored weekly. After 15 weeks of high-fat diet feeding, the mice were sacrificed, and the liver, abdominal fat, and pancreas were removed and weighed and recorded.
  • NCoR knockout in conditional intestinal epithelial cells has no effect on the body weight of mice fed a normal diet, but can significantly inhibit high-fat diet-induced obesity, and significantly reduce the weight of abdominal fat and liver and their respective proportions in body weight. , it can also significantly increase the proportion of pancreas to body weight; but has no significant effect on the food intake of mice.
  • mice in the WT and IKO groups in Example 1 were fed with the high-fat diet, an oral glucose tolerance test was performed while still being fed with normal feed. After the mice were fasted for 6 hours, blood was taken from the tail tip to measure fasting (0 time) blood glucose, and then glucose solution (2g/kg) was administered intragastrically at 15 minutes, 30 minutes, 60 minutes and 120 minutes after glucose stimulation. Take blood to measure blood sugar level. At the 9th week of high-fat diet feeding, an oral glucose tolerance test was conducted with the same method as above. At the 10th week of high-fat diet feeding, an insulin tolerance test was conducted.
  • mice After the mice were fasted for 6 hours, blood was taken from the tail tip to measure fasting (0 time) blood glucose, and then insulin (0.3 U/kg) was injected subcutaneously at the tail tip 15 minutes, 30 minutes, 60 minutes and 120 minutes after insulin injection. Take blood to measure blood sugar level.
  • conditional knockout of NCoR in intestinal epithelial cells had no effect on glucose tolerance in mice fed a normal diet, but could significantly improve glucose tolerance and insulin sensitivity abnormalities caused by high-fat diet feeding.
  • Example 3 Effects of NCoR knockout in conditional intestinal epithelial cells on insulin and glucoinsulin-stimulating hormone
  • Example 1 In the 11th week of high-fat feeding, the WT and IKO mice in Example 1 were fasted for 6 hours. Blood was collected from the tail tip, placed on ice, and glucose solution (2g/kg) was administered orally. Collect blood from the tip of the tail and place on ice. Centrifuge at 12,000 rpm for 1 min, aspirate the supernatant, and measure blood insulin levels using Alpco mouse insulin ELISA kit.
  • the WT and IKO mice in Example 1 were fasted for 6 hours, and sitagliptin (25 mg/kg, DPP4 enzyme inhibitor) was administered intragastrically at 5.25 hours after fasting.
  • Glucose solution (2g/kg) was administered intragastrically every hour.
  • Blood was collected from the tail tip 15 minutes after glucose stimulation and placed in a centrifuge tube with EDTA anticoagulant and protease inhibitor added in advance. Place it on ice and centrifuge at 1000g for 10 minutes at 4 degrees. , draw the supernatant, and use Alpco's mouse active GLP-1 ELISA kit to measure blood active GLP-1 levels.
  • the WT and IKO mice in Example 1 were fasted for 4 hours, anesthetized with carbon dioxide, and the thorax and heart were opened to collect blood. In the blood vessel, centrifuge at 1000g and 4 degrees for 20 minutes, aspirate the supernatant, and use the Alpco mouse active GLP-1 ELISA kit to measure the blood active GLP-1 level.
  • conditional intestinal epithelial cell NCoR knockout can significantly improve hyperinsulinemia caused by high-fat diet and obesity, and significantly increase the levels of active intestinal insulin hormone GLP-1 after fasting and 15 minutes of sugar stimulation, indicating that NCoR Knockout can promote insulin secretion and improve insulin sensitivity by increasing the level of GLP-1.
  • Example 4 Precise evaluation of the effect of NCoR knockout on insulin sensitivity in conditional intestinal epithelial cells
  • the glucose infusion rate at this time is the GIR
  • the blood sample at the steady state is taken.
  • use the steele formula to calculate the hepatic glucose output HGP at the basal state and steady state and calculate the inhibition rate, glucose disposal rate GDR, and the main response muscles Insulin-stimulated glucose disposal rate of glucose uptake rate IS-GDR.
  • Blood free fatty acid FFA and blood insulin levels were measured at basal and steady states, and the inhibition rate of insulin on free fatty acid levels, which mainly reflects the insulin sensitivity of adipose tissue, was calculated.
  • conditional intestinal epithelial cell NCoR knockout can significantly increase the glucose infusion rate GIR, glucose disposal rate GDR and exogenous insulin in the IKO group of mice compared with WT mice.
  • the inhibition rate of glucose output and the inhibition rate of free fatty acids, while the insulin-stimulated glucose disposal rate IS-GDR, which reflects muscle insulin sensitivity, has an increasing trend, but there is no significant difference, indicating that conditional intestinal epithelial cell NCoR knockout It can significantly improve the insulin sensitivity of mice overall and in liver and adipose tissue.
  • Example 5 Effects of conditional intestinal epithelial cell NCoR knockout on lipid levels, etc.
  • the WT and IKO mice in Example 1 were sacrificed after being fed a high-fat diet for 15 weeks, and blood was taken from the heart.
  • the total triglyceride (TG) and total cholesterol (TC) kits of Zhongsheng Beikong Company were used to measure the blood levels.
  • the contents of TG and TC were measured using the NEFA kit from Wako Company to determine the level of free fatty acids (FFA) in the blood.
  • Example 1 After the WT and IKO mice in Example 1 were fed a high-fat diet for 15 weeks, they were sacrificed and their livers were removed and cryopreserved. After grinding and homogenizing small pieces of tissue, the corresponding lipid levels were measured using the aforementioned TG, TC and FFA kits.
  • each mouse was raised in a single cage, and the feces collected for 24 hours was dried at 60 degrees and methanol:chloroform (1:2, V/V ), extract at 37 degrees for 12 hours, take the supernatant, evaporate to dryness again, and redissolve the precipitate by adding 10% TritonX-100 isopropyl alcohol solution.
  • the corresponding lipid levels were determined using the aforementioned TG, TC and FFA kits.
  • conditional intestinal epithelial cell NCoR knockout can significantly reduce the blood triglyceride and total cholesterol levels of IKO group mice compared with the WT group of mice, but has no significant effect on blood free fatty acid levels. Influence. Liver triglyceride, total cholesterol and free fatty acid contents in the IKO group were also significantly reduced, indicating that conditional intestinal epithelial cell NCoR knockout can also significantly improve liver lipid accumulation caused by high-fat diet and obesity.
  • conditional intestinal epithelial cell NCoR knockout may inhibit intestinal lipid absorption, thereby reducing weight, improve obesity, etc.
  • Another batch of WT and IKO mice obtained by the method in Example 1 were divided into 4 groups from the beginning of weaning.
  • the WT and IKO groups were raised separately according to genotype from the beginning of weaning after 3 weeks of age.
  • the CO-WT and CO-IKO groups were mixed and raised starting from weaning at 3 weeks of age, so as to compare the phenotypic differences between different groups to determine the intestinal flora in conditional intestinal epithelial cell NCoR knockout mice. role in phenotype.
  • the mice were fed a high-fat diet for 10 weeks, and an oral glucose tolerance test was performed. The method was the same as in Example 2. In the 12th week of high-fat diet feeding, an insulin tolerance test was conducted, and the method was the same as in Example 2.
  • Example 7 Effects of conditional intestinal epithelial cell NCoR knockout on energy metabolism in high-fat diet-fed mice.
  • Example 8 Effects of conditional intestinal epithelial cell NCoR knockout on bile acid composition in high-fat diet-fed mice.
  • mice in Example 1 were fed a high-fat diet for 15 weeks, the mice were sacrificed, feces, ileal mucosal tissue and blood samples were collected. After bile acid extraction, the UPLC/Synapt G2-Si QTOF MS system was used to determine its content concentration. .

