Skip to main content
Springer Nature Link
Log in

High fat diet-induced downregulation of TRPV2 mediates hepatic steatosis via p21 signalling

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

The global prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) are exhibiting an increasing trend. NAFLD is characterized by a significant accumulation of lipids, though its underlying mechanism is still unknown. Here we report that high-fat diet (HFD) feeding induced hepatic steatosis in mice, which was accompanied by a reduction in the expression and function of hepatic TRPV2. Moreover, conditional knockout of TRPV2 in hepatocytes exacerbated HFD-induced hepatic steatosis. In an in vitro model of NAFLD, TRPV2 regulated lipid accumulation in HepG2 cells, and TRPV2 activation inhibited the expression of the cellular senescence markers p21 and p16, all of which were mediated by AMPK phosphorylation. Finally, we found that administration of probenecid, a TRPV2 agonist, impaired HFD-induced hepatic steatosis and suppressed HFD-induced elevation in p21 and p16. Collectively, our findings imply that hepatic TRPV2 protects against the accumulation of lipids by modulating p21 signalling.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

HFD:

High-fat diet

TRPV2:

Transient receptor potential vanilloid 2

NASH:

Nonalcoholic steatohepatitis

CDK:

Cyclin/cyclin-dependent kinase

TRP:

Transient Receptor Potential

NW:

Normal water

RT:

Room temperature

TG:

Triacyl glyceride

PBS:

Phosphate-buffered saline

HRP:

Horseradish peroxidase

2-APB:

2-Aminoethoxydiphenyl borate

SKF:

SKF 96365 hydrochloride

References

  1. Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9(6):400–414. https://doi.org/10.1038/nrc2657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Aravinthan, A., Scarpini, C., Tachtatzis, P., Verma, S., Penrhyn-Lowe, S., Harvey, R., . . . Alexander, G. (2013). Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J Hepatol, 58(3), 549–556 https://doi.org/10.1016/j.jhep.2012.10.031

  3. Bort A, Sánchez BG, Mateos-Gómez PA, Díaz-Laviada I, Rodríguez-Henche N (2019) Capsaicin Targets Lipogenesis in HepG2 Cells Through AMPK Activation, AKT Inhibition and PPARs Regulation. Int J Mol Sci, 20(7) https://doi.org/10.3390/ijms20071660

  4. Carling D, Zammit VA, Hardie DG (1987) A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett 223(2):217–222. https://doi.org/10.1016/0014-5793(87)80292-2

    Article  CAS  PubMed  Google Scholar 

  5. Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico, A., . . . Gores, G. (2011). Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol 301(5) G825–834 https://doi.org/10.1152/ajpgi.00145.2011

  6. Clapham DE, Julius D, Montell C, Schultz G (2005) International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels. Pharmacol Rev 57(4):427–450. https://doi.org/10.1124/pr.57.4.6

    Article  CAS  PubMed  Google Scholar 

  7. Eynaudi A, Díaz-Castro F, Bórquez JC, Bravo-Sagua R, Parra V, Troncoso R (2021) Differential Effects of Oleic and Palmitic Acids on Lipid Droplet-Mitochondria Interaction in the Hepatic Cell Line HepG2. Front Nutr 8:775382. https://doi.org/10.3389/fnut.2021.775382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Feng Q, Liu C, Gao W, Geng XL, Dai N (2019) Salidroside-Mitigated Inflammatory Injury of Hepatocytes with Non-Alcoholic Fatty Liver Disease via Inhibition TRPM2 Ion Channel Activation. Diabetes Metab Syndr Obes 12:2755–2763. https://doi.org/10.2147/dmso.S210764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ferreira-Gonzalez S, Rodrigo-Torres D, Gadd VL, Forbes SJ (2021) Cellular Senescence in Liver Disease and Regeneration. Semin Liver Dis 41(1):50–66. https://doi.org/10.1055/s-0040-1722262

    Article  CAS  PubMed  Google Scholar 

  10. Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226(1):497–509

    Article  CAS  PubMed  Google Scholar 

  11. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ (2018) Mechanisms of NAFLD development and therapeutic strategies. Nat Med 24(7):908–922. https://doi.org/10.1038/s41591-018-0104-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Guo, J., Ozaki, I., Xia, J., Kuwashiro, T., Kojima, M., Takahashi, H., . . . Matsuhashi, S (2018) PDCD4 Knockdown Induces Senescence in Hepatoma Cells by Up-Regulating the p21 Expression. Front Oncol 8 661 https://doi.org/10.3389/fonc.2018.00661

  13. Guy CD, Suzuki A, Zdanowicz M, Abdelmalek MF, Burchette J, Unalp A, Diehl AM (2012) Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology 55(6):1711–1721. https://doi.org/10.1002/hep.25559

