CN-121971617-A - Use of knockdown or inhibition of intestinal epithelial Ufbp gene expression in the preparation of a medicament for the prevention and/or treatment of obesity

Abstract

An application of knocking out or inhibiting intestinal epithelial Ufbp gene expression in preparing a medicament for preventing and/or treating obesity belongs to the technical field of biological medicines. Aiming at the problems of limited effect, multiple side effects and the like of the existing obesity treatment means, the invention provides Ufbp for the first time that intestinal epithelial cell specific expression is a new anti-obesity intervention target. By knocking out or inhibiting intestinal epithelium Ufbp, it is effective against weight gain induced by high fat diet, adipose tissue accumulation, hyperlipidemia, hepatic steatosis and insulin resistance. The action mechanism is related to influencing the secretion of intestinal apolipoprotein ApoB48/ApoA1, and further regulating and controlling the whole body lipid metabolism. The invention provides definite targets and theoretical basis for developing novel anti-obesity therapies such as small molecule inhibitors, nucleic acid drugs and the like targeting intestinal epithelium Ufbp, and has important clinical transformation prospect.

Inventors

• XU HONG
• WANG YAQUN
• GONG CHENGXIN
• DU YUE
• XIA QING
• Xiong Chaopeng

Assignees

• 南昌大学

Dates

Publication Date

20260505

Application Date

20260206

Claims (5)

1. 1. Use of a substance that knocks out or inhibits intestinal epithelial cell Ufbp gene expression or protein activity in the manufacture of a medicament for the prevention and/or treatment of obesity.
2. 2. The use according to claim 1, wherein the obesity is diet-induced obesity.
3. 3. The use according to claim 2, wherein the diet-induced obesity is high fat diet-induced obesity.
4. 4. The use according to claim 1, wherein the substance is selected from the group consisting of CRISPR/Cas9 gene editing system for Ufbp gene, shRNA, siRNA, antisense oligonucleotide, small molecule inhibitor, neutralizing antibody or a combination thereof.
5. 5. A method of screening for a drug candidate for the prevention and/or treatment of obesity, comprising: a) Testing candidate substances for their effect on Ufbp gene expression or protein activity in an intestinal epithelial cell model or animal model; b) Assessing whether the model of Ufbp1 that is effectively knocked down or inhibited in step a) exhibits a phenotype that is resistant to one or more of high fat diet-induced weight gain, reduced fat accumulation, reduced blood lipid levels, reduced liver steatosis, improved insulin sensitivity; c) If the candidate agent is effective in inhibiting Ufbp a and eliciting phenotype b), the candidate agent is determined to be potentially useful in the prevention and/or treatment of obesity.

Description

Use of knockdown or inhibition of intestinal epithelial Ufbp gene expression in the preparation of a medicament for the prevention and/or treatment of obesity Technical Field The invention relates to the technical field of biological medicines, in particular to a molecular target for preventing and/or treating obesity and related metabolic disorders, and more particularly relates to application of intestinal epithelial cell specific protein Ufbp (Ufl 1 binding protein 1, also called DDRGK 1) in preparing a medicament for preventing and/or treating obesity. Background Obesity and its induced metabolic syndrome such as type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease, etc. have become global significant public health challenges. Current treatments for obesity mainly include lifestyle interventions, drug therapies and metabolic surgery. The traditional medicine such as GLP-1 receptor agonist has certain effects, but has the problems of side effects, high cost, rebound weight after stopping taking, and the like, and the metabolic surgery has remarkable curative effect, but has high invasiveness, high risk and limited application range. Therefore, the development of a safer and more effective anti-obesity strategy based on new targets has urgent clinical needs and important scientific value. Ufbp 1A key linker protein in UFM1 (ubiquitin-like modified protein 1) binding system discovered in recent years forms a core complex of UFM1 modification (UFMylation) together with E3 ligase Ufl1, and is involved in processes such as maintenance of Endoplasmic Reticulum (ER) homeostasis, protein quality control and the like. Ufbp 1A has been reported to play an important role in hematopoietic development, tumorigenesis and inflammatory bowel disease, but its function in the body's energy metabolism balance, in particular in intestinal lipid absorption and transport and systemic obesity regulation has not been elucidated heretofore. Recent studies have revealed that the gut is a key site for dietary lipid absorption and chylomicron assembly. Dietary fat re-esterifies in intestinal epithelial cells and combines with apolipoproteins (e.g. ApoB48, apoA 1) to form chylomicrons, which are eventually secreted into the lymphatic circulation. If this process is impaired, it may lead to abnormal accumulation of intestinal lipids or altered systemic lipid profiles. Based on this background, the inventors found that specific knockout of Ufbp gene in intestinal epithelial cells significantly resisted HFD-induced obesity, hyperlipidemia, insulin resistance and hepatic steatosis in adult individuals facing High Fat Diet (HFD) challenges. This finding reveals a completely new and key role for Ufbp in intestinal lipid processing and systemic energy metabolism, providing direct evidence for its use as a new target for anti-obesity drugs. To date, no published technology or study has suggested intestinal epithelial cells Ufbp1 as a target for the prevention or treatment of obesity. Disclosure of Invention The present invention aims to provide intestinal epithelial cells Ufbp as novel targets for the prevention and/or treatment of obesity and related metabolic disorders, as well as intervention strategies based on such targets. In order to achieve the above purpose, the invention adopts the following technical scheme: in a first aspect, the present invention provides the use of a substance that knocks out or inhibits expression of the intestinal epithelial cell Ufbp gene or protein activity in the manufacture of a medicament for the prevention and/or treatment of obesity. Preferably, the obesity is diet-induced obesity, in particular High Fat Diet (HFD) -induced obesity. Preferably, the effect of knocking out or inhibiting Ufbp1 to prevent and treat obesity is achieved by one or more of the following mechanisms: -lowering the plasma apolipoprotein (in particular ApoB48 and ApoA 1) levels; -lowering serum Total Cholesterol (TC), triglyceride (TG) levels; -lowering liver TC and TG levels, reducing liver steatosis; reducing the accumulation of white adipose tissue (including subcutaneous fat and visceral fat); -improving glucose tolerance and insulin sensitivity. Preferably, the agent is selected from the group consisting of CRISPR/Cas9 gene editing system for Ufbp gene, shRNA, siRNA, antisense oligonucleotide (ASO), small molecule inhibitor, neutralizing antibody, or a combination thereof. In a second aspect, the present invention provides a method of screening candidate drugs for the prevention and/or treatment of obesity, the method comprising: a) Testing candidate substances for their effect on Ufbp gene expression or protein activity in an intestinal epithelial cell model or animal model; b) Assessing a model of Ufbp1 being effectively inhibited in step a) for its phenotype or not that is/are one or more of weight gain induced by resistance to high fat diet, reduced fat accumulation, reduced blood lipid levels, redu