Transcriptional factors of FAT/CD36, PTP1B, SREBP-1c and HNF4A are involved in dyslipidemia following Cyclosporine A treatment in the liver of male rats: The protective effect of curcumin

Document Type : Original Articles

Authors

Urmia University of Medical Sciences, Urmia, Iran

10.32592/ARI.2025.80.1.233

Abstract

Cyclosporine A (CsA) is a potent immunosuppressive drug which has been reported to cause various disorders including hepatotoxicity. However, the precise molecular mediators participated in CsA-induced liver injury remains poorly understood. This study aimed to characterize the transcription factors involved in lipid metabolism in the context of hepatic injury induced by cyclosporine A (CsA), both independently and in conjunction with curcumin. A total of twenty -eight male adult Wistar rats were assigned into four groups including control (Con), sham, cyclosporine A (CsA) and cyclosporineA +curcumin (CsA+cur). The rats were administered CsA at a dosage of 30 mg/kg and curcumin at 40 mg/kg via a gastric tube for a duration of 28 days. RT-PCR and also Masson trichrome staining were employed to measure related changes. Finally, CsA exposure caused a significant increase in protein tyrosine phosphatase 1B (PTP1B), Fatty acid translocase CD36 (FAT/CD36), sterol regulatory element-binding protein-1c (SREBP-1c) and a significant decrease in hepatocyte nuclear factor 4 Alpha (HNF4A) genes expressions compared to the control and sham group. The CsA treatment also significantly elevated plasma lipids (LDL, cholesterol, triglyceride) and liver enzymes (alanine aminotransferase (ALT) aspartate aminotransferase (AST), alkaline phosphatase (ALP)), compared to the control and sham group. Fibrotic changes were detected in CsA group by Masson trichrome staining. Curcumin consumption resulted in a considerable improvement in histological disorders and molecular mediators involved in liver injury following CsA treatment. Taken together, these findings proposed that CsA can cause deleterious effect to liver tissue via lipid homeostasis disorders mediated by FAT/CD36, PTP1B and HNF4A gene expression alterations. It also reveals that these negative effects of CsA can be mitigated by using curcumin as an antioxidant and anti-inflammatory supplement.

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References

  1. Korolczuk A, Caban K, Amarowicz M, Czechowska G, Irla-Miduch J. Oxidative Stress and Liver Morphology in Experimental Cyclosporine A-Induced Hepatotoxicity. BioMed research international. 2016;2016:5823271.
  2. Bemer V, Motta I, Perret R, Truffa-Bachi P. Interleukin-2 down-modulates memory T helper lymphocyte development during antigenic stimulation in vitro. European journal of immunology. 1995;25(12):3394-401.
  3. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47(2-3):119-25.
  4. Badi N, Fazelipour S, Naji T, Babaei M, Kalantari Hesari A. Histomorphometric and biochemical study of liver and thyroid hormones following administration of MoO3 nanoparticles in female rats. Iranian Journal of Veterinary Medicine. 2022;16(2):188-201.
  5. Moghadasian MH. Dietary phytosterols reduce cyclosporine-induced hypercholesterolemia in apolipoprotein E-knockout mice. Transplantation. 2006;81(2):207-13.
  6. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011;141(5):1572-85.
  7. Tréguier M, Doucet C, Moreau M, Dachet C, Thillet J, Chapman MJ, et al. Transcription factor sterol regulatory element binding protein 2 regulates scavenger receptor Cla-1 gene expression. Arteriosclerosis, thrombosis, and vascular biology. 2004;24(12):2358-64.
  8. Guvenc M, Dogan I. Effect of Helichrysum plicatum Subs. plicatum on Fructose-induced Nonalcoholıc Fatty Liver. Iranian Journal of Veterinary Medicine. 2024;18(1).
  9. Shirpoor A, Heshmati E, Kheradmand F, Gharalari FH, Chodari L, Naderi R, et al. Increased hepatic FAT/CD36, PTP1B and decreased HNF4A expression contributes to dyslipidemia associated with ethanol-induced liver dysfunction: Rescue effect of ginger extract. Biomedicine & pharmacotherapy=Biomedecine & pharmacotherapie. 2018;105:144-50.
  10. Stremmel W, Staffer S, Wannhoff A, Pathil A, Chamulitrat W. Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2014;28(7):3159-70.
  11. Greco D, Kotronen A, Westerbacka J, Puig O, Arkkila P, Kiviluoto T, et al. Gene expression in human NAFLD. American journal of physiology Gastrointestinal and liver physiology. 2008;294(5):G1281-7.
  12. Waring JF, Ciurlionis R, Clampit JE, Morgan S, Gum RJ, Jolly RA, et al. PTP1B antisense-treated mice show regulation of genes involved in lipogenesis in liver and fat. Molecular and cellular endocrinology. 2003;203(1-2):155-68.
  13. Chen PJ, Cai SP, Huang C, Meng XM, Li J. Protein tyrosine phosphatase 1B (PTP1B): A key regulator and therapeutic target in liver diseases. Toxicology. 2015;337:10-20.
  14. Xu J, Xu Y, Li Y, Jadhav K, You M, Yin L, et al. Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury. Scientific reports. 2016;6:24277.
  15. Rahmani S, Asgary S, Askari G, Keshvari M, Hatamipour M, Feizi A, et al. Treatment of Non-alcoholic Fatty Liver Disease with Curcumin: A Randomized Placebo-controlled Trial. Phytotherapy research : PTR. 2016;30(9):1540-8.
  16. Huang J, Yao X, Weng G, Qi H, Ye X. Protective effect of curcumin against cyclosporine A‑induced rat nephrotoxicity. Molecular medicine reports. 2018;17(4):6038-44.
  17. Bhutani MK, Bishnoi M, Kulkarni SK. Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes. Pharmacology, biochemistry, and behavior. 2009;92(1):39-43.
  18. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. Journal of clinical pathology. 1988;41(4):467-70.
  19. Irannejad A, Khatamsaaz S, Mokhtari MJ. Effect of hydro-alcoholic extract of rosemary on lipid profile and liver enzymes in male wistar rats fed with high-fat diet. Iranian Journal of Veterinary Medicine. 2022.
  20. Akbulut S, Elbe H, Eris C, Dogan Z, Toprak G, Yalcin E, et al. Effects of antioxidant agents against cyclosporine-induced hepatotoxicity. The Journal of surgical research. 2015;193(2):658-66.
  21. Jin S, Mathis AS, Rosenblatt J, Minko T, Friedman GS, Gioia K, et al. Insights into cyclosporine A-induced atherosclerotic risk in transplant recipients: macrophage scavenger receptor regulation. Transplantation. 2004;77(4):497-504.
  22. Borlak J, Niehof M. HNF4alpha and HNF1alpha dysfunction as a molecular rational for cyclosporine induced posttransplantation diabetes mellitus. PloS one. 2009;4(3):e4662.
  23. Samarghandian S, Azimi-Nezhad M, Farkhondeh T, Samini F. Anti-oxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2017;87:223-9.
  24. Salimi A, Kheiripour N, Fathi Jouzdani A, Ghasemi H, Soleimani Asl S, Ghafouri-Khosrowshahi A, et al. Nanocurcumin Improves Lipid Status, Oxidative Stress, and Function of the Liver in Aluminium Phosphide-Induced Toxicity: Cellular and Molecular Mechanisms. BioMed research international. 2022;7659765.
  25. Kunchandy E, Rao M. Oxygen radical scavenging activity of curcumin. International journal of pharmaceutics. 1990;58(3):237-40.
Archives of Razi Institute
Volume 80, Issue 1
January and February 2025
Pages 233-241

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