Skip to main content

Advertisement

SpringerLink
Log in

Investigation of the hepatic mTOR/S6K1/SREBP1 signalling pathway in rats at different ages: from neonates to adults

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

Dysfunctions in the lipogenic process controlled by the hepatic mTOR/S6K1/SREBP-1c signaling pathway may contribute to the pathogenesis of various chronic diseases. In the present study, we aimed to determine age-related changes in the mTOR/S6K1/SREBP1 pathway in rat liver tissues.

Methods and results

We performed Western Blot analysis to determine age-related changes in the mTOR/S6K1/SREBP1 pathway in Sprague Dawley male rats liver tissues of six different age groups representing neonatal, infant, weaning, puberty, young adult, adult life periods, and Oil Red O staining to evaluate age-related lipid accumulation. We observed an increase in Akt and p-Akt levels with age in compared to the 0-day-old group. Total mTOR and SREBP1 expression increased from the 0-day-old to the 28-day-old group but decreased in the following age groups. p-mTOR and p-S6K1 levels in the 0-day-old group were higher than the other groups. S6K1 expression was lowest in the 0-day-old group and showed changes among the age groups. Lipid accumulation was seen in liver sections taken from the 12-month-old group. mTOR/S6K1/SREBP1 pathway expression showed changes with age during the neonatal-adult life cycle stages in rat liver tissues.

Conclusion

We suggest that understanding the molecular mechanisms age-related changes of lipogenesis function is necessary to contribute to the development of therapeutic approaches.

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

Similar content being viewed by others

Data availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Code availability

Not applicable.

References

  1. Bhate A, Parker DJ, Bebee TW et al (2015) ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation. Nat Commun 6:8768. https://doi.org/10.1038/ncomms9768

    Article  CAS  PubMed  Google Scholar 

  2. C H, (2014) Natural modulators of liver X receptors. J Integr Med 12:76–85. https://doi.org/10.1016/S2095-4964(14)60013-3

    Article  Google Scholar 

  3. Benedict M, Zhang X (2017) Non-alcoholic fatty liver disease: An expanded review. World J Hepatol 9:715. https://doi.org/10.4254/WJH.V9.I16.715

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P (2018) Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci 75:3313–3327. https://doi.org/10.1007/s00018-018-2860-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sanders FWB, Griffin JL (2016) De novo lipogenesis in the liver in health and disease: More than just a shunting yard for glucose. Biol Rev 91:452–468. https://doi.org/10.1111/brv.12178

    Article  PubMed  Google Scholar 

  6. Düvel K, Yecies JL, Menon S et al (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39:171–183. https://doi.org/10.1016/j.molcel.2010.06.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Owen JL, Zhang Y, Bae S-H et al (2012) Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc Natl Acad Sci 109:16184–16189. https://doi.org/10.1073/pnas.1213343109

    Article  PubMed  PubMed Central  Google Scholar 

  8. Porstmann T, Santos CR, Griffiths B et al (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8:224–236. https://doi.org/10.1016/j.cmet.2008.07.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shimano H, Sato R (2017) SREBP-regulated lipid metabolism: convergent physiology—divergent pathophysiology. Nat Rev Endocrinol 13:710–730. https://doi.org/10.1038/nrendo.2017.91

    Article  CAS  PubMed  Google Scholar 

  10. Zhou Y, Yu S, Cai C et al (2018) LXRα participates in the mTOR/S6K1/SREBP-1c signaling pathway during sodium palmitate-induced lipogenesis in HepG2 cells. Nutr Metab. https://doi.org/10.1186/s12986-018-0268-9

    Article  Google Scholar 

  11. Li X, Wu JB, Chung LWK, Huang W-C (2015) Anti-cancer efficacy of SREBP inhibitor, alone or in combination with docetaxel, in prostate cancer harboring p53 mutations. Oncotarget 6:41018–41032. https://doi.org/10.18632/oncotarget.5879

    Article  PubMed  PubMed Central  Google Scholar 

  12. Tao T, Su Q, Xu S et al (2019) Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis. J Cell Physiol 234:3088–3104. https://doi.org/10.1002/jcp.27129

