Skip to main content
SpringerLink
Log in

Relationships between Cxcl12, Tweak, Notch1, and Yap mRNA Expression Levels in Molecular Mechanisms of Liver Fibrogenesis

  • CELL MOLECULAR BIOLOGY
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract

Current data on the molecular mechanisms of liver fibrosis and cirrhosis fail to fully explain all stages of their development. Interactions between individual genes and signaling pathways are known to play an important role in their functions. However, data on their relationships are insufficient and often contradictory. For the first time, mRNA expression of Notch1, Notch2, Yap1, Tweak (Tnfsf12), Fn14 (Tnfrsf12a), Ang, Vegfa, Cxcl12 (Sdf), Nos2, and Mmp-9 was studied in detail at several stages of thioacetamide-induced liver fibrosis in Wistar rats. A factor analysis isolated three factors, which combined highly correlated target genes. The first factor included four genes: Cxcl12 (r = 0.829, p < 0.05), Tweak (r = 0.841, p < 0.05), Notch1 (r = 0.848, p < 0.05), and Yap1 (r = 0.921, p < 0.05). The second factor described the correlation between Mmp-9 (r = 0.791, p < 0.05) and Notch2 (r = 0.836, p < 0.05). The third factor included Ang (r = 0.748, p < 0.05) and Vegfa (r = 0.679, p < 0.05). The Nos2 and Fn14 genes were not included in any of the factors. The gene grouping by mRNA expression levels made it possible to assume a pathogenetic relationship between their products in the development of fibrotic changes due to liver toxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.

REFERENCES

  1. Zhang D., Zhang Y., Sun B. 2022. The molecular mechanisms of liver fibrosis and its potential therapy in application. Int. J. Mol. Sci. 23 (20), 12572. https://doi.org/10.3390/ijms232012572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Graupera I., Isus L., Coll M., Pose E., Díaz A., Vallverdú J., Rubio-Tomás T., Martínez-Sánchez C., Huelin P., Llopis M., Solé C., Fondevila C., Lozano J.J., Sancho-Bru P., Ginès P., Aloy P. 2022. Molecular characterization of chronic liver disease dynamics: from liver fibrosis to acute-on-chronic liver failure. JHEP Rep. 4 (6), 100482. https://doi.org/10.1016/j.jhepr.2022.100482

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kachanova O., Lobov A., Malashicheva A. 2022. The role of the Notch signaling pathway in recovery of cardiac function after myocardial infarction. Int. J. Mol. Sci. 23 (20), 12509. https://doi.org/10.3390/ijms232012509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yuan C., Ni L., Zhang C., Wu X. 2020. The role of Notch3 signaling in kidney disease. Oxid. Med. Cell Longev. 2020, 1809408. https://doi.org/10.1155/2020/1809408

  5. Salazar J.L., Yang S.A., Yamamoto S. 2020. Post-developmental roles of notch signaling in the nervous system. Biomolecules. 10 (7), 985. https://doi.org/10.3390/biom10070985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hosseini-Alghaderi S., Baron M. 2020. Notch3 in development, health and disease. Biomolecules. 10(3), 485. https://doi.org/10.3390/biom10030485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen Y., Gao W.K., Shu Y.Y., Ye J. 2022. Mechanisms of ductular reaction in non-alcoholic steatohepatitis. World J. Gastroenterol. 28 (19), 2088‒2099. https://doi.org/10.3748/wjg.v28.i19.2088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vera L., Garcia-Olloqui P., Petri E., Viñado A.C., Valera P.S., Blasco-Iturri Z., Calvo I.A., Cenzano I., Ruppert C., Zulueta J.J., Prosper F., Saez B., Pardo-Saganta A. 2021. Notch3 deficiency attenuates pulmonary fibrosis and impedes lung-function decline. Am. J. Respir. Cell Mol. Biol. 64 (4), 465‒476. https://doi.org/10.1165/rcmb.2020-0516OC

