تحلیل بیوانفورماتیکی شبکه‌های ژنی و تحلیل مسیر رونویسی کبد چرب غیرالکلی در پاسخ به تمرین ورزشی

نوع مقاله : مقاله مروری

نویسندگان

گروه علوم ورزشی، دانشگاه اصفهان، اصفهان، ایران

چکیده

بیماری کبد چرب غیرالکلی (NAFLD) از شایع‌ترین علل اختلال عملکرد کبد است و شیوع آن به‌طور چشمگیری افزایش یافته است. بر پایة پژوهش‌های انجام‌گرفته فعالیت بدنی ضمن افزایش بیان پروتئین‌هایی مانند PPARα با افزایش هزینة انرژی سبب کاهش انباشت چربی در کبد می‌شود و از این راه بر NAFLD تأثیر می‌گذارد. هدف پژوهش حاضر، شناسایی ژن‌های حیاتی و مسیرهای کلیدی وابسته به NAFLD و بررسی شبکه‌های ژنی درگیر در این بیماری، به‌همراه تأثیر فعالیت ورزشی بر این مسیرهاست. همچنین تحلیل‌های بیوانفورماتیکی انجام‌گرفته به شفاف‌سازی ارتباطات و تعاملات میان این ژن‌ها و مسیرها کمک می‌کند. مسیرها را با استفاده از داده‌های رونویسی تحلیل و ژن هاب درگیر در مسیرهای وابسته به  NAFLD تعیین کردیم. تجزیه‌وتحلیل خوشة شبکه نتیجة تجزیه‌وتحلیل GO و کیوتو دایرة‌المعارف ژن و ژنوم (KEGG) را تأیید کرد. ژن‌های کشف‌شدة FASN, ACOX1, SREBF1-c, PPARA هستند که در فرایندهای بیماری‌زایی یا مقاومت در برابر NAFLD نقش دارند. نتایج این پژوهش فهرستی از ژن‌های هاب، مسیرهای مهم و بینش‌های جدید برای توسعة آتی درمان NAFLD ارائه کرده و سازوکار اساسی پاسخ کبد را به فعالیت ورزشی روشن می‌کند.

کلیدواژه‌ها

موضوعات

عنوان مقاله [English]

Bioinformatic analysis of gene networks and transcriptional pathway analysis of non-alcoholic fatty liver disease (NAFLD) in response to exercise training

نویسندگان [English]

  • Zahra Asheghi
  • Sayed Mohammad Marandi
Department of Sport Sciences,University of Isfahan, Isfahan,Iran
چکیده [English]

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver dysfunction, and its prevalence has increased significantly. Based on the research conducted, physical activity while increasing the expression of proteins such as peroxisome proliferator-activated receptor alpha (PPARα) with increasing energy consumption causes a decrease in the accumulation of fat in the liver and thus affects NAFLD. The goal of the present study is to identify critical genes and key pathways associated with NAFLD, and to analyze the gene networks involved in this disease, alongside the impact of exercise on these pathways. Furthermore, bioinformatics analyses have been conducted to clarify the interactions between these genes and pathways. We determined the pathways by using the analyzed transcriptional data and hub genes involved in NAFLD-related pathways. Network cluster analysis confirmed the result of Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The discovered genes are fatty acid synthase (FASN), acyl-CoA oxidase 1 (ACOX1), Sterol regulatory element-binding transcription factor 1 (SREBF1-c), PPARα, which are involved in the processes of pathogenesis or resistance to NAFLD. The results of this study provide a list of hub genes, important pathways and new insights for the future development of NAFLD treatment and elucidate the underlying mechanism of liver response to exercise.

کلیدواژه‌ها [English]

  • Bioinformatics
  • Protein-protein interaction
  • Gene networks
  • Non-alcoholic fatty liver
  • Exercise