    Article  CAS  PubMed  Google Scholar 

  13. Zhang M, Chi X, Qu N, Wang C (2018) Long noncoding RNA lncARSR promotes hepatic lipogenesis via Akt/SREBP-1c pathway and contributes to the pathogenesis of nonalcoholic steatohepatitis. Biochem Biophys Res Commun 499:66–70. https://doi.org/10.1016/j.bbrc.2018.03.127

    Article  CAS  PubMed  Google Scholar 

  14. Conjeevaram Selvakumar PK, Kabbany MN, Lopez R et al (2018) Prevalence of Suspected nonalcoholic fatty liver disease in lean adolescents in the United States. J Pediatr Gastroenterol Nutr 67:75–79. https://doi.org/10.1097/MPG.0000000000001974

    Article  PubMed  Google Scholar 

  15. Woo Baidal JA, Elbel EE, Lavine JE et al (2018) Associations of early to mid-childhood adiposity with elevated mid-childhood alanine aminotransferase levels in the project viva cohort. J Pediatr 197:121-127.e1. https://doi.org/10.1016/j.jpeds.2018.01.069

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhang X, Wu M, Liu Z et al (2021) Increasing prevalence of NAFLD/NASH among children, adolescents and young adults from 1990 to 2017: a population-based observational study. BMJ Open 11:e042843. https://doi.org/10.1136/BMJOPEN-2020-042843

    Article  PubMed  PubMed Central  Google Scholar 

  17. Doycheva Iliana, Watt Kymberly D, Alkhouri Naim (2017) Nonalcoholic fatty liver disease in adolescents and young adults: The next frontier in the epidemic. Hepatology 65:2100–2109. https://doi.org/10.1002/HEP.29068

    Article  PubMed  Google Scholar 

  18. National Research Council, Division on Earth and Life Studies, Institute for Laboratory Animal Research, Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011) Guide for the Care and Use of Laboratory Animals. National Academies Press, Washington, DC

    Google Scholar 

  19. Lee C (2007) Protein Extraction From Mammalian Tissues. Methods Mol Biol 362:385–389

    Article  CAS  Google Scholar 

  20. Adomshick V, Pu Y, Veiga-Lopez A (2020) Automated lipid droplet quantification system for phenotypic analysis of adipocytes using cell profiler. Toxicol Mech Methods 30:378. https://doi.org/10.1080/15376516.2020.1747124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kwekel JC, Desai VG, Moland CL et al (2010) Age and sex dependent changes in liver gene expression during the life cycle of the rat. BMC Genomics 11:675. https://doi.org/10.1186/1471-2164-11-675

    Article  PubMed  PubMed Central  Google Scholar 

  22. Nguyen P, Valanejad L, Cast A et al (2018) Elimination of age-associated hepatic steatosis and correction of aging phenotype by inhibition of cdk4-C/EBPα-p300 axis. Cell Rep 24:1597–1609. https://doi.org/10.1016/j.celrep.2018.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sengupta P (2013) The laboratory rat: relating its age with human’s. Int J Prev Med 4:624–630

    PubMed  PubMed Central  Google Scholar 

  24. Hadem I, Sharma R (2015) Age- and tissue-dependent modulation of IGF-1/PI3K/Akt protein expression by dietary restriction in mice. Horm Metab Res 48:201–206. https://doi.org/10.1055/s-0035-1559770

    Article  CAS  PubMed  Google Scholar 

  25. Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17:596–603. https://doi.org/10.1016/j.ceb.2005.09.009

    Article  CAS  PubMed  Google Scholar 

  26. Petersen Shay K, Hagen TM (2009) Age-associated impairment of Akt phosphorylation in primary rat hepatocytes is remediated by alpha-lipoic acid through PI3 kinase, PTEN, and PP2A. Biogerontology 10:443–456. https://doi.org/10.1007/s10522-008-9187-x

