CN116445516A - Application of ALKBH1 as adipocyte aging marker - Google Patents
Application of ALKBH1 as adipocyte aging marker Download PDFInfo
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Abstract
The invention discloses application of ALKBH1 as an adipocyte aging marker. Altered expression of ALKBH1 can cause alterations in the aging state, inflammatory levels, and insulin sensitivity of adipocytes, and can be detected by detecting the level of ALKBH1 expression in response to the degree of aging of adipose tissue. By taking an adipocyte Alkbh1 gene specific knockout mouse as a model, researches show that Alkbh1 gene knockout can cause accelerated aging of adipose tissues, chronic inflammation and exacerbation of insulin resistance of fat mice fed with high fat. Meanwhile, the Alkbh1 can be knocked out or over expressed on the in vitro adipocytes to promote or relieve the aging of the adipocytes.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to application of ALKBH1 as a biomarker for adipocyte aging, which can be used for predicting adipocyte aging, chronic inflammation and change of insulin sensitivity.
Background
Aging can lead to public health problems with aging. The incidence rate of cardiovascular and cerebrovascular diseases, malignant tumors and other diseases of the old is obviously increased, so that the life expectancy of the old is shortened, and the death rate is increased. Meanwhile, age-related metabolic diseases and degenerative diseases such as type 2 diabetes, osteoarthritis, vascular dementia, etc. seriously affect the quality of life of the elderly, further increasing social burden. Therefore, prevention of unhealthy aging and how to healthy aging are important subjects of research in the field of life sciences.
Adipose tissue is closely related to the occurrence and development of age-related metabolic dysfunction. With age, the content and distribution of adipose tissue are obviously changed, which is manifested by subcutaneous adipose tissue reduction, and obvious ectopic deposition of adipose tissue in organs such as liver, muscle, bone marrow and the like. And then dysfunction of adipose tissues occurs, which causes reduced insulin sensitivity, abnormal secretory function of adipose tissues and systemic chronic inflammation. Aggregation of large amounts of P16 in senescent adipose tissue Ink4a Positive aging cells can be removed by transgenic technology or molecular targeting drugs, which is helpful for relieving adipose tissue inflammation and delaying body aging. Thus, adipocyte aging plays an important role in causing age-related adipose tissue inflammation and insulin resistance.
ALKBH1 is a member of the Fe (II) -alpha-ketoglutarate dioxygenase superfamily ALKB and has a close relationship with the 5-mC demethylase Tet family. Research shows that ALKBH1 can perform different functions aiming at different catalytic substrates, including RNA processing and stability regulation by catalyzing the demethylation of RNAm 5C; catalyzing the demethylation of tRNA m1A thereby affecting translation; as RNA m6A demethylase, alk bh1 can inhibit tumor cell invasion and metastasis; mediate DNA 6mA demethylation, and can be used as a potential target for cancer treatment. Recently, it has been found that the knockout of Alkbh1 on human mesenchymal stem cells (hMSC) can promote hMSC cell senescence, however, the role of ALKBH1 in adipocyte senescence is rarely reported.
Disclosure of Invention
The first object of the present invention is to address the deficiencies of the prior art and to propose the use of ALKBH1 as a biomarker of adipocyte senescence.
Preferably, ALKBH1 expression decreases with increasing senolytic protein P16 expression.
Preferably, the knockout of the Alkbh1 gene on adipocytes in vitro promotes adipocyte aging, and overexpression of the Alkbh1 gene relieves adipocyte aging.
The second object of the invention is to provide a detection product of the fat cell senescence marker, which comprises a reagent for detecting ALKBH 1.
Preferably, the detection product comprises a kit or chip.
Preferably, the kit comprises a probe that specifically recognizes ALKBH 1.
Preferably, the chip comprises a solid support, a probe specifically recognizing ALKBH1 or a primer specifically amplifying the Alkbh1 gene attached thereto.
The third object of the invention is to provide an application of the biomarker ALKBH1 in preparing an anti-aging product.