    Article  CAS  PubMed  Google Scholar 

  14. Han J, Kaufman RJ (2016) The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res 57(8):1329–1338. https://doi.org/10.1194/jlr.R067595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hernandez-Segura A, Nehme J, Demaria M (2018) Hallmarks of Cellular Senescence. Trends Cell Biol 28(6):436–453. https://doi.org/10.1016/j.tcb.2018.02.001

    Article  CAS  PubMed  Google Scholar 

  16. Hilton JK, Rath P, Helsell CV, Beckstein O, Van Horn WD (2015) Understanding thermosensitive transient receptor potential channels as versatile polymodal cellular sensors. Biochemistry 54(15):2401–2413. https://doi.org/10.1021/acs.biochem.5b00071

    Article  CAS  PubMed  Google Scholar 

  17. Hirsova P, Ibrabim SH, Gores GJ, Malhi H (2016) Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res 57(10):1758–1770. https://doi.org/10.1194/jlr.R066357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hotamisligil GS (2017) Inflammation, metaflammation and immunometabolic disorders. Nature 542(7640):177–185. https://doi.org/10.1038/nature21363

    Article  CAS  PubMed  Google Scholar 

  19. Hsu, W. L., Tsai, M. H., Wu, C. Y., Liang, J. L., Lu, J. H., Kahle, J. S., . . . Yoshioka, T. (2020). Nociceptive transient receptor potential canonical 7 (TRPC7) mediates aging-associated tumorigenesis induced by ultraviolet B. Aging Cell 19(1) e13075 https://doi.org/10.1111/acel.13075

  20. Hydbring P, Larsson LG (2010) Cdk2: a key regulator of the senescence control function of Myc. Aging (Albany NY) 2(4):244–250. https://doi.org/10.18632/aging.100140

    Article  CAS  PubMed  Google Scholar 

  21. Kreis NN, Louwen F, Yuan J (2019) The Multifaceted p21 (Cip1/Waf1/CDKN1A) in Cell Differentiation, Migration and Cancer Therapy. Cancers (Basel), 11(9) https://doi.org/10.3390/cancers11091220

  22. LaPak KM, Burd CE (2014) The molecular balancing act of p16(INK4a) in cancer and aging. Mol Cancer Res 12(2):167–183. https://doi.org/10.1158/1541-7786.Mcr-13-0350

    Article  CAS  PubMed  Google Scholar 

  23. Li, L., Chen, J., Ni, Y., Feng, X., Zhao, Z., Wang, P., . . . Zhu, Z. (2012). TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice. Pflugers Arch 463(5) 727–732 https://doi.org/10.1007/s00424-012-1078-y

  24. Meijnikman AS, Herrema H, Scheithauer TPM, Kroon J, Nieuwdorp M, Groen AK (2021) Evaluating causality of cellular senescence in non-alcoholic fatty liver disease. JHEP Rep 3(4):100301. https://doi.org/10.1016/j.jhepr.2021.100301

    Article  PubMed  PubMed Central  Google Scholar 

  25. Moustakas, II, Katsarou, A., Legaki, A. I., Pyrina, I., Ntostoglou, K., Papatheodoridi, A. M., . . . Chatzigeorgiou, A. (2021). Hepatic Senescence Accompanies the Development of NAFLD in Non-Aged Mice Independently of Obesity. Int J Mol Sci, 22(7)https://doi.org/10.3390/ijms22073446

  26. Papatheodoridi AM, Chrysavgis L, Koutsilieris M, Chatzigeorgiou A (2020) The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis. Hepatology 71(1):363–374. https://doi.org/10.1002/hep.30834

    Article  CAS  PubMed  Google Scholar 

  27. Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM, Sanyal AJ (2008) Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134(2):568–576. https://doi.org/10.1053/j.gastro.2007.10.039

    Article  CAS  PubMed  Google Scholar 

  28. Richardson, M. M., Jonsson, J. R., Powell, E. E., Brunt, E. M., Neuschwander-Tetri, B. A., Bhathal, P. S., . . . Clouston, A. D. (2007). Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology, 133(1), 80–90 https://doi.org/10.1053/j.gastro.2007.05.012

  29. Rychkov GY, Barritt GJ (2011) Expression and function of TRP channels in liver cells. Adv Exp Med Biol 704:667–686. https://doi.org/10.1007/978-94-007-0265-3_35

    Article  CAS  PubMed  Google Scholar 

  30. Sacks, D., Baxter, B., Campbell, B. C. V., Carpenter, J. S., Cognard, C., Dippel, D., . . . Vorwerk, D. (2018). Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke. Int J Stroke, 13(6), 612–632 https://doi.org/10.1177/1747493018778713

  31. Severgnini, M., Sherman, J., Sehgal, A., Jayaprakash, N. K., Aubin, J., Wang, G., . . . Fitzgerald, K. (2012). A rapid two-step method for isolation of functional primary mouse hepatocytes: cell characterization and asialoglycoprotein receptor based assay development. Cytotechnology, 64(2), 187–195 https://doi.org/10.1007/s10616-011-9407-0

