BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Metformin ameliorates bile duct ligation-induced acute hepatic injury via regulation of ER stress

  • Lee, Chi-Ho (Department of Pharmacology and Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine) ;
  • Han, Jung-Hwa (Department of Pharmacology and Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine) ;
  • Kim, Sujin (Department of Pharmacology and Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine) ;
  • Lee, Heejung (Department of Pharmacology and Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine) ;
  • Kim, Suji (Department of Pharmacology and Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine) ;
  • Nam, Dae-Hwan (Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University) ;
  • Cho, Du-Hyong (Department of Pharmacology and Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine) ;
  • Woo, Chang-Hoon (Department of Pharmacology and Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine)
  • Received : 2019.07.08
  • Accepted : 2019.11.13
  • Published : 2020.06.30
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Abstract

Cholestasis is a condition in which the bile duct becomes narrowed or clogged by a variety of factors and bile acid is not released smoothly. Bile acid-induced liver injury is facilitated by necrotic cell death, neutrophil infiltration, and inflammation. Metformin, the first-line treatment for type 2 diabetes, is known to reduce not only blood glucose but also inflammatory responses. In this study, we investigated the effects of metformin on liver injury caused by cholestasis with bile acid-induced hepatocyte injury. Static bile acid-induced liver injury is thought to be related to endoplasmic reticulum (ER) stress, inflammatory response, and chemokine expression. Metformin treatment reduced liver injury caused by bile acid, and it suppressed ER stress, inflammation, chemokine expression, and neutrophil infiltration. Similar results were obtained in mouse primary hepatocytes exposed to bile acid. Hepatocytes treated with tauroursodeoxycholic acid, an ER stress inhibitor, showed inhibition of ER stress, as well as reduced levels of inflammation and cell death. These results suggest that metformin may protect against liver injury by suppressing ER stress and inflammation and reducing chemokine expression.

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References

  1. Bailey CJ and Turner RC (1996) Metformin. N Engl J Med 334, 574-579 https://doi.org/10.1056/NEJM199602293340906
  2. Rena G, Pearson ER and Sakamoto K (2013) Molecular mechanism of action of metformin: old or new insights? Diabetologia 56, 1898-1906 https://doi.org/10.1007/s00125-013-2991-0
  3. Kim J, Kwak HJ, Cha JY et al (2014) Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction. J Biol Chem 289, 23246-23255 https://doi.org/10.1074/jbc.M114.577908
  4. Dai J, Liu M, Ai Q et al (2014) Involvement of catalase in the protective benefits of metformin in mice with oxidative liver injury. Chem Biol Interact 216, 34-42 https://doi.org/10.1016/j.cbi.2014.03.013
  5. Wheaton WW, Weinberg SE, Hamanaka RB et al (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 3, e02242 https://doi.org/10.7554/elife.02242
  6. Jung TW, Lee MW, Lee YJ and Kim SM (2012) Metformin prevents endoplasmic reticulum stress-induced apoptosis through AMPK-PI3K-c-Jun NH2 pathway. Biochem Biophys Res Commun 417, 147-152 https://doi.org/10.1016/j.bbrc.2011.11.073
  7. Trauner M, Meier PJ and Boyer JL (1998) Molecular pathogenesis of cholestasis. N Engl J Med 339, 1217-1227 https://doi.org/10.1056/NEJM199810223391707
  8. Kaplowitz N (2004) Drug-induced liver injury. Clin Infect Dis 38 Suppl 2, S44-S48 https://doi.org/10.1086/381446
  9. Cai SY, Ouyang X, Chen Y et al (2017) Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight 2, e90780
  10. Tamaki N, Hatano E, Taura K et al (2008) CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am J Physiol Gastrointest Liver Physiol 294, G498-505 https://doi.org/10.1152/ajpgi.00482.2007
  11. Gujral JS, Farhood A, Bajt ML and Jaeschke H (2003) Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice. Hepatology 38, 355-363
  12. Schroder M and Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569, 29-63 https://doi.org/10.1016/j.mrfmmm.2004.06.056
  13. Lee DH, Lee B, Park JS et al (2019) Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: possible involvement of ER stress and S6K1 activation. BMB Rep 52, 190-195 https://doi.org/10.5483/bmbrep.2019.52.3.083
  14. Kwon MY, Hwanf N, Lee SJ and Chung SW (2019) Nucleotide-binding oligomerization domain protein 2 attenuates ER stress-induced cell death in vascular smooth muscle cells. BMB Rep 52, 665-670 https://doi.org/10.5483/bmbrep.2019.52.11.176
  15. Woudenberg-Vrenken TE, Conde de la Rosa L, Buist-Homan M, Faber KN and Moshage H (2013) Metformin protects rat hepatocytes against bile acid-induced apoptosis. PLoS One 8, e71773 https://doi.org/10.1371/journal.pone.0071773
  16. Tag CG, Sauer-Lehnen S, Weiskirchen S et al (2015) Bile duct ligation in mice: induction of inflammatory liver injury and fibrosis by obstructive cholestasis. J Vis Exp 96, e52438
  17. Georgiev P, Jochum W, Heinrich S et al (2008) Characterization of time-related changes after experimental bile duct ligation. Br J Surg 95, 646-656 https://doi.org/10.1002/bjs.6050
  18. Afonso MB, Rodrigues PM, Simao AL et al (2016) Activation of necroptosis in human and experimental cholestasis. Cell Death Dis 7, e2390 https://doi.org/10.1038/cddis.2016.280
  19. Kossor DC, Goldstein RS, Ngo W et al (1995) Biliary epithelial cell proliferation following alpha-naphthylisothiocyanate (ANIT) treatment: relationship to bile duct obstruction. Fundam Appl Toxicol 26, 51-62 https://doi.org/10.1006/faat.1995.1074
  20. Sadeghi H, Jahanbazi F, Sadeghi H et al (2019) Metformin attenuates oxidative stress and liver damage after bile duct ligation in rats. Res Pharm Sci 14, 122-129 https://doi.org/10.4103/1735-5362.253359
  21. Lien F, Berthier A, Bouchaert E et al (2014) Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. J Clin Invest 124, 1037-1051 https://doi.org/10.1172/JCI68815
  22. Noguchi H, Yamada S, Nabeshima A et al (2014) Depletion of apoptosis signal-regulating kinase 1 prevents bile duct ligation-induced necroinflammation and subsequent peribiliary fibrosis. Am J Pathol 184, 644-661 https://doi.org/10.1016/j.ajpath.2013.11.030