    Article  CAS  PubMed  Google Scholar 

  9. Adams J.M., Jafar-Nejad H. 2019. The roles of notch signaling in liver development and disease. Biomolecules. 9 (10), 608. https://doi.org/10.3390/biom9100608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pelullo M., Zema S., Nardozza F., Checquolo S., Screpanti I., Bellavia D. 2019. Wnt, Notch, and TGF-β pathways impinge on hedgehog signaling complexity: an open window on cancer. Front. Genet. 10, 711. https://doi.org/10.3389/fgene.2019.00711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dai Y., Hao P., Sun Z., Guo Z., Xu H., Xue L., Song H., Li Y., Li S., Gao M., Si T., Zhang Y., Qi Y. 2021. Liver knockout YAP gene improved insulin resistance-induced hepatic fibrosis. J. Endocrinol. 249 (2), 149‒161. https://doi.org/10.1530/JOE-20-0561

    Article  CAS  PubMed  Google Scholar 

  12. Yu H.X., Yao Y., Bu F.T., Chen Y., Wu Y.T., Yang Y., Chen X., Zhu Y., Wang Q., Pan X.Y., Meng X.M., Huang C., Li J. 2019. Blockade of YAP alleviates hepatic fibrosis through accelerating apoptosis and reversion of activated hepatic stellate cells. Mol. Immunol. 107, 29‒40. https://doi.org/10.1016/j.molimm.2019.01.004

    Article  CAS  PubMed  Google Scholar 

  13. Zheng C., Luo J., Yang Y., Dong R., Yu F.X., Zheng S. 2021. YAP activation and implications in patients and a mouse model of biliary atresia. Front. Pediatr. 8, 618226. https://doi.org/10.3389/fped.2020.618226

    Article  PubMed  PubMed Central  Google Scholar 

  14. He X., Tolosa M.F., Zhang T., Goru S.K., Ulloa Severino L., Misra P.S., McEvoy C.M., Caldwell L., Szeto S.G., Gao F., Chen X., Atin C., Ki V., Vukosa N., Hu C., Zhang J., Yip C., Krizova A., Wrana J.L., Yuen D.A. 2022. Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis. JCI Insight. 7 (4), e146243. https://doi.org/10.1172/jci.insight.146243

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wang M., Xie Z., Xu J., Feng Z. 2020. TWEAK/Fn14 axis in respiratory diseases. Clin. Chim. Acta. 509, 139‒148. https://doi.org/10.1016/j.cca.2020.06.007

    Article  CAS  PubMed  Google Scholar 

  16. Dwyer B.J., Jarman E.J., Gogoi-Tiwari J., Ferreira-Gonzalez S., Boulter L., Guest R.V., Kendall T.J., Kurian D., Kilpatrick A.M., Robson A.J., O’Duibhir E., Man T.Y., Campana L., Starkey Lewis P.J., Wigmore S.J., Olynyk J.K., Ramm G.A., Tirnitz-Parker J.E.E., Forbes S.J. 2021. TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression. J. Hepatol. 74 (4), 860‒872. https://doi.org/10.1016/j.jhep.2020.11.018

    Article  CAS  PubMed  Google Scholar 

  17. Zhang Y., Zeng W., Xia Y. 2021. TWEAK/Fn14 axis is an important player in fibrosis. J. Cell. Physiol. 236 (5), 3304‒3316. https://doi.org/10.1002/jcp.30089

    Article  CAS  PubMed  Google Scholar 

  18. Lin Y., Dong M.Q., Liu Z.M., Xu M., Huang Z.H., Liu H.J., Gao Y., Zhou W. 2022. A strategy of vascular-targeted therapy for liver fibrosis. J. Hepatology. 76 (3), 660‒675. https://doi.org/10.1002/hep.32299

    Article  CAS  Google Scholar 

  19. Lefere S., Devisscher L., Geerts A. 2020. Angiogenesis in the progression of non-alcoholic fatty liver disease. Acta Gastroenterol. Belg. 83 (2), 301‒307.

