CN116251187B - Application of UFM1 modification reagent for improving UFBP1 protein K267 site in metabolism related fatty liver disease - Google Patents
Application of UFM1 modification reagent for improving UFBP1 protein K267 site in metabolism related fatty liver disease Download PDFInfo
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Abstract
The invention relates to the technical field of biology, in particular to application of a reagent for improving UFM1 modification level of UFBP1 protein K267 site in preparation of a medicament for preventing and/or treating metabolic-related fatty liver disease (MAFLD). The invention discloses that the agent for improving the UFM1 modification level of the UFBP1K267 can specifically inhibit the MAFLD for the first time, and discloses that the UFM1 modification level of the UFBP1K267 is closely related to lipid synthesis and endoplasmic reticulum stress of the MAFLD for the first time, thereby providing a new target point for preventing and treating the MAFLD.
Description
Technical Field
The invention relates to the field of biotechnology, in particular to application of a reagent for improving the UFM1 modification level of UFBP1 protein K267 site in preparing a medicament for preventing and/or treating metabolic-related fatty liver disease (MAFLD).
Background
Metabolic-related fatty liver disease (Metabolic associated fatty liver disease, MAFLD), known as nonalcoholic fatty liver disease (Nonalcoholic Fatty Liver Disease, NAFLD), is a metabolic disorder liver disease characterized by abnormal accumulation of lipids in the liver and stress of liver cells. MAFLD is currently the most prevalent liver disease in the world, and if not effectively controlled, MAFLD will progress from pure non-alcoholic fatty liver (Nonalcoholic Fatty Liver, NAFL) with purely reversible large bleb-based steatosis to non-alcoholic steatohepatitis (Nonalcoholic Steatohepatitis, NASH) with concomitant inflammation and liver injury (with or without fibrosis). NASH is further aggravated, resulting in end-stage liver disease such as cirrhosis, liver failure, hepatocellular carcinoma, etc. In addition, MAFLD can also increase the risk of other metabolic-related diseases such as diabetes, atherosclerosis, hypertension, coronary heart disease, ischemic and hemorrhagic stroke, and atrial fibrillation. Therefore, MAFLD places a great health and economic burden on society. Compared with the current situation of the prevalence of MAFLD and the harm to health, the mechanism of occurrence and progress of MAFLD is not clear, and the current treatment means for NAFLD are limited to nonspecific treatments such as lifestyle change, lipid reduction, liver insulin resistance alleviation, injury and the like, but lack of specific treatment means for MAFLD which are clinically licensed. Therefore, the pathogenesis of MAFLD is deeply revealed, potential intervention targets are found, and the research hotspots in the liver field and the metabolic field are formed.
The progress of the basic research suggests that MAFLD is a process of abnormal synthesis and deposition of hepatocyte lipid and leads to intracellular cell stress such as endoplasmic reticulum stress. In recent years, many scholars research shows that under the induction of factors such as high-fat diet, insulin resistance and the like, a large amount of Free Fatty Acids (FFA) are transported to the liver through blood and promote the increase of the expression of various genes related to lipid synthesis, so that accumulation of liver lipid and increase of lipotoxic metabolites are caused, and pathophysiological reactions such as endoplasmic reticulum stress, oxidative stress, inflammatory reaction and the like are further caused, and the stress reactions further aggravate lipid anabolism abnormality of the liver, so as to form multiple hits in the onset of MAFLD. These studies have found that MAFLD is a disease process which is participated in and actively regulated by multiple factors such as lipid synthesis and cell stress, so that the reagent aiming at MAFLD liver lipid synthesis and cell stress has high application value in preventing or treating non-alcoholic fatty liver disease.