مراجع

  1. Guo Z, Yu X, Fang Z, Yang K, Liu C, Dong Z, Liu C. The role of endoplasmic reticulum stress-related genes in the diagnosis and subtyping of non-alcoholic fatty liver disease. Gen Physiol Biophys. 2024 Mar;43(2):85-102. doi: 10.4149/gpb_2023042. PMID: 38477602
  2. Kounatidis D, Vallianou NG, Geladari E, Panoilia MP, Daskou A, Stratigou T, Karampela I,Tsilingiris D, Dalamaga M. NAFLD in the 21st Century: Current Knowledge Regarding Its Pathogenesis, Diagnosis and Therapeutics. Biomedicines. 2024; 12(4):826. https://doi.org/10.3390/biomedicines12040826
  3. Yasmin T, Rahman MM, Khan F, Kabir F, Nahar K, Lasker S, Islam MD, Hossain MM, Hasan R, Rana S, Alam MA. Metformin treatment reverses high fat diet- induced non-alcoholic fatty liver diseases and dyslipidemia by stimulating multiple antioxidant and anti-inflammatory pathways. Biochem Biophys Rep. 2021 Nov 17;28:101168. doi: 10.1016/j.bbrep.2021.101168. PMID: 34825068; PMCID: PMC8605070.
  4. Yousof TR, Bouchard CC, Alb M, Lynn EG, Lhoták S, Jiang H, MacDonald M, Li H, Byun JH, Makda Y, Athanasopoulos M, Maclean KN, Cherrington NJ, Naqvi A, Igdoura SA, Krepinsky JC, Steinberg GR, Austin RC. Restoration of the ER stress response protein TDAG51 in hepatocytes mitigates NAFLD in mice. J Biol Chem. 2024 Feb;300(2):105655. doi: 10.1016/j.jbc.2024.105655. Epub 2024 Jan 16. PMID: 38237682; PMCID: PMC10875272.-09
  5. Zhang L, Fan JB, Zhang XW, Liu Y, Shi WY, Hidayat K, Xu JY, Yuan L, Qin LQ. Organic selenium ameliorates non-alcoholic fatty liver disease through 5-hydroxytryptamine/bile acid enterohepatic circulation in mice. Journal of Functional Foods. 2023 Jul 1;106:105596. https://doi.org/10.1016/j.jff.2023.105596
  6. Powell, E. E., Wong, V. W., & Rinella, M. (2021). Non-alcoholic fatty liver disease. Lancet (London, England), 397(10290), 2212–2224. https://doi.org/10.1016/S0140-6736(20)32511-3
  7. Zeng Q, Liu CH, Ampuero J, Wu D, Jiang W, Zhou L, Li H, Bai L, Romero-Gómez M, Tang H. Circular RNAs in non-alcoholic fatty liver disease: Functions and clinical significance. RNA Biol. 2024 Jan;21(1):1-15. doi: 10.1080/15476286.2023.2290769. Epub 2023 Dec 19. PMID: 38113132; PMCID: PMC10761141.
  8. Ezhilarasan D. Deciphering the molecular pathways of saroglitazar: A dual PPAR α/γ agonist for managing metabolic NAFLD. Metabolism. 2024 Jun;155:155912. doi: 10.1016/j.metabol.2024.155912. Epub 2024 Apr 11. PMID: 38609038.
  9. Huang, W. C., Xu, J. W., Li, S., Ng, X. E., & Tung, Y. T. (2022). Effects of exercise on high-fat diet-induced non-alcoholic fatty liver disease and lipid metabolism in ApoE knockout mice. Nutrition & metabolism, 19(1), 10. https://doi.org/10.1186/s12986-022-00644-w
  10. Danielewski, M.; Rapak, A.; Kruszyńska, A.; Małodobra-Mazur, M.; Oleszkiewicz, P.; Dzimira, S.; Kucharska, A.Z.; Słupski, W.; Matuszewska, A.; Nowak, B.; et al. Cornelian Cherry (Cornus mas L.) Fruit Extract Lowers SREBP-1c and C/EBPα in Liver and Alters Various PPAR-α, PPAR-γ, LXR-α Target Genes in Cholesterol-Rich Diet Rabbit Model. Int. J. Mol. Sci. 2024, 25, 1199. https://doi.org/10.3390/ijms25021199
  11. Love, M. I., Huber, W., & Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology, 15(12), 550. https://doi.org/10.1186/s13059-014-0550-8
  12. Li M, Li D, Tang Y, Wu F, Wang J. CytoCluster: A Cytoscape Plugin for Cluster Analysis and Visualization of Biological Networks. International Journal of Molecular Sciences. 2017; 18(9):1880. https://doi.org/10.3390/ijms18091880
