The expression levels of genes involved in JNK signaling decrease by aging in the liver
The expression levels of genes involved in JNK signaling decrease by aging in the liver
Aim: The c-Jun NH2-terminal kinases (JNK) signaling pathway is an important signaling pathway in liver regeneration. it was planned to investigate the expression levels of Mitogen Activated Protein Kinase Kinase (MKK)-4 and -7 (MKK7), which are mediator molecules involved in the JNK signaling pathway and Activating Transcription Factor (ATF) 2 transcription factor genes, which are in the last stage of the signaling pathway, in liver tissues in young and old mice. In addition, it was aimed to examine the ultrastructural changes caused by aging in hepatocytes. Material and Methods: We examined MKK4, MKK7 and ATF2 expression levels by using Real Time Polymerase Chain Reaction (RT-qPCR) method. Transmission electron microscopy (TEM) was used to observe the ultrastructural changes of hepatocytes. Results: While MKK4 and ATF2 gene expressions reduced in the liver of aged mice, MKK7 gene expression did not change. In TEM examinations, granular endoplasmic reticulum loss and mitochondrial damage were observed in elderly individuals. Conclusion: According to these results, spontaneous liver damage that can be seen in aged subjects may be caused by disruption in cellular signaling pathways and organelle damage in hepatocytes.
___
- 1. Kim IH, Kisseleva T, Brenner DA. Aging and liver disease. Current opinion in gastroenterology. 2015;313:184-91.
- 2. Michielsen P, Vandewoude M. Liver diseases in the older adult. Acta Gastroenterol Belg. 2010;731:1-4.
- 3. Carrier P, Debette-Gratien M, Jacques J, Loustaud-Ratti V. Cirrhotic patients and older people. World J Hepatol. 2019;119:663- 77.
- 4. Schmucker DL, Sanchez H. Liver regeneration and aging: a current perspective. Current gerontology and geriatrics research. 2011;2011:526379-.
- 5. Durand F, Levitsky J, Cauchy F, et al. Age and liver transplantation. Journal of Hepatology. 2019;704:745-58.
- 6. Wuestefeld T, Pesic M, Rudalska R, et al. A Direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell. 2013;1532:389-401.
- 7. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;751:50-83.
- 8. Lin A. Activation of the JNK signaling pathway: breaking the brake on apoptosis. Bioessays. 2003;251:17-24.
- 9. Gupta S, Barrett T, Whitmarsh AJ, et al. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 1996;1511:2760-70.
- 10. Bode AM, Dong Z. The functional contrariety of JNK. Mol Carcinog. 2007;468:591-8.
- 11. Kyriakis JM, Banerjee P, Nikolakaki E, et al. The stressactivated protein kinase subfamily of c-Jun kinases. Nature. 1994;3696476:156-60.
- 12. Fedarko NS. The biology of aging and frailty. Clin Geriatr Med. 2011;271:27-37.
- 13. Ishigami A, Reed TD, Roth GS. Effect of aging on EGF stimulated DNA synthesis and EGF receptor levels in primary cultured rat hepatocytes. Biochem Biophys Res Commun. 1993;1961:181-6.
- 14. Atadja PW, Stringer KF, Riabowol KT. Loss of serum response element-binding activity and hyperphosphorylation of serum response factor during cellular aging. Mol Cell Biol. 1994;147:4991- 9.
- 15. Riabowol K, Schiff J, Gilman MZ. Transcription factor AP-1 activity is required for initiation of DNA synthesis and is lost during cellular aging. Proceedings of the National Academy of Sciences. 1992;891:157-61.
- 16. Kurtoğlu EL, Kayhan B, Gül M, et al. A bioactive product lipoxin A4 attenuates liver fibrosis in an experimental model by regulating immune response and modulating the expression of regeneration genes. Turk J Gastroenterol. 2019;308:745-57.
- 17. Kim IH, Kisseleva T, Brenner DA. Aging and liver disease. Curr Opin Gastroenterol. 2015;313:184-91.
- 18. Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;18024:396- 405.
- 19. de Los Reyes Corrales T, Losada-Pérez M, Casas-Tintó S. JNK Pathway in CNS Pathologies. International journal of molecular sciences. 2021;228:3883.
- 20. Zhao J, Wang L, Dong X, et al. The c-Jun N-terminal kinase (JNK) pathway is activated in human interstitial cystitis (IC) and rat protamine sulfate induced cystitis. Scientific Reports. 2016;61:19670.
- 21. Yamasaki T, Deki-Arima N, Kaneko A, et al. Age-dependent motor dysfunction due to neuron-specific disruption of stress-activated protein kinase MKK7. Scientific Reports. 2017;71:7348.
- 22. Seki E, Brenner DA, Karin M. A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology. 2012;1432:307-20.
- 23. Degli Esposti D, Hamelin J, Bosselut N, et al. Mitochondrial roles and cytoprotection in chronic liver injury. Biochem Res Int. 2012;2012:387626-.
- 24. Mansouri A, Gattolliat CH, Asselah T. Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases. Gastroenterology. 2018;1553:629-47.
- 25. Lane M, Boczonadi V, Bachtari S, et al. Mitochondrial dysfunction in liver failure requiring transplantation. J Inherit Metab Dis. 2016;393:427-36.
- 26. Cichoż-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol. 2014;2025:8082-91.
- 27. Liguori I, Russo G, Curcio F, et al. Oxidative stress, aging, and diseases. Clin Interv Aging. 2018;13:757-72.
- 28. Kozakiewicz M, Kornatowski M, Krzywińska O, KędzioraKornatowska K. Changes in the blood antioxidant defense of advanced age people. Clin Interv Aging. 2019;14:763-71.
- 29. Zhong HH, Hu SJ, Yu B, et al. Apoptosis in the aging liver. Oncotarget. 2017;860:102640-52.
- 30. Hu S-J, Jiang S-S, Zhang J, et al. Effects of apoptosis on liver aging. World J Clin Cases. 2019;76:691-704.
- 31. Tournier C, Dong C, Turner TK, et al. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev. 2001;1511:1419-26.
- 32. Rmilah A A LK, Zhou W, et al. Pharmacological MKK4 inhibition enhances liver regeneration in a pig model of hepatectomy. The Liver Meeting 2020 of the American Association for the Study of Liver Diseases (AASLD), 16 Nowember 2020. Tubingen, Germany, 72.
- 33. Timchenko NA. Aging and liver regeneration. Trends Endocrinol Metab. 2009;204:171-6.
- 34. Xu F, Hua C, Tautenhahn HM, et al. The Role of Autophagy for the Regeneration of the Aging Liver. Int J Mol Sci. 2020;2110.