Currently, lipid lowering drugs for MAFLD clinically include mainly statin drugs and fibrates. However, these drugs are mainly aimed at MAFLD patients complicated with cardiovascular and cerebrovascular diseases or dyslipidemia, and the most widely applied lipid-lowering drugs all have different degrees of liver injury risks and other adverse reactions, and considering that the liver of MAFLD population has multiple striking of steatosis and inflammation, safer specific lipid-lowering treatment aiming at MAFLD needs to be explored. Liver adipogenesis is regulated by a complex network of transcription factors, including transcription factors such as sterol regulatory element binding protein 1/2 (SREBP 1/2), peroxisome proliferator-activated receptor gamma (PPARgamma) and the like, stearoyl-CoA desaturase 1 (SCD 1), fatty Acid Synthase (FASN), acetyl-CoA carboxylase α1 (ACC 1), diacylglycerol o-acyltransferase 2 (DGAT 2), CD36 and the like, and fat synthesis-related proteins. In the inactive state, SREBP1/2 exists in the endoplasmic reticulum as an inactive precursor, whereas during the progression of MAFLD, the shear maturation of SREBP1/2 increases, leading to abnormal synthesis of lipids in the liver of MAFLD. Among them, SREBP1 is mainly responsible for the synthesis of fatty acids and triglycerides and promotes liver steatosis, while SREBP2 is responsible for cholesterol production and promotes progression of MAFLD to NASH. Pparγ is also an important transcription factor for liver adipogenesis and steatosis. Pparγ promotes uptake of fatty acids and lipid synthesis in the liver and progression of NAFLD by promoting CD36 expression. DGAT2 is another liver lipid synthesis gene widely involved in synthesis of triglycerides in the liver of MAFLD and liver steatosis, and thus DGAT2 is also a therapeutic target for MAFLD. Therefore, inhibition of expression and function of genes related to lipid synthesis in the liver of MAFLD is one of the important directions for preventing and alleviating MAFLD.
In many cellular stresses associated with MAFLD, endoplasmic reticulum should be stimulated to play an important role. Accumulation of lipids and their metabolites in hepatocytes can trigger an endoplasmic reticulum stress response (unfolded protein response) consisting of the inositol-essential enzyme 1α (IRE 1 α) pathway, the PRKR-like endoplasmic reticulum kinase (PERK) pathway, and the activated transcription factor 6 (ATF 6) pathway. After IRE1 alpha phosphorylation is activated, on one hand, expression of XBP1s and Caspase 2 is promoted by functioning as an endonuclease, and on the other hand, phosphorylation of JNK is promoted by functioning as a protein kinase. Wherein, the expression and activation of Caspase 2 can promote the shearing and activation of S1P to SREBP1/2, and the increase of the expression of XBP1S can promote the transcription of lipid synthesis related genes DGAT2, SCD1, ACC2 and SREBP 1; whereas phosphorylation of JNK promotes the development of insulin resistance and inflammatory responses in the liver. After activation of PERK phosphorylation, protein translation of ATF4 is promoted by promoting eIF2 alpha phosphorylation, and ATF4 promotes expression of CHOP and lipid synthesis genes SREBP1 and PPARgamma, thereby promoting liver lipid synthesis and inflammatory reaction. The N-terminus of ATF6 is sheared off and enters the nucleus to play a role of cytokines, and the functions of ATF6 channels are multiple and overlap with IRE1α and PERK channels, but ATF6 has also been reported to inhibit the occurrence and development of MAFLD (Villeneuve J, lepreux S, mulot A, et al Aproteive roll for CD154 in hepatic steatosis in micro.hepatology.2010.52 (6): 1968-79.Xiao G,Zhang T,Yu S,et al.ATF4 protein deficiency protects against high fructose-induced hypertriglyceridemia in micro.J Biol chem.2013.288 (35): 25350-25361.Chen X,Zhang F,Gong Q,et al.Hepatic ATF6 Increases Fatty Acid Oxidation to Attenuate Hepatic Steatosis in Mice Through Peroxisome Proliferator-Activated Receptor α. Diabetes.2016.65 (7): 1904-15.Zeng L,Lu M,Mori K,et al.ATF6 modulates SREBP2-mediated lipogenis.EMBO J.2004.23 (4): 950-8.). However, there is no effective drug for MAFLD treatment against hepatic endoplasmic reticulum stress.