The invention has the beneficial effects that:
the invention discloses ALKBH1 as a biomarker for aging of fat cells for the first time, and the aging state, chronic inflammation and insulin resistance of fat tissues can be predicted by detecting the expression level of the ALKBH 1. In adipose tissue of aged and obese mice, ALKBH1 expression was significantly reduced with increased expression of senescent protein P16. Knocking out or over-expressing Alkbh1 on in vitro adipocytes can promote or delay the aging of the adipocytes. By taking an adipocyte Alkbh1 gene specific knockout mouse as a model, it is found that Alkbh1 gene knockout can cause accelerated aging of adipose tissues, chronic inflammation and exacerbation of insulin resistance of fat-fed obese mice. The above results also reveal the role of ALKBH1 in adipocyte aging.
Drawings
FIG. 1 shows that the expression of white fat ALKBH1 of old mice is obviously reduced, wherein (a) is a representative western blot chart, and (b) is a western blot quantitative result.
FIG. 2 shows that the expression of white fat senescence protein P16 of a fat mouse induced by high fat is obviously increased, and the expression of ALKBH1 is obviously reduced, wherein (a) is a representative western blot chart, and (b) is a western blot quantitative result.
FIG. 3 is a graph showing knockdown or overexpression of Alkbh1 expression on C3H10T1/2 mouse embryonic fibroblasts.
FIG. 4 shows bleomycin-induced C3H10T1/2 cell senescence, alkbh1 knockdown promotes cell senescence, whereas Alkbh1 overexpression inhibits cell senescence, where (a) is a representative cell SA- β -gal staining pattern and (b) is a quantitative SA- β -gal staining result.
FIG. 5 shows the effect of knocking down Alkbh1 on mature adipocytes to promote cell senescence, where (a) is a representative cell SA- β -gal staining pattern and (b) is a quantitative result of SA- β -gal staining.
FIG. 6 shows that knocking down Alkbh1 on mature adipocytes promotes senescence-associated gene expression.
FIG. 7 shows the overexpression of Alkbh1 on mature adipocytes to delay adipocyte senescence, where (a) is a representative cell SA- β -gal staining pattern and (b) is a quantitative result of SA- β -gal staining.
FIG. 8 is a graph showing the knock-out efficiency verification of fat specific Alkbh1 gene knockout mice.
FIG. 9 shows Alkbh1 gene knockout promotion of white fat premature senility in high fat diet-induced obese mice, wherein (a) is a representative white fat SA-beta-gal staining pattern, and (b) is qPCR detection of white fat senescence-associated gene expression.
FIG. 10 shows the macrophage infiltration of adipose tissue of Alkbh1 knockout-weighted high fat diet fed obese mice, wherein (a) is a representative white adipose tissue section F4/80 immunofluorescent staining result, and (b) is a F4/80 staining quantification result.
FIG. 11 shows the glucose tolerance abnormality and insulin resistance of Alkbh1 knockout aggravated high fat diet fed obese mice, wherein (a) is the oral glucose tolerance test result and (b) is the insulin tolerance test result.
Detailed Description
The invention is further described below, without limiting the invention, in connection with the examples and the figures.
Adipose tissue-specific Alkbh1 Gene knockout mice (Alkbh 1) Adp/Adp ) And clean-grade C57BL/6 mice were housed in a clean-grade animal house from a laboratory animal center at a university of Hangzhou. All operations in the whole in vivo experimental process follow the 'experimental animal use regulations' set by the ethical committee of the university of Hangzhou. All antibodies used in the present invention, unless otherwise specified, were purchased from Abcam corporation, usa. All experimental results were obtained from three independent replicates using unpaired t-testAnalytical data, all indicated by the solsd. P value<0.05 is a significant difference criterion (x)<0.05，**<0.01)。
Embodiment one: ALKBH1 expression is reduced in the aging process of adipose tissues, and Alkbh1 gene knockout promotes the aging of adipocytes.
The expression change of ALKBH1 in the white fat aging process is detected by Western Blot, and the influence of Alkbh1 gene knockout and overexpression on the aging of fat cells is detected by lentivirus infection, SA-beta-gal staining and real-time PCR, and the specific operation is as follows:
1)Western Blot
(1) Preparation of tissue protein samples: weighing a proper amount of adipose tissue, adding the adipose tissue into the tissue lysate, homogenizing by a homogenizer, and homogenizing for three times at 60HZ and 90 s. Centrifuging at 12000rpm for 10min, collecting supernatant until no obvious fat precipitate is present, adding 5×loadingbuffer, and boiling for 10min.
