Protective effects of curcumin against chronic alcohol-induced liver injury in mice through modulating mitochondrial dysfunction and inhibiting endoplasmic reticulum stress

  • Baoying Wang Henan University of Chinese Medicine
  • Xiaolin Gao
  • Baoguang Liu
  • Yucheng Li
  • Ming Bai
  • Zhenqiang Zhang
  • Erping Xu
  • Zhang’e Xiong
  • Yunlian Hu
Keywords: curcumin; alcohol; liver injury; mitochondria; endoplasmic reticulum stress; inflammation


Background: Curcumin is a major active ingredient extracted from powdered dry rhizome of Curcuma longa.
In Ayurveda and traditional Chinese medicine, it has been used as a hepatoprotective agent for centuries.
However, the underlying mechanisms are not clear.

Objective: The present study is to investigate the hepatoprotective effects of curcumin in chronic alcohol-induced liver injury and explore its mechanism.

Design: Alcohol-exposed Balb/c mice were treated with curcumin (75 and 150 mg/kg) once per day for 8 weeks. Tissue from individual was fixed with formaldehyde for pathological examination. The activities of mitochondrial antioxidant enzymes, Na+/k+-ATPase, Ca2+-ATPase, and Ca2+Mg2+-ATPase, were determined. The level of mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (MPTP)
opening was also determined. The expression of PGC-1α, NRF1, Mn-SOD, GRP78, PERK, IRE1α, nuclear
NF-κB, and phosphorylated IκBα was quantified by western blot. The contents of TNF-α, IL-1β, and IL-6 in
the liver were measured using the ELISA method.

Results: Curcumin significantly promoted hepatic mitochondrial function by reducing the opening of MPTP,
thus increasing the MMP, promoting the activity of Na+/k+-ATPase, Ca2+-ATPase, and Ca2+/Mg2+-ATPase,
and attenuating oxidative stress. Curcumin upregulated the expression of PGC-1α, NRF1, and Mn-SOD, and
downregulated the expression of GRP78, PERK, and IRE1α in hepatic tissue. Curcumin also attenuated inflammation by inhibiting the IκBα–NF-κB pathway, which reduced the production of TNF, IL-1β, and IL-6.

Conclusion: Curcumin attenuates alcohol-induced liver injury via improving mitochondrial function and attenuating endoplasmic reticulum stress and inflammation. This study provides strong evidence for the beneficial effects of curcumin in the treatment of chronic alcohol-induced liver injury.


Download data is not yet available.


  1. Khan A, Tansel A, White DL, Kayani WT, Bano S, Lindsay J, et al. Efficacy of psychosocial interventions in inducing and maintaining alcohol abstinence in patients with chronic liver disease: a systematic review. Clin Gastroenterol Hepatol 2016; 14(2): 191–202.e4. doi: 10.1016/j.cgh.2015.07.047

  2. Dang XY, Fan JG. A Summary of the 2012 Asia-Pacific liver disease annual meeting on alcoholic liver diseases. J Pract Liver Dis 2012; 3: 177–80. doi: 10.3969/j.issn.1672-5069.2012.03.001

  3. Cederbaum AI. Cytochrome P450 2E1-dependent oxidant stress and upregulation of antioxidant defense in liver cells. J Gastroenterol Hepatol 2006; Suppl. 3: S22–5. doi: 10.1111/j.1440-1746.2006.04595.x

  4. Yip WW, Burr AD. Alcoholic liver disease. Semin Diap Pathol 2006; 23(3–4): 149–60. doi: 10.1053/j.semdp.2006.11.002

  5. Tang Y, Gao C, Xing M, Li Y, Zhu L, Wang D, et al. Quercetin prevents ethanol-induced dyslipidemia and mitochondrial oxidative damage. Food Chem Toxicol 2012; 50(5): 1194–200. doi: 10.1016/j.fct.2012.02.008

  6. Shalbueva N, Mareninova OA, Gerloff A, Yuan J, Waldron RT, Pandol SJ, et al. Effects of oxidative alcohol metabolism on the mitochondrial permeability transition pore and necrosis in a mouse model of alcoholic pancreatitis. Gastroenterology 2013; 144(2): 437–46. doi: 10.1053/j.gastro.2012.10.037