UFBP1 (UFM 1-Binding And PCI Domain-Containing Protein 1) is a newly discovered endoplasmic reticulum stress regulating protein. UFBP1 is mainly located in the endoplasmic reticulum of cells, and when endoplasmic reticulum stress occurs, transcriptional expression of UFBP1 is activated and thus participates in maintenance of endoplasmic reticulum homeostasis, so that the absence of UFBP1 often leads to severe endoplasmic reticulum stress and apoptosis, which is related to impaired endoplasmic reticulum development, impaired stability of endoplasmic reticulum stress receptor protein IRE1a, and autophagy disorder of the endoplasmic reticulum caused by the absence of UFBP 1. The main domain of UFBP1 is its PCI domain (AA 229-273), which is responsible for binding proteins that interact with UFBP1, and thus regulate folding, degradation, and transport of these proteins, and notably, ubiquitin-like fold modifier 1 (UFM 1-Binding And PCIDomain-Containing Protein 1, UFM 1) can modify the highly conserved 267 th lysine of this PCI domain, which is critical for the functioning of UFBP 1. After the UFM1 precursor protein is hydrolyzed and cut by UFM1Specific protease UFM1Specific Peptidase 2, the 83 th glycine of the UFM1 is exposed to form mature UFM1, and then UFM1 is subjected to continuous actions of UFM1 activating enzyme UBA5 (Ubiquitin Like Modifier Activating Enzyme), UFM1 binding enzyme UFM1 (Ubiquinin-Fold Modifier Conjugating Enzyme 1) and UFM1 Ligase UFM1 (UFM 1Specific Ligase 1) to form covalent connection between the 83 th glycine residue of the UFM1 and the 267 th lysine residue (K267) of the UFM1, thereby realizing UFM1 modification of the UFM1 protein (Kang SH, kim GR, seong M, et al.two novellubiquitin-fold modifier 1 (Ufm 1) -Specific proteases, UFM1 and UFM 2.J Biol chem 2007.282 (8): 5256-92 a transactivation and breast cancer development.2014.3556-140): 140. Meanwhile, UFBP1 located in the endoplasmic reticulum can be identified by the unique domain at the N end of UFBP 2, and UFM1 protein coupled with UFBP1K267 is sheared, so that UFM1 modification is achieved (Ha BH, jeon YJ, shin SC, et al Structure of ubquitin-fold modifier 1-specific protease UFSP2.J Biol chem 2011.286 (12): 10248-57.).
UFM1 modification of UFBP1 has been shown to be involved in many biological processes, but at present, the specific role of UFBP1 and UFM1 modification in MAFLD and its mechanism have not been reported.
Disclosure of Invention
The present invention is significantly different from the prior art and the current trend that UFM1 modification of UFBP1 is considered one of the potential therapeutic targets of MAFLD, and prevention and treatment of MAFLD is performed by providing a method for increasing the level of UFM1 modification of lysine residue 267 (K267) of UFBP1 protein. The present invention aims to provide a novel medical use of an agent for improving the UFM1 modification level of UFBP1K267 in the prevention or treatment of MAFLD.
To achieve the object of alleviating MAFLD, the present invention provides in a first aspect the use of an agent for increasing the level of UFM1 modification of the 267 th lysine residue (K267) of UFBP1 in the manufacture of a medicament for the prevention and/or treatment of metabolic-related fatty liver disease (Metabolic associated fatty liver disease, MAFLD).
Further, the agent for increasing the UFM1 modification level of UFBP1K267 comprises any one of the following:
a) UFBP1 protein and UFM1 protein purified in vitro;
b) Recombinant viruses containing UFBP1 protein or UFM1 protein-encoding genes;
c) Recombinant virus containing UFBP1 protein and UFM1 protein coding gene; recombinant virus containing UFBP1 and UFM1 fusion protein coding gene;
d) And (3) a medicine for promoting UFBP1 to undergo UFM1 modification or inhibiting UFBP1 to undergo UFM1 modification.
The B/C) may be a recombinant lentivirus, a recombinant adenovirus, a recombinant adeno-associated virus, or the like, which contains a gene encoding a related protein.
The above-mentioned D) may be a polypeptide or compound that promotes the binding of UFBP1 to UFM 1-modified E3 ligase UFL1 thereof, or a polypeptide or compound that inhibits the binding of UFBP1 to UFM 1-modified protease UFSP2 thereof.
Further, the agent for increasing UFM1 modification level of UFBP1K267 acts to alleviate MAFLD by effectively alleviating MAFLD-related symptoms including obesity, liver steatosis, abnormal accumulation of liver lipid, ballooning of liver cells, elevated blood lipid, and insulin resistance, and by inhibiting liver lipid synthesis pathway and endoplasmic reticulum stress pathway.
In a second aspect of the present invention, there is provided a pharmaceutical composition for preventing and/or treating MAFLD, wherein the active ingredient is an agent for increasing the UFM1 modification level of UFBP1K 267.
Further, the pharmaceutical composition for preventing and/or treating MAFLD also comprises a pharmaceutically acceptable carrier or auxiliary material.
Furthermore, the medicine for preventing and/or treating MAFLD is a medicine composition which is prepared from an agent for improving the UFM1 modification level of UFBP1K267 as an active ingredient and a conventional medicinal carrier.
Further, the pharmaceutical composition is a tablet, a capsule, a pill, a granule, an injection, a powder injection or an aerosol.
In a third aspect of the present invention, there is provided a method for screening a drug for preventing or treating MAFLD by selecting a drug that increases the level of UFM1 modification of UFBP1K267 in the liver from among the obtained potential substances.
Further, the screening method further comprises the following steps: further cellular and/or animal experiments are performed on the potential substances obtained to further select and determine substances useful for preventing or treating MAFLD from among candidate substances.