(2) SDS-PAGE: and carrying out protein gel electrophoresis on the obtained tissue protein sample.
(3) Transferring: transferring film by using a film transfer instrument, soaking PVDF film in methanol for 5min in advance for activation, and then treating with small molecule treatment liquid.
(4) Closing: the mixture was blocked with 5% nonfat dry milk at room temperature for 1 hour.
(5) Incubation resistance: the primary antibody was diluted with 5% BSA and incubated overnight at 4 ℃. TBST was washed 10min X3 times.
(6) Secondary antibody incubation: the secondary fluorescent antibody was diluted with 5% BSA and incubated at room temperature for 1 hour. The secondary antibody was blotted off and washed 10min×3 times with TBST.
(7) Exposure: the image is preserved by exposure with a developer.
2) Lentiviral packaging and infection
(1) Packaging lentiviruses using HEK293T cells: HEK293T cells (transfectable state) were prepared at 90% density in 10cm dish and replaced with 8mL fresh DMEM medium 1 hour prior to transfection. Preparation of PEI-DNA mixture: 500. Mu.l Opti-MEM was added to a sterile 1.5mL EP tube, followed by 60. Mu.l PEI, gently mixed, and allowed to stand at room temperature for 5min; another 500. Mu.l of Opti-MEM was prepared, and 14. Mu.g of pLKO.1-Alkbh1-shRNA knockdown or pTSB-CMV-Alkbh1-3FLAG over-expression plasmid, packaging plasmid pspAX 210. Mu.g, envelope plasmid pMD2G 6. Mu.g was added and gently mixed. The PEI mixture was gently mixed with the plasmid mixture, incubated at room temperature for 15min, the prepared PEI-DNA mixture was added to a petri dish, gently shaken back and forth, left and right, placed in a 5% carbon dioxide incubator at 37℃for 8 hours, and then the DMEM medium was changed. The virus supernatants were collected for 24h, 48h and 72h and concentrated by ultracentrifugation.
(2) Lentiviruses infect adipocytes: C3H10T1/2 cells which are not induced and successfully induced to differentiate are prepared, the slow virus is infected for 8 hours, then the liquid is changed, and the infection is repeated for a plurality of times so as to achieve higher infection efficiency. Western blot detects ALKBH1 protein knockdown or over-expression efficiency.
3) SA-beta-gal staining
(1) Cell preparation: the number of cells should be controlled within 100-150 per field of view, too closely to result in false positives. Fixing solution: taking 3.5mm dish as an example, 16. Mu.l glutaraldehyde, 108. Mu.l 37% formaldehyde, was fixed to a volume of 2mL with PBS and allowed to stand at room temperature for 5min. The fixative was decanted and washed 2 times with PBS.
(2) Dyeing: immersing the cells in SA-beta-gal staining solution, placing in a 37 ℃ incubator in a dark place, taking out the cells after 12-14 hours for microscopic examination, and calculating the proportion of the blue positive cells to all the cells.
4) Real-time PCR detection
(1) Extracting tissue or cellular RNA: about 50mg of tissue was homogenized by electric homogenization after adding Trizol, or the amount of cells in one well of a 6-well plate was increased, chloroform was added in an amount of 0.2mL of chloroform per 1mL of Trizol, vortexed for 15 seconds, and after standing at room temperature for 3 minutes, it was centrifuged at 12000rpm (4 ℃) for 15 minutes, and after centrifugation, it was separated into 3 layers, RNA in the upper aqueous phase, DNA in the middle layer, and protein in the lower organic phase. The upper aqueous phase was carefully aspirated and placed in a fresh EP tube, 0.5mL of isopropanol was added per 1mL of LTrilol, and after 10 minutes of standing at 4℃it was centrifuged at 12000rpm (4 ℃) for 10 minutes. Washing with 1mL of 75% ethanol (DEPC water) added to 1mL of Trizol, centrifuging at 7500rpm (4 ℃) for 5min, and discarding the supernatant; repeating the washing once more, and allowing the precipitated RNA to dry at room temperature for about 5min; RNA pellet was dissolved with 20. Mu.l RNase-free water. RNA purity was checked by OD260/280 and stored in a-80℃refrigerator. (2) reverse transcription and qPCR: equal quality RNA is taken, reverse transcription is carried out by using Fast King RT Kit, the mRNA is reversely transcribed into cDNA according to a product specification system, and then the expression change of the aging related gene mRNA is detected by qPCR. The qPCR primer sequences and reaction systems are shown in tables 1 and 2.
