切换至 "中华医学电子期刊资源库"

中华临床医师杂志(电子版) ›› 2024, Vol. 18 ›› Issue (05) : 481 -490. doi: 10.3877/cma.j.issn.1674-0785.2024.05.007

循证医学

T2DM、Obesity、NASH、PCOS共同致病因素相关的分子机制
王星1, 陈园1, 热孜万古丽·乌斯曼1, 郭艳英1,()   
  1. 1. 830001 新疆乌鲁木齐,新疆维吾尔自治区人民医院内分泌与代谢病科
  • 收稿日期:2024-02-25 出版日期:2024-05-15
  • 通信作者: 郭艳英

Co-pathogenic genes and potential common molecular mechanisms of type 2 diabetes mellitus, obesity, nonalcoholic steatohepatitis, and polycystic ovary syndrome

Xing Wang1, Yuan Chen1, , Wusman Rezi Wan Guli1, Yanying Guo1,()   

  1. 1. Department of Endocrine and Metabolic Diseases, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China
  • Received:2024-02-25 Published:2024-05-15
  • Corresponding author: Yanying Guo
引用本文:

王星, 陈园, 热孜万古丽·乌斯曼, 郭艳英. T2DM、Obesity、NASH、PCOS共同致病因素相关的分子机制[J/OL]. 中华临床医师杂志(电子版), 2024, 18(05): 481-490.

Xing Wang, Yuan Chen, , Wusman Rezi Wan Guli, Yanying Guo. Co-pathogenic genes and potential common molecular mechanisms of type 2 diabetes mellitus, obesity, nonalcoholic steatohepatitis, and polycystic ovary syndrome[J/OL]. Chinese Journal of Clinicians(Electronic Edition), 2024, 18(05): 481-490.

目的

探讨T2DM、Obesity、NASH、PCOS共同致病基因和潜在分子机制。

方法

从GEO数据库下载了GSE20966、GSE17470、GSE88837、GSE34526基因表达谱(DEGs),使用limma包分别进行差异分析,再对4组差异基因取交集,确定并进行功能富集分析,构建蛋白-蛋白相互作用网络(PPI)。采用CIBERSORT算法对不同患者RNA-seq数据进行分析,用来推断22种免疫浸润细胞的相对比例。采用GSVA算法对每个基因集合进行综合打分,评估不同样本潜在的生物学功能变化。

结果

5个交集基因被确定,分别为PTPN3、GBP2、ARL1、NEDD4L、PTPN11。其中PTPN11、NEDD4L、GBP2与胰岛素相关通路相关。进一步通过GSVA验证3个核心基因涉及的具体信号通路,为高表达GBP2与P53 PATHWAY、KRAS SIGNALING、APOPTOSIS等信号通路相关;高表达NEDD4L与G2M CHECKPOINT、TGF BETA SIGNALING、ADIPOGENESIS等信号通路相关;高表达PTPN11与PROTEIN SECRETION、ADIPOGENESIS、FATTY ACID METABOLISM等信号通路相关。

结论

新发现2型糖尿病、肥胖、非酒精性脂肪肝/非酒精性脂肪性肝炎、多囊卵巢综合征的共病基因及其代谢相关信号通路,为其治疗及诊断提供了新靶点及生物标志物。

Objective

To explore the co-pathogenic genes and potential common molecular mechanisms of type 2 diabetes mellitus (T2DM), obesity, nonalcoholic steatohepatitis (NASH), and polycystic ovary syndrome (PCOS).

Methods

The gene expression datasets GSE20966, GSE17470, GSE88837, and GSE34526 were downloaded from the GEO database, and differentially expressed genes were identified with limma package. Then, the four groups of differentially expressed genes were intersected, and function enrichment analysis was performed to construct a protein-protein interaction (PPI) network. CIBERSORT algorithm was used to analyze the RNA-seq data of different patients, so as to infer the relative proportion of 22 kinds of immune infiltrating cells. GSVA algorithm was used to comprehensively score each gene set and evaluate the potential biological function changes of different samples.