In a fourth aspect of the invention, there is provided a method of delaying or treating MAFLD, the method comprising: upregulating the UFM1 modification level of UFBP1K267 in the target body to delay the occurrence of MAFLD, wherein UFM1 modification defect of UFBP1K267 promotes the progress of MAFLD.
The invention has the advantages that:
the invention discloses that the agent for improving the UFM1 modification level of the UFBP1K267 can specifically inhibit the MAFLD for the first time, and discloses that the UFM1 modification level of the UFBP1K267 is closely related to lipid synthesis and endoplasmic reticulum stress of the MAFLD for the first time, thereby providing a new target point for preventing and treating the MAFLD.
Drawings
FIG. 1. Analysis of changes in UFM1 modification levels of UFBP1 in MAFLD liver.
A, quantitative PCR showed that UFM1 and UFBP1 had higher liver expression in MAFLD mice than in the control group. B, western blot detects the expression levels of UFM1 modification system proteins (UFM 1, UBA5, UFC1, UFL1 and UFBP 1) and liver proteins coupled with UFM1 in the liver of the MAFLD mouse, and the result shows that the expression levels of the UFM1 modification system proteins and the liver proteins coupled with UFM1 in the MAFLD liver are increased and the UFM1 modification of UFBP1 is increased (black arrow). Immunohistochemical staining showed elevated expression of UFM1, UFBP1 in the liver of the MAFLD mice. D, immunohistochemical staining showed increased expression of UFM1, UFBP1 in the liver of the MAFLD patients.
Figure 2. In vitro experiments knockdown of UFBP1 promotes the MAFLD process.
A, oil red staining showed a significant increase in free fatty acid-induced lipid accumulation in L02 cells of the liver cell line after knocking down UFBP1, compared to the control group. B, quantitative PCR showed that transcription of lipid synthesis-related genes (SREBP 1, SCD1, DGAT2, PPARgamma and CD 36) was elevated in the L02 cells of the liver cell line after knocking down UFBP1, compared with the control group. C, western blot detection shows that the protein level of lipid synthesis related genes (SREBP 1, SCD1, DGAT2, PPARgamma and CD 36) in the L02 cells of the liver cell line after knocking down the UFBP1 is increased, and the shear level of SREBP1 protein is increased compared with a control group. The quantitative PCR showed that transcription of endoplasmic reticulum stress-related genes (GRP 78, XBP1s and Caspase 2) was elevated in L02 cells of the liver cell line after knocking down UFBP1, compared with the control group. E, western blot detection shows that the protein level (GRP 78, ATF4, XBP1s, caspase 2 and ATF 6) or protein phosphorylation level (PERK, eIF2 alpha and IRE1 alpha) of the L-02 intracellular plasma screen stress related genes is increased after UFBP1 is knocked down compared with a control group. .
FIG. 3 shows that overexpression of UFBP1 in vivo can alleviate MAFLD process in a manner dependent on modification of UFM 1.
A, compared with the control group, the injection of the adeno-associated virus expressing the wild type UFBP1 (WT UFBP 1) can relieve the obesity of the MAFLD mice, but the injection of the adeno-associated virus expressing the UFBP1 mutant (UFBP 1K 267R) which cannot be modified by UFBP1 can not exert the effect. B, compared with the control group, the liver over-expression of WT UFBP1 can reduce the volume and weight of the liver of the MAFLD mouse, and the over-expression of UFBP1K267R cannot exert the effect. C, oil red staining and HE staining showed that over-expression of WT UFBP1 in liver reduced lipid accumulation and cell balloon-like changes in the liver of the mamld mice compared to the control, but over-expression of UFBP1K267R did not reduce the number of liver cell balloon-like changes and instead increased lipid accumulation in liver tissue. D, lipid content detection shows that overexpression of WT UFBP1 can reduce Triglyceride (TG) content in NAFLD liver and serum, and overexpression of UFBP1K267R can not reduce TG content in liver and serum; and overexpression of UFBP1K267R in the liver resulted in an increase in serum cholesterol levels, whereas there was no statistical difference in serum cholesterol levels changes after overexpression of WT UFBP 1. E, GTT experiments show that the overexpression of WT-UFBP1 or UFBP1K267R can improve the glucose tolerance of MAFLD mice compared with a control group. F, ITT showed that overexpression of WT-UFBP1 increased insulin sensitivity in MAFLD mice compared to the control group, whereas overexpression of UFBP1K267R did not.
