Skip to main content

Advertisement

SpringerLink
Log in

Comparison of the effects of cholesterol, palmitic acid, and glucose on activation of human hepatic stellate cells to induce liver fibrosis

  • Research article
  • Published:
Journal of Diabetes & Metabolic Disorders Aims and scope Submit manuscript

Abstract

Background

In hepatic damage, Hepatic stellate cells (HSCs) become active, proliferate, and change to myofibroblasts. Increasing the fibrogenic genes, such as Transforming growth factor-β (TGF-β), Alpha Smooth Muscle Actin (α-SMA), and Collagen1 α (COL 1α) show that the activation of HSCs can lead to hepatic fibrosis.

Purpose

These days people consume much cholesterol, palmitic acid, and glucose which can have adverse effects on an individuals’ health, but their influences on activating human HSCs and inducing liver fibrosis have not been assessed. Our purpose is to investigate the effects of these three main and abundant ingredients in the diet on the activation of human HSCs and inducing liver fibrosis.

Methods

To measure cholesterol, palmitic acid, and glucose cytotoxic effects on the viability of the cells, the MTT technique was used. Then the treated cells were incubated in media containing cholesterol, palmitic acid, and glucose with different concentrations for 24 h. At last, the α-SMA, COL 1α, and TGF-β, genes mRNA expression were measured by real-time PCR.

Results and Conclusions

Our results demonstrated that high concentrations of cholesterol and palmitic acid can activate human HSCs that lead to an increase in the mRNA expressions of fibrogenic genes. Thus, controlling fat intaking and knowing its mechanism is crucial to prevent and attenuate hepatic fibrosis.

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

Similar content being viewed by others

Data availability

The data in this study are present from the corresponding author if requested.

Abbreviations

TGF-β:

1-Transforming growth factor-β

α-SMA:

2-Alpha Smooth Muscle Actin

COL 1α:

3-Collagen1 α

HSCS:

Human hepatic stellate cells

ECM:

Extracellular matrix

NAFLD:

Non-alcoholic fatty liver disease

MTT assay:

3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2 H-tetrazolium bromide

FFA:

free fatty acids

TGs:

triglycerides

References

  1. Roehlen N, Crouchet E, Baumert TF. Liver fibrosis: mechanistic concepts and therapeutic perspectives. Cells. 2020;9(4):875.

    Article  CAS  PubMed Central  Google Scholar 

  2. Friedman SL, Maher JJ, Bissell DM. Mechanisms and therapy of hepatic fibrosis: report of the AASLD Single Topic Basic Research Conference. 2000, Wiley Online Library.

  3. Wells RG. The role of matrix stiffness in hepatic stellate cell activation and liver fibrosis. J Clin Gastroenterol. 2005;39(4):S158-61.

    Article  CAS  PubMed  Google Scholar 

  4. Altamirano-Barrera A, Barranco-Fragoso B, Méndez-Sánchez N. Management strategies for liver fibrosis. Ann Hepatol. 2017;16(1):48–56.

    Article  CAS  PubMed  Google Scholar 

  5. Smith A, Baumgartner K, Bositis C. Cirrhosis: diagnosis and management. Am Family Phys. 2019;100(12):759–70.

    Google Scholar 

  6. Juakiem W, Torres DM, Harrison SA. Nutrition in cirrhosis and chronic liver disease. Clin Liver Dis. 2014;18(1):179–90.

    Article  PubMed  Google Scholar 

  7. Winau F, et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity. 2007;26(1):117–29.

    Article  CAS  PubMed  Google Scholar 

  8. Eng FJ, Friedman SL. Fibrogenesis I. New insights into hepatic stellate cell activation: the simple becomes complex. Am J Physiology-Gastrointestinal Liver Physiol. 2000;279(1):G7-11.

    Article  CAS  Google Scholar 

  9. Krizhanovsky V, et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008;134(4):657–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liu X, Hu H, Yin JQ. Therapeutic strategies against TGF-β signaling pathway in hepatic fibrosis. Liver Int. 2006;26(1):8–22.

    Article  PubMed  Google Scholar 

  11. Bissell D, et al. Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Investig. 1995;96(1):447–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bissell DM, Roulot D, George J. Transforming growth factor β and the liver. Hepatology. 2001;34(5):859–67.

    Article  CAS  PubMed  Google Scholar 

  13. Martin M, Lefaix J-L, Delanian S. TGF-β1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiation Oncology* Biology* Phys. 2000;47(2):277–90.

    Article  CAS  Google Scholar 

  14. Kweon Y-O, et al. Gliotoxin-mediated apoptosis of activated human hepatic stellate cells. J Hepatol. 2003;39(1):38–46.

    Article  CAS  PubMed  Google Scholar 

  15. Sumiyoshi M, Sakanaka M, Kimura Y. Chronic intake of a high-cholesterol diet resulted in hepatic steatosis, focal nodular hyperplasia and fibrosis in non-obese mice. Br J Nutr. 2010;103(3):378–85.

    Article  CAS  PubMed  Google Scholar 

  16. Kainuma M, et al. Cholesterol-fed rabbit as a unique model of nonalcoholic, nonobese, non-insulin-resistant fatty liver disease with characteristic fibrosis. J Gastroenterol. 2006;41(10):971–80.