    Article  CAS  Google Scholar 

  27. Kennedy BK, Lamming DW (2016) The mechanistic target of rapamycin: the grand conductor of metabolism and aging. Cell Metab 23:990–1003. https://doi.org/10.1016/j.cmet.2016.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Antikainen H, Driscoll M, Haspel G, Dobrowolski R (2017) TOR-mediated regulation of metabolism in aging. Aging Cell 16:1219–1233. https://doi.org/10.1111/acel.12689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Houtkooper RH, Argmann C, Houten SM et al (2011) The metabolic footprint of aging in mice. Sci Rep 1:134. https://doi.org/10.1038/srep00134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Baar EL, Carbajal KA, Ong IM, Lamming DW (2016) Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging Cell 15:155–166. https://doi.org/10.1111/acel.12425

    Article  CAS  PubMed  Google Scholar 

  31. Sengupta S, Peterson TR, Laplante M et al (2010) mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468:1100–1104. https://doi.org/10.1038/nature09584

    Article  CAS  PubMed  Google Scholar 

  32. Yang W, Burkhardt B, Fischer L et al (2015) Age-dependent changes of the antioxidant system in rat livers are accompanied by altered mapk activation and a decline in motor signaling. EXCLI J 14:1273–1290. https://doi.org/10.17179/excli2015-734

    Article  PubMed  PubMed Central  Google Scholar 

  33. Engelking LJ, Cantoria MJ, Xu Y, Liang G (2018) Developmental and extrahepatic physiological functions of SREBP pathway genes in mice. Semin Cell Dev Biol 81:98–109. https://doi.org/10.1016/j.semcdb.2017.07.011

    Article  CAS  PubMed  Google Scholar 

  34. Lee SM, Zhang Y, Tsuchiya H et al (2015) Small heterodimer partner/neuronal PAS domain protein 2 axis regulates the oscillation of liver lipid metabolism. Hepatology 61:497–505. https://doi.org/10.1002/hep.27437

    Article  CAS  PubMed  Google Scholar 

  35. Salamanca A, Bárcena B, Arribas C et al (2015) Aging impairs the hepatic subcellular distribution of ChREBP in response to fasting/feeding in rats: Implications on hepatic steatosis. Exp Gerontol 69:9–19. https://doi.org/10.1016/j.exger.2015.05.009

    Article  CAS  PubMed  Google Scholar 

  36. Wei Q, Zhou B, Yang G et al (2018) JAZF1 ameliorates age and diet-associated hepatic steatosis through SREBP-1c -dependent mechanism. Cell Death Dis 9:859. https://doi.org/10.1038/s41419-018-0923-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the Scientific and Technological Research Council of Turkey (TUBITAK) [Grant Number: 119S221].

Funding

This study was supported by the Scientific and Technological Research Council of Turkey (TUBITAK) [Grant Number: 119S221].

Author information

Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Yeditepe University, İnönü District, Kayışdağı Street, August 26 Campus, Atasehir, İstanbul, Turkey, 34755

    Meltem Yalçın & Mehtap Kaçar

  2. Department of Pathophysiology, Graduate School of Health Sciences, Yeditepe University, İnönü District, Kayışdağı Street, August 26 Campus, Atasehir, İstanbul, Turkey, 34755

    Mehtap Kaçar

Authors
  1. Meltem Yalçın
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mehtap Kaçar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by MY. The first draft of the manuscript was written by MY and MK. All authors commented on previous versions of the manuscript. The research project and the manuscript was supervised, reviewed, and edited by MK All authors read and approved the final manuscript.

Corresponding author

Correspondence to Mehtap Kaçar.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical approval

Experimental procedures were approved by Yeditepe University Local Ethic Committee. Animals were treated in accordance with Guide for the Care and Use of Laboratory Animals.

Consent to participate

Not applicable.

Consent to publish

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (docx 68 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yalçın, M., Kaçar, M. Investigation of the hepatic mTOR/S6K1/SREBP1 signalling pathway in rats at different ages: from neonates to adults. Mol Biol Rep 48, 7415–7422 (2021). https://doi.org/10.1007/s11033-021-06757-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06757-4

Keywords

Search

Navigation