Table 1: qPCR primer sequences
| Primer name | Sequence (5 '-3') |
| p53For | AGAGACCGCCGTACAGAAGA |
| p53Rev | CTGTAGCATGGGCATCCTTT |
| p21For | GTCAGGCTGGTCTGCCTCCG |
| p21Rev | CGGTCCCGTGGACAGTGAGCAG |
| P16For | CCCAACGCCCCGAACT |
| P16Rev | GCAGAAGAGCTGCTACGTGAA |
| Alkbh1For | AAGCGAAGACCCCGAAGTTTA |
| Alkbh1Rev | CAGTGGCGACTTGCTCTGA |
| IL6For | CTTCCATCCAGTTGCCTTCTTG |
| IL6Rev | GTGCTGCCTAATGTCCCCTTGAATC |
| Mmp3For | CAGACTTGTCCCGTTTCCAT |
| Mmp3Rev | GGTGCTGACTGCATCAAAGA |
| Cxcl1For | CACACTCAAGAATGGTCGCGA |
| Cxcl1Rev | TTGTCAGAAGCCAGCGTTCAC |
Table 2: qPCR reaction system (10 μl)
| SYBR | 5μl |
| Primerl | 0.5μl |
| Primer2 | 0.5μl |
| cDNA | 4μl |
The results are shown in FIGS. 1-7. Abdominal (eWAT) and subcutaneous (iWAT) white fat ALKBH1 expression was significantly reduced in 24 month old aged mice compared to 2-3 month old young mice (FIG. 1). The fat mice were induced with high-fat diet feeding, the expression of white liposenin P16 was significantly increased, and the expression of albh 1 was significantly decreased (fig. 2). The above results indicate that the expression level of ALKBH1 is inversely related to the aging degree of white fat.
On C3H10T1/2 mouse embryonic fibroblasts, alkbh1 gene knockout and overexpression were achieved by lentiviruses (fig. 3), and as a result, it was found that Alkbh1 gene knockout accelerated bleomycin-induced cell senescence, while Alkbh1 overexpression delayed bleomycin-induced cell senescence (fig. 4). On mature adipocytes, the same Alkbh1 gene knockout promoted adipocyte senescence, while Alkbh1 overexpression inhibited adipocyte senescence (FIGS. 5-7). The above results suggest that the aging state of adipocytes can be regulated by changing the expression level of ALKBH 1.
Embodiment two: alkbh1 gene knockout can lead to accelerated aging, chronic inflammation and exacerbation of insulin resistance in adipose tissue of high-fat fed obese mice
The in-vivo white fat Alkbh1 gene knockout efficiency is verified through Western blot, the white fat aging condition is detected through SA-beta-gal staining and real-time PCR, F4/80 immunofluorescence staining shows the fat tissue inflammatory cell infiltration condition, and finally, the change of the whole body insulin sensitivity degree of an Alkbh1 gene knockout mouse is verified through GTT and ITT experiments. The specific operation is as follows:
1) GTT detection
Obesity is induced by feeding 60% kcal of high fat diet to 8 week old mice for more than 12 weeks continuously. Mice were weaned 12h earlier and allowed to empty overnight. Blood was collected by tail tip excision, and fasting blood glucose values were measured and recorded. 10% glucose (1 g/kg body weight) was intraperitoneally injected, and then the blood glucose levels of the mice were measured at 15, 30, 60, 90, 120min points, respectively, to examine the response of the mice to high doses of glucose.
2) ITT detection
Mice were weaned 4h in advance and fasting blood glucose was measured. The blood glucose levels of mice were measured and recorded at 15, 30, 60, 90, 120min after intraperitoneal injection of 0.5U/kg body weight insulin, respectively, to determine the response of the mice to high doses of insulin.
3) F4/80 immunofluorescent staining
(1) Dewaxing: the tissue sections were dewaxed in xylene for 20min x2 times; then sequentially placing the mixture to 100%,95%,80% and 60% alcohol for gradient elution for 5min for 1 time; finally distilled water is eluted for 1min multiplied by 2 times
(2) Fixing: fixing with 4% paraformaldehyde for 10min, washing with distilled water for 1min×3 times
(3) Antigen retrieval: boiling in antigen retrieval liquid with high fire for 2-3min, keeping boiling with low fire for 10min, naturally cooling at room temperature for 30min, washing with distilled water for 1 time, and washing with TBST for 3min×2 times.