  13. Binenbaum, I., Atamni, H. A., Fotakis, G., Kontogianni, G., Koutsandreas, T., Pilalis, E., Mott, R., Himmelbauer, H., Iraqi, F. A., & Chatziioannou, A. A. (2020). Container-aided integrative QTL and RNA-seq analysis of Collaborative Cross mice supports distinct sex-oriented molecular modes of response in obesity. BMC genomics, 21(1), 761. https://doi.org/10.1186/s12864-020-07173-x
  14. Zhu, Z., Chen, Y., Qin, X., Liu, S., Wang, J., & Ren, H. (2023). Multidimensional landscape of non‐alcoholic fatty liver disease‐related disease spectrum uncovered by big omics data: Profiling evidence and new perspectives. Smart Medicine, 2(2), e20220029. https://doi.org/10.1002/SMMD.20220029
  15. Feng, J., Wang, S., Chen, F., Zhang, J., Wang, Q., Jiang, L., ... & Shen, Q. (2024). Effects of triglyceride and ethyl ester forms of EPA on hepatic lipid metabolism in mice with non-alcoholic fatty liver disease. Journal of Functional Foods, 116, 106179. https://doi.org/10.1016/j.jff.2024.106179
  16. Cebola, I. (2020). Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 12(3), e1480. https://doi.org/10.1002/wsbm.1480
  17. Melo L, Hagar A, Klaunig JE. Gene expression signature of exercise and change of diet on non-alcoholic fatty liver disease in mice. Comparative Exercise Physiology. 2022 Feb 22;18(2):143-54. https://doi.org/10.3920/CEP210033
  18. Xu L, Yin L, Qi Y, Tan X, Gao M, Peng J. 3D disorganization and rearrangement of genome provide insights into pathogenesis of NAFLD by integrated Hi-C, Nanopore, and RNA sequencing. Acta Pharm Sin B. 2021 Oct;11(10):3150-3164. doi: 10.1016/j.apsb.2021.03.022. Epub 2021 Apr 6. PMID: 34729306; PMCID: PMC8546856.
  19. Damian Szklarczyk, Andrea Franceschini, Stefan Wyder, Kristoffer Forslund, Davide Heller, Jaime Huerta-Cepas, Milan Simonovic, Alexander Roth, Alberto Santos, Kalliopi P. Tsafou, Michael Kuhn, Peer Bork, Lars J. Jensen, Christian von Mering, STRING v10: protein–protein interaction networks, integrated over the tree of life, Nucleic Acids Research, Volume 43, Issue D1, 28 January 2015, Pages D447–D452, https://doi.org/10.1093/nar/gku1003
  20. Michael E. Smoot, Keiichiro Ono, Johannes Ruscheinski, Peng-Liang Wang, Trey Ideker, Cytoscape 2.8: new features for data integration and network visualization, Bioinformatics, Volume 27, Issue 3, February 2011, Pages 431–432, https://doi.org/10.1093/bioinformatics/btq675
  21. Chin, C. H., Chen, S. H., Wu, H. H., Ho, C. W., Ko, M. T., & Lin, C. Y. (2014). cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC systems biology, 8 Suppl 4(Suppl 4), S11. https://doi.org/10.1186/1752-0509-8-S4-S11
  22. Yon Rhee, S., Wood, V., Dolinski, K. et al. Use and misuse of the gene ontology annotations. Nat Rev Genet 9, 509–515 (2008). https://doi.org/10.1038/nrg2363
  23. Romero-Gómez, M., Zelber-Sagi, S., Martín, F., Bugianesi, E., & Soria, B. (2023). Nutrition could prevent or promote non-alcoholic fatty liver disease: an opportunity for intervention. BMJ (Clinical research ed.), 383, e075179. https://doi.org/10.1136/bmj-2023-075179
  24. Geng, Y., Faber, K. N., de Meijer, V. E., Blokzijl, H., & Moshage, H. (2021). How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?. Hepatology international, 15(1), 21–35. https://doi.org/10.1007/s12072-020-10121-2
  25. Shen Q, Yang M, Wang S, Chen X, Chen S, Zhang R, Xiong Z, Leng Y. The pivotal role of dysregulated autophagy in the progression of non-alcoholic fatty liver disease. Frontiers in Endocrinology. 2024 Aug 8;15:1374644. https://doi.org/10.3389/fendo.2024.1374644