Results

Five intersecting genes were identified, namely, PTPN3, GBP2, ARL1, NEDD4L, and PTPN11. PTPN11, NEDD4L, and GBP2 are related to insulin-related pathways. Furthermore, the specific signal pathways involved in the three core genes were verified by GSVA, which showed that the high expression of GBP2 is related to P53 PATHWAY, KRAS SIGNALING, APOPTOSIS, and other signal pathways. The high expression of NEDD4L is related to G2M CHECKPOINT, TGF BETA SIGNALING, and ADIPOGENESIS. High expression of PTPN11 is related to PROTEIN SECRETION, ADIPOGENESIS, FATTY ACID METABOLISM, and other signal pathways.

Conclusion

The newly discovered comorbid genes and the related metabolic signal pathways in T2DM, obesity, NASH, and PCOS provide new targets and biomarkers for their treatment and diagnosis.

图1 差异基因Venn图
图2a 差异基因通路富集分析
图2b 关键基因PPI网络
图3 关键基因与胰岛素相关通路
图4 疾病组T cells CD8、Macrophages M2均显著上调
图5a 为GBP2与Macrophages M2显著正相关,与B cells memory、Macrophages M0显著负相关
图5b NEDD4L与Eosinophils显著正相关,与Monocytes、Macrophages M1显著负相关
图5c PTPN11与Dendritic cells activated、Eosinophils、B cells naïve显著正相关,与Monocytes、Plasma cells、Dendritic cells resting、T cells CD8显著负相关
图6a 高表达GBP2相关信号通路
图6b 高表达NEDD4L相关信号通路
图6c 高表达PTPN11相关通路
1
Dogruel H, Balci MK. Development of therapeutic options on type 2 diabetes in years: Glucagon-like peptide-1 receptor agonist's role intreatment; from the past to future [J]. World J Diabetes, 2019, 10(8): 446-453.
2
Brunetti A, Chiefari E, Foti D. Recent advances in the molecular genetics of type 2 diabetes mellitus [J]. World J Diabetes, 2014, 5(2): 128-140.
3
Harding JL, Pavkov ME, Magliano DJ, et al. Global trends in diabetes complications: a review of current evidence [J]. Diabetologia, 2019, 62(1): 3-16.
4
Ashcroft FM, Rorsman P. Diabetes mellitus and the β cell: the last ten years [J]. Cell, 2012, 148(6): 1160-1171.
5
Hotamisligil GS. Endoplasmic reticulum stress and inflammation in obesity and type 2 diabetes [J]. Novartis Found Symp, 2007, 286: 86-94; discussion 94-98, 162-3, 196-203.
6
Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes [J]. Nature, 2006, 444(7121): 840-846.
7
Hotamisligil GS. Inflammation and metabolic disorders [J]. Nature, 2006, 444(7121): 860-867.
8
Andronescu CI, Purcarea MR, Babes PA. Nonalcoholic fatty liver disease: epidemiology, pathogenesis and therapeutic implications [J]. J Med Life, 2018, 11(1): 20-23.
9
Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis [J]. N Engl J Med, 2017, 377(21): 2063-2072.
10
Funke A, Schreurs M, Aparicio-Vergara M, et al. Cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male LDL receptor knockout mice [J]. Atherosclerosis, 2014, 232(2): 390-396.
11
Petersen MC, Shulman GI. Roles of diacylglycerols and ceramides in hepatic insulin resistance [J]. Trends Pharmacol Sci, 2017, 38(7): 649-665.
12
Conway G, Dewailly D, Diamanti-Kandarakis E, et al. European survey of diagnosis and management of the polycystic ovary syndrome: results of the ESE PCOS special interest group's questionnaire [J]. Eur J Endocrinol, 2014, 171(4): 489-498.
13
Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications [J]. Endocr Rev, 2012, 33(6): 981-1030.
14
Anagnostis P, Tarlatzis BC, Kauffman RP. Polycystic ovarian syndrome (PCOS): Long-term metabolic consequences [J]. Metabolism, 2018, 86: 33-43.
15
Vassilatou E, Lafoyianni S, Vryonidou A, et al. Increased androgen bioavailability is associated with non-alcoholic fatty liver disease in women with polycystic ovary syndrome [J]. Hum Reprod, 2010, 25(1): 212-220.
16
Macut D, Tziomalos K, Božić-Antić I, et al. Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome [J]. Hum Reprod, 2016, 31(6): 1347-1353.
17
Petta S, Ciresi A, Bianco J, et al. Insulin resistance and hyperandrogenism drive steatosis and fibrosis risk in young females with PCOS [J]. PLoS One, 2017, 12(11): e0186136.
18
Wu J, Yao XY, Shi RX, et al. A potential link between polycystic ovary syndrome and non-alcoholic fatty liver disease: an update meta-analysis [J]. Reprod Health, 2018, 15(1): 77.
19
Vassilatou E. Nonalcoholic fatty liver disease and polycystic ovary syndrome [J]. World J Gastroenterol, 2014, 20(26): p 8351-8563.
20
Macut D, Bjekić-Macut J, Livadas S, et al. Nonalcoholic fatty liver disease in patients with polycystic ovary syndrome [J]. Curr Pharm Des, 2018, 24(38): 4593-4597.
21
Vestal DJ, Buss JE, McKercher SR, et al. Murine GBP-2: a new IFN-gamma-induced member of the GBP family of GTPases isolated from macrophages [J]. J Interferon Cytokine Res, 1998, 18(11): 977-985.
22
Decker T, Lew DJ, Cheng YS, et al. Interactions of alpha- and gamma-interferon in the transcriptional regulation of the gene encoding a guanylate-binding protein [J]. EMBO J, 1989, 8(7): 2009-2014.
23
Boehm U, Guethlein L, Klamp T, et al. Two families of GTPases dominate the complex cellular response to IFN-gamma [J]. J Immunol, 1998, 161(12): 6715-6723.
24
Meunier E, Wallet P, Dreier RF, et al. Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida [J]. Nat Immunol, 2015, 16(5): 476-484.
25
Man SM, Place DE, Kuriakose T, et al. Interferon-inducible guanylate-binding proteins at the interface of cell-autonomous immunity and inflammasome activation [J]. J Leukoc Biol, 2017, 101(1): 143-150.
26
Christian SL, Zu D, Licursi M, et al. Suppression of IFN-induced transcription underlies IFN defects generated by activated Ras/MEK in human cancer cells [J]. PLoS One, 2012, 7(9): e44267.
27
Rahvar F, Salimi M, Mozdarani H. Plasma GBP2 promoter methylation is associated with advanced stages in breast cancer [J]. Genet Mol Biol, 2020, 43(4): e20190230.
28
Yu S, Yu X, Sun L, et al. GBP2 enhances glioblastoma invasion through Stat3/fibronectin pathway [J]. Oncogene, 2020, 39(27): 5042-5055.
29
Basu S, Murphy ME. Genetic modifiers of the p53 pathway [J]. Cold Spring Harb Perspect Med, 2016, 6(4): a026302.
30
Vousden KH, Prives C. Blinded by the light: the growing complexity of p53 [J]. Cell, 2009, 137(3): 413-431.
31
Goel P, Manning JA, Kumar S. NEDD4-2 (NEDD4L): the ubiquitin ligase for multiple membrane proteins [J]. Gene, 2015, 557(1): 1-10. d
32