(4) Endogenous peroxidase blockade: the histochemical pen was circled out of the tissue area on the slide and incubated for 10min with 3% H2O 2.
TBST 5min X3 times
(5) Closing: blocking was performed with 5% BSA at room temperature for 30min.
(6) Binding of primary antibody the slides were placed in a wet box, primary antibody F4/80 was diluted with 5% BSA, primary antibody was added and incubated at room temperature for 60min, TBST was washed 3min X3 times.
(7) Secondary antibody binding: the secondary fluorescent antibody was diluted with 5% BSA and incubated at room temperature for 10min. TBST was washed 3min X2 times.
(8) Dye binding: the 520nm dye was diluted with signal amplification solution, incubated at room temperature in the dark for 10min, and washed 3min×3 times with TBST.
(9) Antigen retrieval: boiling in antigen retrieval liquid with high fire for 2-3min, keeping boiling with low fire for 10min, naturally cooling at room temperature for 30min, washing with distilled water for 1 time, and washing with TBST for 3min×2 times.
(10) Closing: blocking with 5% BSA at RT for 10min
(11) Binding of primary antibody the slides were placed in a wet box, the primary antibody Perlipin was diluted with 5% BSA, primary antibody was added and incubated at room temperature for 60min, and TBST was washed 3min X3 times.
(12) Secondary antibody binding: the secondary fluorescent antibody was diluted with 5% BSA and incubated at room temperature for 10min. TBST was washed 3min X2 times.
(13) Dye binding: the 620nm dye was diluted with signal amplification solution, incubated at room temperature in the dark for 10min, and washed 3min×3 times with TBST.
(14) Antigen retrieval: boiling in antigen retrieval liquid with high fire for 2-3min, keeping boiling with low fire for 10min, naturally cooling at room temperature for 30min, washing with distilled water for 1 time, and washing with TBST for 3min×2 times.
(15) DAPI binding: DAPI was incubated for 5min at room temperature and TBST was washed 3min X3 times.
(16) Sealing and detecting, namely dripping the anti-quenching agent sealing sheet, and performing fluorescence microscopy.
(17) Photographing and counting
As shown in FIGS. 8 to 11, the above results indicate that adipocyte-specific Alkbh1 gene knockout (Alkbh 1 AKO ) The mice and their littermates control wild mice (FIG. 8) were fed with a high fat diet for more than 3 months, resulting in Alkbh1 AKO The staining of mouse adipose tissue SA-beta-Gal was aggravated, and the senescence-associated gene expression was markedly increased (FIG. 9). At the same time, alkbh1 AKO The adipose tissue of the mice showed apparent macrophage infiltration (fig. 10), with an increased abnormal glucose tolerance and a further decrease in insulin sensitivity (fig. 11). The results show that Alkbh1 gene knockout can induce adipose tissue to age, promote inflammation development and insulin resistance.
The above embodiments are not intended to limit the present invention, and the present invention is not limited to the above embodiments, and falls within the scope of the present invention as long as the present invention meets the requirements.
Claims (8)
- The use of alk bh1 as a biomarker of adipocyte aging.
- 2. The use according to claim 1, wherein the expression of albh 1 decreases with increasing expression of senolytic protein P16.
- 3. The use according to claim 1, wherein knocking out the Alkbh1 gene on adipocytes in vitro promotes adipocyte aging and overexpression of the Alkbh1 gene relieves adipocyte aging.
- 4. A product for detecting an adipocyte aging marker, which is characterized by comprising a reagent for detecting ALKBH 1.
- 5. The test product of claim 4, wherein the test product comprises a kit or chip.
- 6. The test product of claim 4, wherein the kit comprises a probe that specifically recognizes alk bh 1.
- 7. The test product of claim 4, wherein the chip comprises a solid support and attached thereto a probe that specifically recognizes ALKBH1 or a primer that specifically amplifies the Alkbh1 gene.
- 8. Application of biomarker ALKBH1 in preparation of anti-aging products.
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