FIG. 4 overexpression of UFBP1 inhibits lipid synthesis in MAFLD liver and relieves endoplasmic reticulum stress in MAFLD liver in a manner dependent on modification of UFM 1.
A, quantitative PCR showed that the transcription level of lipid synthesis related genes (SREBP 1, SCD1, DGAT2, PPARgamma and CD 36) in MAFLD liver was decreased after overexpression of WT UFBP1, whereas the transcription level of PPARgamma and CD36 in liver was not decreased after overexpression of UFBP1K267R, and the transcription level of SREBP1, SCD1 and DGAT2 was rather increased, compared with the control group. B, western blot detection shows that protein expression of lipid synthesis related genes (SCD 1, DGAT2, PPARgamma and CD 36) in MAFLD liver is reduced after overexpression of UFBP1, and shear maturation of SREBP1 is reduced, while protein expression of PPARgamma and CD36 in liver is not reduced after overexpression of UFBP1K267R, but rather shear maturation of SREBP1 and expression of SCD1 are increased compared with a control group. The quantitative PCR showed that the transcription level of endoplasmic reticulum stress related genes (GRP 78, XBP1s, caspase 2) in the liver was decreased after the overexpression of WT UFBP1, whereas the transcription level of GRP78 and Caspase 2 in the liver was not decreased after the overexpression of UFBP1K267R, and the transcription level of XBP1s was instead increased, compared with the control group. D, western blot detection shows that the protein level (GRP 78, ATF4, XBP1s, caspase 2, ATF 6) or protein phosphorylation level (PERK, eIF2α and IRE1 α) of the endoplasmic reticulum stress related gene in the liver after overexpression of WT UFBP1 is reduced compared with the control group, and the protein level or phosphorylation level of the endoplasmic reticulum stress related gene in the liver after overexpression of UFBP1K267R is not significantly changed.
Detailed Description
The following provides a detailed description of embodiments of the present invention with reference to examples.
These examples are only intended to illustrate the invention and are not intended to limit the scope of the invention. The experimental methods in which the specific experimental conditions are not specified in the examples below are generallyMolecular cloning (Molecular Cloning: ALaboratory Manual, 3) rd ed.) or as recommended by the manufacturer.
Materials and methods
MAFLD mouse model construction
High fat diet induced MAFLD mouse model: 8 week male C57/BL6J mice of similar body weight were purchased from Shanghai Jieshijie laboratory animals Inc., and the mice were randomly divided into two groups. The high fat group was fed with high fat feed for 12 weeks, and the control group was fed with normal feed.
Patient tissue specimen collection and processing
Human MAFLD liver tissue and control non-pooled MAFLD liver tissue were obtained from the paracancerous tissue of patients who underwent liver surgery due to hepatocellular carcinoma or liver metastatic tumors, as approved by the ethical committee of hospitals and informed consent of the patients. Tissue specimens were rapidly fixed in formalin or frozen in liquid nitrogen to be tested.
In vitro culture of hepatocyte line L-02
Human immortalized hepatocyte line L-02 purchased from the Chinese sciences was placed in RPM1-1640 medium containing streptomycin, penicillin diabody and 10% fetal bovine serum at 5% CO 2 Culturing in a constant temperature incubator at 37 ℃ for every 2-4 days, and replacing liquid for passage.
In vitro MAFLD model construction
In vitro MAFLD cell models were induced using high fat medium formulated to contain 200. Mu. Mol/L oleic acid, 100. Mu. Mol/L palmitic acid.
Overexpression of UFBP1 or UFBP1K267R in MAFLD mouse model liver
Adeno-associated virus AAV 8 overexpressing wild-type UFBP1 or UFBP1K267R was constructed by Hayota biotechnology (Shanghai) limited, and Control adeno-associated virus (AAV-Control), adeno-associated virus overexpressing wild-type UFBP1 (AAV-WT UFBP 1) and adeno-associated virus overexpressing UFBP1 mutated at the primary UFBP1 modification site (AAV-UFBP 1K 267R) were injected into mice fed with high fat for 12 weeks, each group was fed with high fat for 5 animals, and the high fat feeding was continued for 12 weeks, respectively, so that adeno-associated virus was sufficiently expressed in the livers of the mice.
Detection of glucose tolerance in mice (GTT)
After 10 weeks of intraperitoneal injection of adeno-associated virus, mice IPGTT: the day before the test, a glucose solution of 100mg/ml was prepared with physiological saline, the body weight of the mice to be tested was measured, and 1mg of glucose was injected per gram of body weight to prepare an injection for each mouse. Mice were treated on an empty stomach for 12 hours, their rat tail tips were removed, their fasting blood glucose was measured with a glucometer, and the mice were injected with glucose prepared in advance, returned to their cage, and their rat tail tips were measured after 0, 15, 30, 60 and 120 minutes of injection.