Dunn DM, Ishigami T, Pankow J, et al. Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript [J]. J Hum Genet, 2002, 47(12): 665-676.
33
Russo CJ, Melista E, Cui J, et al. Association of NEDD4L ubiquitin ligase with essential hypertension [J]. Hypertension, 2005, 46(3): 488-491.
34
Svensson-Färbom P, Wahlstrand B, Almgren P, et al. A functional variant of the NEDD4L gene is associated with beneficial treatment response with β-blockers and diuretics in hypertensive patients [J]. J Hypertens, 2011, 29(2): 388-395.
35
Duerr J, Leitz DHW, Szczygiel M, et al. Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice [J]. Nat Commun, 2020, 11(1): 2012.
36
Song R, Peng W, Zhang Y, et al. Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders [J]. Nature, 2013, 494(7437): 375-379.
37
Cao XR, Lill NL, Boase N, et al. Nedd4 controls animal growth by regulating IGF-1 signaling [J]. Sci Signal, 2008, 1(38): ra5.
38
Li JJ, Ferry RJJr, Diao S, et al. Nedd4 haploinsufficient mice display moderate insulin resistance, enhanced lipolysis, and protection against high-fat diet-induced obesity [J]. Endocrinology, 2015, 156(4): 1283-1291.
39
Ranza E, Guimier A, Verloes A, et al. Overlapping phenotypes between SHORT and Noonan syndromes in patients with PTPN11 pathogenic variants [J]. Clin Genet, 2020, 98(1): 10-18.
[1] 曹雯佳, 刘学兵, 罗安果, 钟释敏, 邓岚, 王玉琳, 李赵欢. 超声矢量血流成像对2型糖尿病患者颈动脉壁剪切应力的研究[J/OL]. 中华医学超声杂志(电子版), 2024, 21(07): 709-717.
[2] 向韵, 卢游, 杨凡. 全氟及多氟烷基化合物暴露与儿童肥胖症相关性研究现状[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(05): 569-574.
[3] 陈嘉婷, 杜美君, 石冰, 黄汉尧. 母体系统性疾病对新生儿唇腭裂发生的影响[J/OL]. 中华口腔医学研究杂志(电子版), 2024, 18(04): 262-268.
[4] 赵丽霞, 王春霞, 陈一锋, 胡东平, 张维胜, 王涛, 张洪来. 内脏型肥胖对腹腔镜直肠癌根治术后早期并发症的影响[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 35-39.
[5] 孟令凯, 李大勇, 王宁, 王桂明, 张炳南, 李若彤, 潘立峰. 袖状胃切除术对肥胖伴2型糖尿病大鼠的作用及机制研究[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(06): 638-642.
[6] 李猛, 姜腊, 董磊, 吴情, 贾犇黎. 腹腔镜胃袖状切除术治疗肥胖合并2型糖尿病及脂肪胰的临床研究[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(05): 554-557.
[7] 杨波, 胡旭, 何金艳, 谢铭. 腹腔镜袖状胃切除术管胃固定研究现状[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(04): 452-455.
[8] 吉顺富, 汤晓燕, 徐进. 腹腔镜近端胃癌根治术中拓展胃后间隙在肥胖患者中的应用研究[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(04): 393-396.
[9] 玉素江·图荪托合提, 韩琦, 麦麦提艾力·麦麦提明, 黄旭东, 王浩, 克力木·阿不都热依木, 艾克拜尔·艾力. 腹腔镜袖状胃切除或联合食管裂孔疝修补术对肥胖症合并胃食管反流病的中期疗效分析[J/OL]. 中华疝和腹壁外科杂志(电子版), 2024, 18(05): 501-506.
[10] 刘见, 杨晓波, 何均健, 等. 应用电钩三孔法腹腔镜袖状胃切除术[J/OL]. 中华腔镜外科杂志(电子版), 2024, 17(06): 363-364.
[11] 谢浩文, 丁建英, 刘小霞, 冯毅, 姚婧. 椎旁神经阻滞对微创胃切除肥胖患者术中血流、术后应激及康复质量的影响[J/OL]. 中华消化病与影像杂志(电子版), 2024, 14(06): 569-573.
[12] 唐小久, 胡曼, 许必君, 肖亚. 肥胖合并胃食管反流病患者严重程度与其焦虑抑郁及营养状态的相关性研究[J/OL]. 中华消化病与影像杂志(电子版), 2024, 14(04): 360-364.
[13] 王璇, 娜扎开提·尼加提, 雒洋洋, 蒋升. 皮肤晚期糖基化终末产物浓度与2型糖尿病微血管并发症的相关性[J/OL]. 中华临床医师杂志(电子版), 2024, 18(05): 447-454.
[14] 袁捷, 乔钰琪, 李彦冬. 二甲双胍、来曲唑联合地屈孕酮治疗多囊卵巢综合征合并不孕症的效果评价[J/OL]. 中华临床医师杂志(电子版), 2024, 18(04): 343-347.
[15] 中国医师协会外科医师分会肥胖代谢病综合管理与护理专家工作组, 中国医师协会外科医师分会肥胖和代谢病外科专家工作组, 中国肥胖代谢外科研究协作组. 肥胖代谢外科医学科普中国专家共识(2024 版)[J/OL]. 中华肥胖与代谢病电子杂志, 2024, 10(04): 227-234.
阅读次数
全文


摘要


AI


AI小编
你好!我是《中华医学电子期刊资源库》AI小编,有什么可以帮您的吗?