    Article  CAS  PubMed  Google Scholar 

  17. Teratani T, et al. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology. 2012;142(1):152–64.

    Article  CAS  PubMed  Google Scholar 

  18. Nehra V, et al. Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis. Dig Dis Sci. 2001;46(11):2347–52.

    Article  CAS  PubMed  Google Scholar 

  19. Seki S, et al. In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J Hepatol. 2002;37(1):56–62.

    Article  CAS  PubMed  Google Scholar 

  20. Pérez-Carreras M, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003;38(4):999–1007.

    Article  PubMed  Google Scholar 

  21. Reeves HL, et al. Hepatic stellate cell activation occurs in the absence of hepatitis in alcoholic liver disease and correlates with the severity of steatosis. J Hepatol. 1996;25(5):677–83.

    Article  CAS  PubMed  Google Scholar 

  22. Vazquez-Jimenez JG, et al. Palmitic acid but not palmitoleic acid induces insulin resistance in a human endothelial cell line by decreasing SERCA pump expression. Cell Signal. 2016;28(1):53–9.

    Article  Google Scholar 

  23. Kleinfeld AM, et al. Increases in serum unbound free fatty acid levels following coronary angioplasty. Am J Cardiol. 1996;78(12):1350–4.

    Article  CAS  PubMed  Google Scholar 

  24. Takkunen MJ, et al. Longitudinal associations of serum fatty acid composition with type 2 diabetes risk and markers of insulin secretion and sensitivity in the Finnish Diabetes Prevention Study. Eur J Nutr. 2016;55(3):967–79.

    Article  CAS  PubMed  Google Scholar 

  25. Dong Z, et al. Palmitic acid stimulates NLRP3 inflammasome activation through TLR4-NF-κB signal pathway in hepatic stellate cells. Ann Trans Med. 2020;8(5).

  26. Kiss K, et al. Chronic hyperglycaemia induced alterations of hepatic stellate cells differ from the effect of TGFB1, and point toward metabolic stress. Pathol Oncol Res. 2020;26(1):291–9.

  27. Perdomo CM, Frühbeck G, Escalada J. Impact of nutritional changes on nonalcoholic fatty liver disease. Nutrients. 2019;11(3):677.

    Article  CAS  PubMed Central  Google Scholar 

  28. Zhou L, et al. miR-185 inhibits fibrogenic activation of hepatic stellate cells and prevents liver fibrosis. Mol Therapy-Nucleic Acids. 2018;10:91–102.

    Article  CAS  Google Scholar 

  29. Iredale J. Defining therapeutic targets for liver fibrosis: exploiting the biology of inflammation and repair. Pharmacol Res. 2008;58(2):129–36.

    Article  CAS  PubMed  Google Scholar 

  30. Liu Z, et al. Transforming growth factor β (TGFβ) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation. J Biol Chem. 2019;294(9):3137–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Seki E, Brenner DA. Recent advancement of molecular mechanisms of liver fibrosis. J Hepato-Biliary‐Pancreatic Sci. 2015;22(7):512–8.

    Article  Google Scholar 

  32. Carpino G, et al. Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation. Dig Liver Dis. 2005;37(5):349–56.

    Article  CAS  PubMed  Google Scholar 

  33. Tomita K, et al. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology. 2014;59(1):154–69.

    Article  CAS  PubMed  Google Scholar 

  34. Meissen JK, et al. Temporal metabolomic responses of cultured HepG2 liver cells to high fructose and high glucose exposures. Metabolomics. 2015;11(3):707–21.

    Article  CAS  PubMed  Google Scholar 

  35. Wobser H, et al. Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells. Cell Res. 2009;19(8):996–1005.

    Article  CAS  PubMed  Google Scholar 

  36. Fabregat I, et al. TGF-β signalling and liver disease. FEBS J. 2016;283(12):2219–32.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the University of Medical Sciences of the Ahvaz Jundishapur for the financial support of the study.

Funding

Medical Sciences Ahvaz Jundishapur University has supported this study (grant number. HLRC- CMRC-0009). The funding has not affected any steps of the research.

Author information

Authors and Affiliations

  1. Hyperlipidemia Research Center, Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Ghorban Mohammadzadeh

  2. Cellular and Molecular Research Center, Medical Basic Science Research Institute, Department of Laboratory Sciences, School of ParaMedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Reza Afarin, Samaneh Salehipour Bavarsad, Fereshteh Aslani, Shahla Asadi Zadeh & Elham Shakerian

Authors
  1. Ghorban Mohammadzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reza Afarin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samaneh Salehipour Bavarsad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fereshteh Aslani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shahla Asadi Zadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elham Shakerian
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GHM planned the research. ESH did assay. RA analyses the obtained results. SSB and ESH wrote the manuscript and revised it. FA and SAZ interpreted the data. All authors confirmed the final article.

Corresponding author

Correspondence to Elham Shakerian.

Ethics declarations

Ethics approval to participate

Ethical clearance was not needed and not sought from the Review Board of Ahwaz Jundishapur University of Medical Sciences, because the study was done on cell lines in vitro, and did not use human samples. 

Publication consent

No applicable.

Competing interests

The authors report no conflicts of interest.

Additional information

Publisher’s note

Springer Nature 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

Mohammadzadeh, G., Afarin, R., Bavarsad, S.S. et al. Comparison of the effects of cholesterol, palmitic acid, and glucose on activation of human hepatic stellate cells to induce liver fibrosis. J Diabetes Metab Disord 21, 1531–1538 (2022). https://doi.org/10.1007/s40200-022-01095-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40200-022-01095-z

Keywords

Search

Navigation