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Abstract

La présente invention se rapporte au domaine technique des médicaments et au domaine technique du génie génétique, en particulier à l'utilisation d'un répresseur de récepteurs nucléaires de cellules épithéliales intestinales NCoR comme nouvelle cible pour prévenir et traiter la résistance à l'insuline et les maladies liées à l'obésité. L'invention concerne l'utilisation d'un répresseur de récepteurs nucléaires de cellules épithéliales intestinales NCoR comme cible pour le criblage de médicaments L'utilisation concerne plus particulièrement l'utilisation d'un répresseur de récepteurs nucléaires de cellules épithéliales intestinales NCoR comme cible dans le criblage ou la préparation d'un médicament ou d'une préparation biologique pour prévenir, soulager ou traiter la résistance à l'insuline, l'obésité et les maladies associées. L'invention concerne également l'utilisation du répresseur de récepteurs nucléaires des cellules épithéliales intestinales NCoR dans la préparation d'un modèle murin pour la sensibilisation à l'insuline ou l'hypolipidémie.
PCT/CN2022/098294 2022-06-12 2022-06-12 Utilisation de répresseur de récepteurs nucléaires de cellules épithéliales intestinales ncor comme cibles pour le criblage de médicaments WO2023240376A1 (fr)

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US20160376279A1 (en) * 2014-03-13 2016-12-29 Salk Institute For Biological Studies Fxr agonists and methods for making and using
CN114617965A (zh) * 2020-12-10 2022-06-14 中国医学科学院药物研究所 肠道上皮细胞核受体抑制子NCoR作为靶标在筛选药物中的应用

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GB0127132D0 (en) * 2001-11-12 2002-01-02 Karobio Ab Assay
WO2009024550A1 (fr) * 2007-08-20 2009-02-26 N.V. Organon Dérivés de n-benzyl, n'-arylcarbonylpipérazine
WO2009143705A1 (fr) * 2008-05-30 2009-12-03 国鼎生物科技股份有限公司 Procédé de criblage pour des antagonistes des récepteurs hépatiques x et son application
US20160376279A1 (en) * 2014-03-13 2016-12-29 Salk Institute For Biological Studies Fxr agonists and methods for making and using
CN114617965A (zh) * 2020-12-10 2022-06-14 中国医学科学院药物研究所 肠道上皮细胞核受体抑制子NCoR作为靶标在筛选药物中的应用

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PINGPING LI; WUQIANG FAN; JIANFENG XU; MIN LU; HIROYASU YAMAMOTO; JOHAN AUWERX; DOROTHYD. SEARS; SASWATA TALUKDAR; DAYOUNG OH; AI : "Adipocyte NCoR Knockout Decreases PPAR Phosphorylation and Enhances PPAR Activity and Insulin Sensitivity", CELL, ELSEVIER, AMSTERDAM NL, vol. 147, no. 4, 23 September 2011 (2011-09-23), Amsterdam NL , pages 815 - 826, XP028109267, ISSN: 0092-8674, DOI: 10.1016/j.cell.2011.09.050 *
SUNGSOON FANG, SUH JAE MYOUNG, REILLY SHANNON M, YU ELIZABETH, OSBORN OLIVIA, LACKEY DENISE, YOSHIHARA EIJI, PERINO ALESSIA, JACIN: "Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance", NATURE MEDICINE, NATURE PUBLISHING GROUP US, NEW YORK, vol. 21, no. 2, 5 January 2015 (2015-01-05), New York, pages 159 - 165, XP055404392, ISSN: 1078-8956, DOI: 10.1038/nm.3760 *

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