Detection of insulin resistance in mice (ITT)
11 weeks after intraperitoneal injection of adeno-associated virus, mice ITT: on the morning of the test, an insulin solution of 0.75U/ml was prepared with physiological saline, the body weight of the mice to be tested was measured, and 0.75mU of insulin was injected per gram of body weight to prepare an injection for each mouse. After withdrawal of the diet, mice were treated on an empty stomach for 6 hours, their rat tail tips were removed, their fasting blood glucose was measured with a glucometer, and insulin solutions prepared in advance were injected, returned to the cage, and the rat tail tips were measured after 0, 15, 30, 60 and 120 minutes of injection.
Detection of sample triglyceride content
Detecting the content of triglyceride in liver and serum of each group of mice by using a TG detection kit of Nanjing established bioengineering institute: in a 96-well plate, 2.5. Mu.l ddH2O was added to a blank well, 2.5. Mu.l standard solution was added to a standard well, 2.5. Mu.l sample solution was added to a sample well, then 250 ml detection solution was added to each well, and the wells were mixed uniformly, incubated at 37℃for 10 minutes, and absorbance was measured at 510 nm for each well.
TG content (mmol/L) = (sample OD value-blank OD value)/(standard OD value-blank OD value) ×standard concentration (2.26 mmol/L).
Measuring cholesterol content of sample
The cholesterol content in liver and serum of each group of mice is detected by using a TC detection kit of Nanjing established bioengineering institute: in a 96-well plate, 2.5. Mu.l ddH was added to a blank well 2 O, standard well was added with 2.5. Mu.l standard solution, sample well was added with 2.5. Mu.l sample solution, and then each well was added with250 ml of detection solution is added, evenly mixed, incubated for 10 minutes at 37 ℃, and absorbance of each hole is detected at 510 nanometers.
TC content (mmol/L) = (sample OD value-blank OD value)/(Standard OD value-blank OD value) ×Standard concentration (5.17 mmol/L)
Oil red dyeing
And (3) preparing an oil red staining solution, staining a frozen section of the liver or a cell climbing sheet, and observing the lipid accumulation condition of the liver cells under a general optical microscope.
HE staining
Dewaxing and hydrating liver slices, staining with hematoxylin/Yin Gong, and dehydrating and sealing. Observation of liver tissue pathological conditions under a general optical microscope
Real-time fluorescent quantitative PCR
Total RNA from human liver tissue and cultured cells was extracted with TRIzol (Invitrogen). The concentration and purity of RNA were determined by UV spectrophotometry. And (3) performing reverse transcription on 1000ng total RNA to obtain cDNA, performing target gene amplification by a PCR method, taking beta-action as an internal reference primer in each reaction system, and determining the specificity of gene amplification by a dissolution curve and agarose gel electrophoresis.
Immunohistochemical staining
MAFLD liver tissue and control liver tissue were fixed overnight with 4% paraformaldehyde and paraffin embedded. Immunohistochemical staining was performed by S-P method after paraffin section (4 μm), anti-UFM1 (1:100, abclon) or Anti-UFBP1 (1:300, proteinech) was diluted in specific ratio using Biyun immunostaining primary Anti-dilution, placed in a wet box at 4℃overnight, corresponding enzyme-labeled secondary antibodies were incubated at room temperature after elution for 30 min, developed with DAB to appear as positive staining with tan, dehydrated sealing after hematoxylin counterstaining, and analyzed under a normal microscope for Image analysis using Image Pro Plus software.
Statistical analysis
Data processing analysis was performed using GraphPad Prism 8.0 software, all data for the metering data were represented as mean ± standard error, and the comparison between groups was statistically significant using t-test, with P <0.05 as the difference.
Example 1: UFM1 modification level analysis of UFBP1
In this example, liver tissue of MAFLD mice was collected as an experimental group, and liver tissue of normal mice was collected as a control group. The real-time fluorescence quantitative PCR method is used for detecting the mRNA level expression change of UFM1 modified system proteins (UFM 1, UBA5, UFC1, UFL1 and UFBP 1) in the liver tissue of the MAFLD mouse, and the result shows that the expression of the UFM1 and the UFBP1 in the liver tissue of the MAFLD mouse is obviously increased (figure 1A). The change of the expression of the UFM1 modified system protein and the expression level of the liver protein coupled with UFM1 in liver tissues were detected by a western blot method, and the results show that UFM1, UBA5, UFC1, UFL1 and UFBP1 are highly expressed in the liver tissues of the MAFLD mice, and the expression level of the liver protein coupled with UFM1 is also increased, which includes UFBP1 (shown by black arrow) coupled with UFM1 (FIG. 1B).
