Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 1, pp 37–43 | Cite as

Targeting HMGB1/TLR4 axis and miR-21 by rosuvastatin: role in alleviating cholestatic liver injury in a rat model of bile duct ligation

  • Enas S. NabihEmail author
  • Omnyah A. El-kharashi
Original Article


Many pathways are involved in the association between biliary obstruction and liver injury. We investigated the intervention influence and effect of rosuvastatin (Rvs) on the high mobility group protein 1 (HMGB1)/toll-like receptor-4 (TLR4) axis and microRNA-21 (miR-21) in cholestatic liver injury. This model was performed by ligating common bile duct of Wistar rats. Saline and Rvs were orally administrated by gastric gavages. Liver and blood samples were collected and subjected to molecular and biochemical evaluation. We found that the daily oral administration of Rvs was protective against the occurrence of cholestatic liver injury. This was evident from the results of hepatic, oxidative stress, and inflammatory biomarkers. This study also revealed the Rvs inhibitory effect on the HMGB1/TLR4 intracellular signaling axis as evidenced by decreasing the levels of nuclear factor κβ (NFκβ), tumor necrosis factor α (TNFα), and interleukin 6 (IL6) production. Furthermore, Rvs-treated group showed a significant reduction in the expression of miR-21 in comparison to the untreated group. Accordingly, rosuvastatin interference with the HMGB1/TLR4 and miR-21 expression could explain its hepatoprotective effect in cholestatic liver injury.


Cholestasis HMGB1 miR-21 Rosuvastatin TLR4 



Alkaline phosphatase


Alanine transaminase


Aspartate transaminase


Bile duct ligation




Hepatocellular carcinoma


High mobility group protein 1


Interleukin 6






Nuclear factor κβ


Polymerase chain reaction


Reactive oxygen species




Signal transducer and activator of transcription 3


Toll-like receptor-4


Author contributions

Enas S. Nabih: Share in idea, design, biochemical work, and writing the manuscript.

Omnyah A. El-Kharashi: Share in idea, design, pharmacological work, and writing the manuscript.

Compliance with ethical standards

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflict of interest.