  32. Sun, W., Uchida, K., Suzuki, Y., Zhou, Y., Kim, M., Takayama, Y., . . . Tominaga, M. (2016). Lack of TRPV2 impairs thermogenesis in mouse brown adipose tissue. EMBO Rep, 17(3), 383–399 https://doi.org/10.15252/embr.201540819

  33. Sun, W., Uchida, K., Takahashi, N., Iwata, Y., Wakabayashi, S., Goto, T., . . . Tominaga, M. (2016). Activation of TRPV2 negatively regulates the differentiation of mouse brown adipocytes. Pflugers Arch, 468(9), 1527–1540https://doi.org/10.1007/s00424-016-1846-1

  34. Sun W, Uchida K, Tominaga M (2017) TRPV2 regulates BAT thermogenesis and differentiation. Channels (Austin) 11(2):94–96. https://doi.org/10.1080/19336950.2016.1228401

    Article  PubMed  Google Scholar 

  35. Tomita, K., Teratani, T., Suzuki, T., Oshikawa, T., Yokoyama, H., Shimamura, K., . . . Hibi, T. (2012). p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. J Hepatol, 57(4), 837–843. https://doi.org/10.1016/j.jhep.2012.05.013

  36. Torbenson M, Yang SQ, Liu HZ, Huang J, Gage W, Diehl AM (2002) STAT-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers. Am J Pathol 161(1):155–161. https://doi.org/10.1016/s0002-9440(10)64167-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vriens J, Janssens A, Prenen J, Nilius B, Wondergem R (2004) TRPV channels and modulation by hepatocyte growth factor/scatter factor in human hepatoblastoma (HepG2) cells. Cell Calcium 36(1):19–28. https://doi.org/10.1016/j.ceca.2003.11.006

    Article  CAS  PubMed  Google Scholar 

  38. Yue Z, Xie J, Yu AS, Stock J, Du J, Yue L (2015) Role of TRP channels in the cardiovascular system. Am J Physiol Heart Circ Physiol 308(3):H157-182. https://doi.org/10.1152/ajpheart.00457.2014

    Article  CAS  PubMed  Google Scholar 

  39. Zeng, X., Zhu, M., Liu, X., Chen, X., Yuan, Y., Li, L., . . . Chen, Y. (2020). Oleic acid ameliorates palmitic acid induced hepatocellular lipotoxicity by inhibition of ER stress and pyroptosis. Nutr Metab (Lond), 17, 11. https://doi.org/10.1186/s12986-020-0434-8

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grant: 81900517), Shenzhen Science and Technology Program (Grant: JCYJ20190808151805516), and Natural Science Foundation of Shenzhen University General Hospital (Grants: SUGH2019QD015 and SUGH2018QD008).

Author information

Author notes

  1. Pengfei Wei, Lixuan Li and Chenqiu Ran contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Shenzhen University General Hospital and Shenzhen University Academy of Clinical Medical Sciences, Shenzhen University, Shenzhen, 518052, Guangdong, China

    Pengfei Wei, Mingyue Jin, Huijuan Zhao, Kelaier Yang, Yu Wang, Huaqiu He, Mengyang Jia, Hongyan Pan, Qiang Li & Jing Guo

  2. Guangdong Medical University, Zhanjiang, 524023, Guangdong, China

    Lixuan Li

  3. School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China

    Chenqiu Ran

Authors
  1. Pengfei Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lixuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chenqiu Ran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mingyue Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huijuan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kelaier Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huaqiu He
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mengyang Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hongyan Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Qiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jing Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JG and QL designed the experiments; PW, LL, and CR performed the experiments; MJ, HZ, KY, YW, HH, and MJ assisted with the experiments; LL and CR analysed the data; JG wrote the manuscript; and QL revised the manuscript. All authors have read and agreed to the published version of the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Qiang Li or Jing Guo.

Ethics declarations

Ethics approval

All animal procedures were approved by the Animal Care and Use Committee of the Health Science Center at Shenzhen University and complied with the relevant ethical guidelines (12W-2ACW-22–008).

Conflict of interest

The authors declare no conflicts of interest related to this work.

Informed consent

Not applicable.

Additional information

Publisher's Note

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

Key points

• HFD-induced hepatic steatosis is accompanied by a reduction in TRPV2 expression.

• TRPV2 activation inhibits HFD-induced lipid accumulation and impairs hepatic steatosis.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (TIF 39939 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wei, P., Li, L., Ran, C. et al. High fat diet-induced downregulation of TRPV2 mediates hepatic steatosis via p21 signalling. J Physiol Biochem 80, 113–126 (2024). https://doi.org/10.1007/s13105-023-00988-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-023-00988-8

Keywords

Search

Navigation