Example 2: UFM1 and UFBP1 expression increase in liver tissue of MAFLD mice and liver tissue of MAFLD patients
In this example, the expression levels of UFM1 and UFBP1 in liver tissue of MAfld mice and liver tissue of MAfld patients were examined by immunohistochemical staining, and as a result, it was found that UFM1 and UFBP1 were highly expressed in MAfld liver tissue (fig. 1C, D).
Example 3: knocking down UFBP1 promotes MAFLD processes
In this example, in vitro culture of human hepatocytes line L-02, UFBP1 was knocked down by recombinant lentivirus expressing shRNA for UFBP1, and MAFLD cell model was induced by high-fat medium. Liver cell lipid accumulation was assessed using oil red staining. Oil red staining showed a significant increase in L-02 cell lipid accumulation after knockdown of UFBP1 (FIG. 2A), increased transcription of lipid synthesis-associated genes in the liver (SREBP 1, SCD1, DGAT2, PPARgamma and CD 36) and increased protein levels, and increased shear levels of SREBP1 protein (FIG. 2B, C) compared to the control group. At the same time, transcription of endoplasmic reticulum stress-related genes (GRP 78, XBP1s and Caspase 2) was increased in L02 cells after knockdown of UFBP1, and protein levels (GRP 78, ATF4, XBP1s, caspase 2, ATF 6) or protein phosphorylation levels (PERK, eif2α and ire1α) of the endoplasmic reticulum stress-related genes were increased (fig. 2D, E).
Example 4: overexpression of UFBP1 can relieve MAFLD process in a mode of UFM1 modification dependence
Example 3 experimental results demonstrate that knockdown of UFBP1 promotes lipid accumulation in the mfld cell model. To better investigate the endogenous function of UFBP1 and its relation to UFM1 modification, this example over-expressed wild-type UFBP1, or UFBP1 mutated at the UFM1 modification site (lysine 267) (UFBP 1K 267R), in the MAFLD liver by intravenous injection of adeno-associated virus (AAV) into the tail of the MAFLD mice. The results showed that over-expression of wild-type UFBP1 reduced the body weight, liver volume and weight of the mamfd mice, and alleviated liver lipid accumulation, reduced levels of triglycerides in liver and serum of the mamfd mice, increased glucose tolerance and insulin sensitivity of the mamfd mice, whereas over-expression of UFBP1K267R failed to exert these mamfd remissions, and instead promoted liver lipid accumulation and elevated serum cholesterol levels in the mamfd mice (fig. 3).
Example 5: overexpression of UFBP1 inhibits lipid synthesis in MAFLD liver and relieves endoplasmic reticulum stress in MAFLD liver in a UFM1 modification-dependent manner
The experiment proves that the UFBP1 can relieve the MAFLD from advancing in a mode of UFM1 modification dependence, the UFBP1 is a protein mainly distributed in an endoplasmic reticulum, the UFBP1 can play an important role in maintaining the steady state of the endoplasmic reticulum in the mode of UFM1 modification dependence, and the endoplasmic reticulum is an important place for lipid synthesis. The invention then uses real-time fluorescence quantitative PCR and western blot to detect the effect of UFM1 modification of UFBP1 in MAFLD liver lipid synthesis and endoplasmic reticulum stress. As a result, it was found that, of the genes involved in lipid synthesis in MAFLD liver, the transcription and cleavage maturation of SREBP1 was decreased and the expression of SCD1, PPARgamma and CD36 was decreased after overexpression of UFBP1K267R, whereas the expression of PPARgamma and CD36 in liver was not decreased after overexpression of UFBP1K267R, but instead, the transcription, cleavage maturation of SREBP1 and the expression of SCD1 and DGAT2 were all increased (FIGS. 4A, B). Meanwhile, after the overexpression of WT UFBP1, the transcription level of endoplasmic reticulum stress related genes (GRP 78, XBP1s and Caspase 2) in the MAFLD liver is reduced, while after the overexpression of UFBP1K267R, the transcription level of GRP78 and Caspase 2 in the liver is not reduced, and the transcription level of XBP1s is increased instead. Meanwhile, protein levels (GRP 78, ATF4, XBP1s, caspase 2, ATF 6) or protein phosphorylation levels (PERK, eif2α, and IRE1 α) of the endoplasmic reticulum stress-related genes in the liver were decreased after overexpression of WT UFBP1, whereas protein levels or phosphorylation levels of the endoplasmic reticulum stress-related genes in the liver were not significantly changed after overexpression of UFBP1K267R (fig. 4c, d).