    CAS  PubMed  Google Scholar 

  20. Yang L., Yue W., Zhang H., Zhang Z., Xue R., Dong C., Liu F., Chang N., Yang L., Li L. 2022. Dual targeting of angipoietin-1 and von Willebrand factor by microRNA-671-5p attenuates liver angiogenesis and fibrosis. Hepatol. Commun. 6 (6), 1425‒1442. https://doi.org/10.1002/hep4.1888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Friedman S.L., Pinzani M. 2022. Hepatic fibrosis 2022: unmet needs and a blueprint for the future. Hepatology. 75(2), 473‒488. https://doi.org/10.1002/hep.32285

    Article  CAS  PubMed  Google Scholar 

  22. Ray P., Stacer A.C., Fenner J., Cavnar S.P., Meguiar K., Brown M., Luker K.E., Luker G.D. 2015. CXCL12-γ in primary tumors drives breast cancer metastasis. Oncogene. 34 (16), 2043‒2051. https://doi.org/10.1038/onc.2014.157

    Article  CAS  PubMed  Google Scholar 

  23. Cui L.N., Zheng X.H., Yu J.H., Han Y. 2021. Role of CXCL12-CXCR4/CXCR7 signal axis in liver regeneration and liver fibrosis. Zhonghua Gan Zang Bing Za Zhi. 29 (9), 900‒903. https://doi.org/10.3760/cma.j.cn501113-20200721-00403

    Article  CAS  PubMed  Google Scholar 

  24. Chiraunyanann T., Changsri K., Sretapunya W., Yuenyongchaiwat K., Akekawatchai C. 2019. CXCL12 G801A polymorphism is associated with significant liver fibrosis in HIV-infected Thais: a cross-sectional study. Asian Pac. J. Allergy Immunol. 37 (3), 162‒170. https://doi.org/10.12932/AP-160917-0162

    Article  CAS  PubMed  Google Scholar 

  25. Zhang J., Li Y., Liu Q., Li R., Pu S., Yang L., Feng Y., Ma L. 2018. SKLB023 as an iNOS inhibitor alleviated liver fibrosis by inhibiting the TGF-beta/Smad signaling pathway. RSC Adv. 8 (54), 30919‒30924. https://doi.org/10.1039/c8ra04955f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ahmad N., Ansari M.Y., Haqqi T.M. 2020. Role of iNOS in osteoarthritis: pathological and therapeutic aspects. J. Cell Physiol. 235 (10), 6366‒6376. https://doi.org/10.1002/jcp.29607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kashfi K., Kannikal J., Nath N. 2021. Macrophage reprogramming and cancer therapeutics: role of iNOS-derived NO. Cells. 10 (11), 3194. https://doi.org/10.3390/cells10113194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tsomidis I., Notas G., Xidakis C., Voumvouraki A., Samonakis D.N., Koulentaki M., Kouroumalis E. 2022. Enzymes of fibrosis in chronic liver disease. Biomedicines. 10 (12), 3179. https://doi.org/10.3390/biomedicines10123179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lachowski D., Cortes E., Rice A., Pinato D., Rombouts K., Hernandez A.D.R. 2019. Matrix stiffness modulates the activity of MMP-9 and TIMP-1 in hepatic stellate cells to perpetuate fibrosis. Sci. Rep. 9 (1), 7299. https://doi.org/10.1038/s41598-019-43759-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Maltais L.J., Blake J.A., Chu T., Lutz C.M., Eppig J.T., Jackson I. 2002. Rules and guidelines for mouse gene, allele, and mutation nomenclature: a condensed version. Genomics. 79 (4), 471‒474. https://doi.org/10.1006/geno.2002.6747

    Article  CAS  PubMed  Google Scholar 

  31. Everhart J.E., Wright E.C., Goodman Z.D., Dienstag J.L., Hoefs J.C., Kleiner D.E., Ghany M.G., Mills A.S., Nash S.R., Govindarajan S., Rogers T.E., Greenson J.K., Brunt E.M., Bonkovsky H.L., Morishima C., Litman H.J. 2010. HALT-C Trial Group. Prognostic value of Ishak fibrosis stage: findings from the hepatitis C antiviral long-term treatment against cirrhosis trial. Hepatology. 51 (2), 585‒594. https://doi.org/10.1002/hep.23315

    Article  PubMed  Google Scholar 

  32. Lebedeva E.I., Shchastny A.T., Babenko A.S. 2022. Stability dynamics of sdha, hprt, prl3d1, and hes1 gene expression in a rat liver fibrosis model. J. Biomed. 18 (2), 17–30.