  26. Habibullah M, Jemmieh K, Ouda A, Haider MZ, Malki MI, Elzouki AN. Metabolic-associated fatty liver disease: A selective review of pathogenesis, diagnostic approaches, and therapeutic strategies. Frontiers in Medicine. 2024 Jan 23;11:1291501. https://doi.org/10.3389/fmed.2024.1291501
  27. Ming, Z., Ruishi, X., Linyi, X., Yonggang, Y., Haoming, L., & Xintian, L. (2024). The gut-liver axis in fatty liver disease: role played by natural products. Frontiers in pharmacology, 15, 1365294. https://doi.org/10.3389/fphar.2024.1365294
  28. Ortiz, C., Schierwagen, R., Schaefer, L., Klein, S., Trepat, X., & Trebicka, J. (2021). Extracellular Matrix Remodeling in Chronic Liver Disease. Current tissue microenvironment reports, 2(3), 41–52. https://doi.org/10.1007/s43152-021-00030-3
  29. Kanehisa, M., & Goto, S. (2000). KEGG: kyoto encyclopedia of genes and genomes. Nucleic acids research, 28(1), 27-30.
  30. [30] Nishimura, T., Takadate, T., Maeda, S. et al. Disease-related protein co-expression networks are associated with the prognosis of resectable node-positive pancreatic ductal adenocarcinoma. Sci Rep 12, 14709 (2022). https://doi.org/10.1038/s41598-022-19182-9
  31. Zhou, F., Ding, M., Gu, Y., Fan, G., Liu, C., Li, Y., Sun, R., Wu, J., Li, J., Xue, X., Li, H., & Li, X. (2022). Aurantio-Obtusin Attenuates Non-Alcoholic Fatty Liver Disease Through AMPK-Mediated Autophagy and Fatty Acid Oxidation Pathways. Frontiers in pharmacology, 12, 826628. https://doi.org/10.3389/fphar.2021.826628
  32. Gao, Y., Zhang, S., Li, J., Zhao, J., Xiao, Q., Zhu, Y., Zhang, J., & Huang, W. (2020). Effect and mechanism of ginsenoside Rg1-regulating hepatic steatosis in HepG2 cells induced by free fatty acid. Bioscience, biotechnology, and biochemistry, 84(11), 2228–2240. https://doi.org/10.1080/09168451.2020.1793293
  33. Chandrasekaran, P.; Weiskirchen, R. The Role of SCAP/SREBP as Central Regulators of Lipid Metabolism in Hepatic Steatosis. Int. J. Mol. Sci. 2024, 25, 1109. https://doi.org/10.3390/ijms25021109
  34. Moldavski, O., Zushin, P. H., Berdan, C. A., Van Eijkeren, R. J., Jiang, X., Qian, M., Ory, D. S., Covey, D. F., Nomura, D. K., Stahl, A., Weiss, E. J., & Zoncu, R. (2021). 4β-Hydroxycholesterol is a prolipogenic factor that promotes SREBP1c expression and activity through the liver X receptor. Journal of lipid research, 62, 100051. https://doi.org/10.1016/j.jlr.2021.100051
  35. Chen S, Ni J, Luo L, Lin J, Peng H, Shen F, Huang Z. Toosendanin induces hepatotoxicity via disrupting LXRα/Lipin1/SREBP1 mediated lipid metabolism. Food Chem Toxicol. 2024 May;187:114631. doi: 10.1016/j.fct.2024.114631. Epub 2024 Apr 1. PMID: 38570025.
  36. Zhang X, Lin W, Lei S, Zhang S, Cheng Y, Chen X, Lu Y, Zhao D, Zhang Y, Guo C. The anti-hyperlipidemic effects of Poria cocos (Schw.) Wolf extract: Modulating cholesterol homeostasis in hepatocytes via PPARα pathway. J Ethnopharmacol. 2024 Mar 1;321:117532. doi: 10.1016/j.jep.2023.117532. Epub 2023 Dec 2. PMID: 38048892.
  37. Monroy-Ramirez, H. C., Galicia-Moreno, M., Sandoval-Rodriguez, A., Meza-Rios, A., Santos, A., & Armendariz-Borunda, J. (2021). PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases. International journal of molecular sciences, 22(15), 8298. https://doi.org/10.3390/ijms22158298