  1. Abdel Motaleb FI, Nabih ES, Mohamed SM et al (2017) Up-regulation of circulating miRNA146a correlates with viral load via IRAK1 and TRAF6 in hepatitis C virus-infected patients. Virus Res 238:24–28. CrossRefGoogle Scholar
  2. Abshagen K, König M, Hoppe A, Müller I, Ebert M, Weng H, Holzhütter HG, Zanger UM, Bode J, Vollmar B, Thomas M, Dooley S (2015) Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice. BMC Syst Biol 9:83CrossRefGoogle Scholar
  3. Afonso MB, Rodrigues PM, Simão AL et al (2018) miRNA-21 ablation protects against liver injury and necroptosis in cholestasis. Cell Death Differ 25:857–872CrossRefGoogle Scholar
  4. Allen K, Jaeschke H, Copple BL (2011) Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am J Pathol 178:175–186CrossRefGoogle Scholar
  5. Asavarut P, Zhao H, Gu J (2013) The role of HMGB1 in inflammation-mediated organ injury. Acta Anaesthesiol Taiwanica 51(1):28–33CrossRefGoogle Scholar
  6. Benias PC, Gopal K, Bodenheimer H et al (2012) Hepatic expression of toll-like receptors 3, 4, and 9 in primary biliary cirrhosis and chronic hepatitis C. Clin Res Hepatol Gastroenterol 36(5):448–454CrossRefGoogle Scholar
  7. Blake G, Ridker P (2000) Are statins anti-inflammatory? Curr Control Trials Cardiovasc Med 1(3):161–165CrossRefGoogle Scholar
  8. Bonaldi T, Talamo F, Scaffidi et al (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 22:5551–5560CrossRefGoogle Scholar
  9. Canbay A, Feldstein AE, Higuchi H et al (2003) Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology 38(5):1188–1198CrossRefGoogle Scholar
  10. Chen R, Hou W, Zhang Q et al (2013) Emerging role of high-mobility group box 1 (HMGB1) in liver diseases. Mol Med 19(1):357–366CrossRefGoogle Scholar
  11. Chen M, Liu Y, Varley P et al (2015) High mobility group box-1 promotes hepatocellular carcinoma progression through miR-21-mediated matrix metalloproteinase activity. Cancer Res 75(8):1645–1656CrossRefGoogle Scholar
  12. Davignon J, Jacob RF, Mason RP (2004) The antioxidant effects of statins. Coron Artery Dis 15(5):251–258CrossRefGoogle Scholar
  13. Esterbauer H, Cheeseman KH (1990) Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods Enzymol 186:407–421CrossRefGoogle Scholar
  14. Gao L, Lv G, Guo X et al (2014) Activation of autophagy protects against cholestasis-induced hepatic injury. Cell Biosci 4:47CrossRefGoogle Scholar
  15. McGill MR, Sharpe MR, Williams CD et al (2012) The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 122:1574–1583CrossRefGoogle Scholar
  16. Musumeci D, Roviello GN, Montesarchio D (2014) An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies. Pharmacol Ther 141(3):347–357CrossRefGoogle Scholar
  17. Poltorak A, He X, Smirnova I et al (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282(5396):2085–2088CrossRefGoogle Scholar
  18. Sahu BD, Kalvala AK, Koneru M, Mahesh Kumar J, Kuncha M, Rachamalla SS, Sistla R (2014) Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defense. PLoS One 9(9):e105070CrossRefGoogle Scholar
  19. Shaker Y, Safaa M, Kamel et al (2015) The role of rosuvastatin in experimentally induced hepatic cholestasis in adult male albino rats: a histological and immunohistochemical study. Egyptian Journal of Histology 38(2):219–227CrossRefGoogle Scholar
  20. Shirin H, Sharvit E, Aeed H et al (2013) Atorvastatin and rosuvastatin do not prevent thioacetamide induced liver cirrhosis in rats. World J Gastroenterol 19(2):241–248CrossRefGoogle Scholar
  21. Tsung A, Hoffman RA, Izuishi K et al (2005a) Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J Immunol 175(11):7661–7668CrossRefGoogle Scholar
  22. Tsung A, Sahai R, Tanaka H et al (2005b) The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med 201(7):1135–1143CrossRefGoogle Scholar
  23. Wang AP, Migita K, Ito M et al (2005) Hepatic expression of toll-like receptor 4 in primary biliary cirrhosis. J Autoimmun 25(1):85–91CrossRefGoogle Scholar
  24. Wang L, Li N, Lin D et al (2017) Curcumin protects against hepatic ischemia/reperfusion induced injury through inhibiting TLR4/NF-κB pathway. Oncotarget 8(39):65414–65420Google Scholar
  25. Woolbright BL, Jaeschke H (2017) Therapeutic targets for cholestatic liver injury. Expert Opin Ther Targets 20(4):463–475CrossRefGoogle Scholar
  26. Xianjin DU, Xiaorong HU, Jie WEI (2013) Postconditioning with rosuvastatin reduces myocardial ischemia-reperfusion injury by inhibiting high mobility group box 1 protein expression. Exp Ther Med 7(1):117–120Google Scholar
  27. Yamaura Y, Nakajima M, Takagi S, Fukami T, Tsuneyama K, Yokoi T (2012) Plasma microRNA profiles in rat models of hepatocellular injury, cholestasis, and steatosis. PLoS One 7(2):e30250CrossRefGoogle Scholar
  28. Yu Y, Tang D, Kang R (2015) Oxidative stress-mediated HMGB1 biology. Front Physiol 6:93. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medical Biochemistry and Molecular Biology, Faculty of MedicineAin Shams UniversityCairoEgypt
  2. 2.Department of Clinical Pharmacology, Faculty of MedicineAin Shams UniversityCairoEgypt

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