The results prove that the UFBP1 can inhibit lipid synthesis in the MAFLD liver and relieve endoplasmic reticulum stress in the MAFLD liver in a mode of being dependent on modification of UFM1, thereby playing a role in relieving the MAFLD.
The invention first determines that the expression of UFBP1 and its UFM1 modification are increased in the MAFLD liver. After the L-02 cells knocked down with UFBP1 are cultured in a high-fat medium to induce a MAFLD cell model, the invention discovers that UFBP1 deletion promotes aggregation of lipids in the MAFLD cell model and promotes lipid synthesis and endoplasmic reticulum stress in the cells. In vivo experiments, however, overexpression of wild-type UFBP1 reduced the body weight and the volume and weight of the liver of the mamfd mice, and overexpression of wild-type UFBP1 also reduced the accumulation of liver lipids in the mamfd mice, reduced the levels of triglycerides in the liver and serum of the mamfd mice, and increased the glucose tolerance and insulin sensitivity of the mamfd mice, suggesting that the mouse's mamfd phenotype was relieved, as opposed to overexpression of UFBP1K267R did not reduce the body weight, liver volume, liver weight, or the levels of triglycerides in the liver and serum of the mamfd mice, and instead promoted the accumulation of liver lipids in the mamfd mice and resulted in elevated serum cholesterol levels. Further experiments show that the effect of UFBP1 in alleviating MAFLD is related to inhibiting lipid synthesis and endoplasmic reticulum stress in the liver of UFM1 modification of UFBP1K267, and theoretical basis is provided for preventing and treating MAFLD by using UFM1 modification of UFBP1K 267.
Also, while the present invention has been described in terms of specific examples involving modulation of MAFLD development, those skilled in the art will readily appreciate that such experiments may predict biological effects on humans or other mammals and/or may be used as models for studying other lipid metabolism and endoplasmic reticulum stress related conditions in humans or other mammals using the present invention.
While the preferred embodiments of the present invention have been illustrated and described, the present invention is not limited to the embodiments, and various equivalent modifications and substitutions can be made by one skilled in the art without departing from the spirit of the present invention, and these equivalent modifications and substitutions are intended to be included in the scope of the present invention as defined in the appended claims.
Claims (4)
1. Use of an agent that increases UFM1 modification level of UFBP1K267 in the manufacture of a medicament for the prevention and/or treatment of metabolic-related fatty liver disease; the reagent for improving the UFM1 modification level of the UFBP1K267 is a recombinant virus containing a UFBP1 protein coding gene.
2. Use of an agent for increasing UFM1 modification level of UFBP1K267 according to claim 1 for the manufacture of a medicament for the prevention and/or treatment of metabolic-related fatty liver disease, wherein said recombinant virus is selected from the group consisting of recombinant lentiviruses, recombinant adenoviruses and recombinant adeno-associated viruses comprising genes encoding related proteins.
3. The use of an agent for elevating UFM 1-modified level of UFBP1K267 according to claim 1 for the preparation of a medicament for preventing and/or treating metabolic-related fatty liver disease, wherein said agent for elevating UFM 1-modified level of UFBP1K267 acts to alleviate metabolic-related fatty liver disease-related symptoms including obesity, liver steatosis, abnormal accumulation of liver lipid, hepatocyte ballooning, elevated blood lipid or insulin resistance by inhibiting the hepatic lipid synthesis pathway and the endoplasmic reticulum stress pathway.
4. The use of an agent for increasing the level of modification of UFM1 of UFBP1K267 according to claim 1 for the manufacture of a medicament for the prevention and/or treatment of metabolic-related fatty liver disease, wherein the medicament for the prevention and/or treatment of metabolic-related fatty liver disease is a pharmaceutical composition comprising the agent for increasing the level of modification of UFM1 of UFBP1K267 as an active ingredient, in association with a conventional pharmaceutical carrier.
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| Proteomic and Biochemical Analyses Reveal a Novel Mechanism forPromoting Protein Ubiquitination and Degradation by UFBP1, a KeyComponent of Ufmylation;Ying Zhu等;Journal of Proteome Research;第17卷(第4期);1335-1748 * |
| Ying Zhu等.Proteomic and Biochemical Analyses Reveal a Novel Mechanism forPromoting Protein Ubiquitination and Degradation by UFBP1, a KeyComponent of Ufmylation.Journal of Proteome Research.2018,第17卷(第4期),1335-1748. * |
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