  38. Ding M, Zhou F, Li Y, Liu C, Gu Y, Wu J, Fan G, Li Y, Li X. Cassiae Semen improves non-alcoholic fatty liver disease through autophagy-related pathway. Chin Herb Med. 2023 Mar 22;15(3):421-429. doi: 10.1016/j.chmed.2022.09.006. PMID: 37538867; PMCID: PMC10394324.
  39. He A, Chen X, Tan M, Chen Y, Lu D, Zhang X, Dean JM, Razani B, Lodhi IJ. Acetyl-CoA Derived from Hepatic Peroxisomal β-Oxidation Inhibits Autophagy and Promotes Steatosis via mTORC1 Activation. Mol Cell. 2020 Jul 2;79(1):30-42.e4. doi: 10.1016/j.molcel.2020.05.007. Epub 2020 May 29. PMID: 32473093; PMCID: PMC7335356.
  40. Berthier, A., Johanns, M., Zummo, F. P., Lefebvre, P., & Staels, B. (2021). PPARs in liver physiology. Biochimica et biophysica acta. Molecular basis of disease, 1867(5), 166097. https://doi.org/10.1016/j.bbadis.2021.166097
  41. Rustgi, V. K., Duff, S. B., & Elsaid, M. I. (2022). Cost-effectiveness and potential value of pharmaceutical treatment of nonalcoholic fatty liver disease. Journal of medical economics, 25(1), 347–355. https://doi.org/10.1080/13696998.2022.2026702
  42. Bai Y, Chen K, Liu J, Wang Y, Wang C, Ju S, Zhou C, Yao W, Xiong B, Zheng C. Activation of AMPK pathway by low‑dose donafenib and atorvastatin combination improves high‑fat diet‑induced metabolic dysfunction‑associated steatotic liver disease. Mol Med Rep. 2024 Mar;29(3):51. doi: 10.3892/mmr.2024.13175. Epub 2024 Feb 1. PMID: 38299233.
  43. Younossi, Z. M., Corey, K. E., & Lim, J. K. (2021). AGA Clinical Practice Update on Lifestyle Modification Using Diet and Exercise to Achieve Weight Loss in the Management of Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology, 160(3), 912–918. https://doi.org/10.1053/j.gastro.2020.11.051
  44. Fredrickson, G., Barrow, F., Dietsche, K., Parthiban, P., Khan, S., Robert, S., Demirchian, M., Rhoades, H., Wang, H., Adeyi, O., & Revelo, X. S. (2021). Exercise of high intensity ameliorates hepatic inflammation and the progression of NASH. Molecular metabolism, 53, 101270. https://doi.org/10.1016/j.molmet.2021.101270
  45. Zou, Y., & Qi, Z. (2020). Understanding the Role of Exercise in Nonalcoholic Fatty Liver Disease: ERS-Linked Molecular Pathways. Mediators of inflammation, 2020, 6412916. https://doi.org/10.1155/2020/6412916
  46. Bae JY. Resistance Exercise Regulates Hepatic Lipolytic Factors as Effective as Aerobic Exercise in Obese Mice. International Journal of Environmental Research and Public Health. 2020; 17(22):8307. https://doi.org/10.3390/ijerph17228307
  47. Melo, L., Bilici, M., Hagar, A., & Klaunig, J. E. (2021). The effect of endurance training on non-alcoholic fatty liver disease in mice. Physiological reports, 9(15), e14926. https://doi.org/10.14814/phy2.14926
  48. Cui, N., Li, H., Dun, Y., Ripley-Gonzalez, J. W., You, B., Li, D., Liu, Y., Qiu, L., Li, C., & Liu, S. (2022). Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease. Frontiers in endocrinology, 13, 961231. https://doi.org/10.3389/fendo.2022.961231
  49. Diniz, T. A., de Lima Junior, E. A., Teixeira, A. A., Biondo, L. A., da Rocha, L. A. F., Valadão, I. C., ... & Neto, J. C. R. (2021). Aerobic training improves NAFLD markers and insulin resistance through AMPK-PPAR-α signaling in obese mice. Life sciences, 266, 118868. DOI: 1016/j.lfs.2020.118868.

 

فایل ها

سابقه مقاله

  • تاریخ دریافت: 24 مرداد 1403
  • تاریخ بازنگری: 18 مهر 1403
  • تاریخ پذیرش: 10 آبان 1403
  • تاریخ اولین انتشار: 10 آبان 1403
  • تاریخ انتشار: 01 آبان 1403

هم رسانی

ارجاع به این مقاله

آمار