    Article  Google Scholar 

  33. Sharma N., Shaikh T.B., Eedara A., Kuncha M., Sistla R., Andugulapati S.B. 2022. Dehydrozingerone ameliorates thioacetamide-induced liver fibrosis via inhibition of hepatic stellate cells activation through modulation of the MAPK pathway. Eur. J. Pharmacol. 937, 175366. https://doi.org/10.1016/j.ejphar.2022.175366

    Article  CAS  PubMed  Google Scholar 

  34. Chandrashekar D.V., DuBois B.N., Rashid M., Mehvar R. 2023. Effects of chronic cirrhosis induced by intraperitoneal thioacetamide injection on the protein content and Michaelis-Menten kinetics of cytochrome P450 enzymes in the rat liver microsomes. Basic Clin. Pharmacol. Toxicol. 132 (2), 197‒210. https://doi.org/10.1111/bcpt.13813

    Article  CAS  PubMed  Google Scholar 

  35. Shareef S.H., Al-Medhtiy M.H., Al Rashdi A.S., Aziz P.Y., Abdulla M.A. 2023. Hepatoprotective effect of pinostrobin against thioacetamide-induced liver cirrhosis in rats. Saudi J. Biol. Sci. 30 (1), 103506. https://doi.org/10.1016/j.sjbs.2022.103506

    Article  CAS  PubMed  Google Scholar 

  36. Walther C.P., Benoit J.S. 2021. Tubular kidney biomarker insights through factor analysis. Am. J. Kidney Dis. 78 (3), 335‒337. https://doi.org/10.1053/j.ajkd.2021.03.016

    Article  PubMed  PubMed Central  Google Scholar 

  37. Muthiah M.D., Huang D.Q., Zhou L., Jumat N.H., Choolani M., Chan J.K.Y., Wee A., Lim S.G., Dan Y.Y. 2019. A murine model demonstrating reversal of structural and functional correlates of cirrhosis with progenitor cell transplantation. Sci. Rep. 9 (1), 15446. https://doi.org/10.1038/s41598-019-51189-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ezhilarasan D. 2023. Molecular mechanisms in thioacetamide-induced acute and chronic liver injury models. Environ. Toxicol. Pharmacol. 104093. https://doi.org/10.1016/j.etap.2023.104093

  39. Lebedeva E.I., Shchastny A.T., Babenko A.S. 2022. Decrease in ANG and VEGF mRNA levels during progressive angiogenesis of the liver venous system of Wistar rats in experimental. Mol. Med. 20 (2), 53‒61.

    Google Scholar 

Download references

Funding

This work was supported by the state program “Basic and Applied Sciences to Medicine” of the Ministry of Health of the Republic of Belarus (assignment no. 2.89, “Study of the role of genes involved in the NOTCH and TWEAK signaling pathways, which are involved in liver cell proliferation and differentiation and normal conditions and toxicity-induced damage to the liver”; project no. 20190107).

Author information

Authors and Affiliations

  1. Vitebsk State Order of Peoples’ Friendship Medical University, 210009, Vitebsk, Belarus

    E. I. Lebedeva & A. T. Shchastniy

  2. Belarussian State Medical University, 220116, Minsk, Belarus

    A. S. Babenka

  3. Gomel State Medical University, 246050, Gomel, Belarus

    D. A. Zinovkin

Authors
  1. E. I. Lebedeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. T. Shchastniy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. S. Babenka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. A. Zinovkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. I. Lebedeva.

Ethics declarations

CONFLICT OF INTEREST

The authors of this work declare that they have no conflicts of interest.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The experimental protocol was approved by the Ethics Committee at the Vitebsk State Order of Peoples’ Friendship Medical University (Protocol no. 6 dated January 3, 2019). All manipulations with animals were performed in compliance with the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes dated March 18, 1986; ,Council Directive of 24 November 1986; and recommendations of the FELASA Working Group Report (1994‒1996).

Additional information

Translated by T. Tkacheva

Publisher’s Note.

Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lebedeva, E.I., Shchastniy, A.T., Babenka, A.S. et al. Relationships between Cxcl12, Tweak, Notch1, and Yap mRNA Expression Levels in Molecular Mechanisms of Liver Fibrogenesis. Mol Biol 58, 102–111 (2024). https://doi.org/10.1134/S0026893324010060

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893324010060

Keywords:

Search

Navigation