  7. Ji C. Dissection of endoplasmic reticulum stress signaling in alcoholic and non-alcoholic liver injury. J Gastroen Hepatol 2008; 23(1): S16–24. doi: 10.1111/j.1440-1746.2007.05276.x

  8. Kaphalia L, Boroumand N, Hyunsu J, Kaphalia BS, Calhoun WJ. Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding. Toxicol Appl Pharm 2014; 277(2): 109–17. doi: 10.1016/j.taap.2014.02.018

  9. Zhang KZ, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature 2008; 454: 455–62. doi: 10.1038/nature07203

  10. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP. et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000; 287: 664–6. doi: 10.1126/science.287.5453.664

  11. Ilaiyaraja N, Khanum F. Amelioration of alcohol-induced hepatotoxicity and oxidative stress in rats by acorus calamus. J Diet Suppl 2011; 8: 331–45. doi: 10.3109/19390211.2011.615805

  12. Siddiqui MA, Ahamed M, Ahmad J, Majeed Khan MA, Musarrat J, Al-Khedhairy AA, et al. Nickel oxide nanoparticles induce cytotoxicity, oxidative stress and apoptosis in cultured human cells that is abrogated by the dietary antioxidant curcumin. Food Chem Toxicol 2012; 50: 641–7. doi: 10.1016/j.fct.2012.01.017

  13. Patwardhan RS, Checker R, Sharma D, Kohli V, Priyadarsini KI, Sandur SK. Dimethoxycurcumin, a metabolically stable analogue of curcumin, exhibits anti-inflammatory activities in murine and human lymphocytes. Biochem Pharmacol 2011; 82: 642–57. doi: 10.1016/j.bcp.2011.06.024

  14. Tiwari H, Rao MV. Curcumin supplementation protects from genotoxic effects of arsenic and fluoride. Food Chem Toxicol 2010; 48: 1234–8. doi: 10.1016/j.fct.2010.02.015

  15. Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Thomas P, Dannenberg AJ. Curcumin prevents alcohol-induced liver disease in rats by inhibiting the expression of NF-B-dependent genes. Am J Physiol Gastrointest Liver Physiol 2003; 284: G321–7. doi: 10.1152/ajpgi.00230.2002

  16. Bao W, Li K, Rong S, Yao P, Hao L, Ying C, et al. Curcumin alleviates ethanol-induced hepatocytes oxidative damage involving heme oxygenase-1 induction. J Ethnopharmacol 2010; 128(2): 549–53. doi: 10.1016/j.jep.2010.01.029

  17. Lu C, Xu W, Zhang F, Shao J, Zheng S. Nrf2 knockdown disrupts the protective effect of curcumin on alcohol-induced hepatocyte necroptosis. Mol Pharm 2016; 13(12): 4043–53. doi: 10.1021/acs.molpharmaceut.6b00562

  18. Lee HI, McGregor RA, Choi MS, Seo KI, Jung UJ, Yeo J, et al. Low doses of curcumin protect alcohol-induced liver damage by modulation of the alcohol metabolic pathway, CYP2E1 and AMPK. Life Sci 2013; 93(18–19): 693–9. doi: 10.1016/j.lfs.2013.09.014

  19. Rong S, Zhao Y, Bao W, Xiao X, Wang D, Nussler AK, et al. Curcumin prevents chronic alcohol-induced liver disease involving decreasing ROS generation and enhancing antioxidative capacity. Phytomedicine 2012; 19(6): 545–50. doi: 10.1016/j.phymed.2011.12.006

  20. Tiwari V, Chopra K. Protective effect of curcumin against chronic alcohol-induced cognitive deficits and neuroinflammation in the adult rat brain. Neuroscience 2013; 244: 147–58. doi: 10.1016/j.neuroscience.2013.03.042

  21. Samuhasaneeto S, Thong-Ngam D, Kulaputana O, Suyasunanont D, Klaikeaw N. Curcumin decreased oxidative stress, inhibited NF-kappa B activation, and improved liver pathology in ethanol-induced liver injury in rats. J Biomed Biotechnol 2009; 2009: 981963. doi: 10.1155/2009/981963

  22. Patel VB, Cunningham CC. Altered hepatic mitochondrial ribosome structure following chronic alcohol consumption. Arch Biochem Biophys 2002; 398: 41–50. doi: 10.1006/abbi.2001.2701

  23. Xiong ZE, Dong WG, Wang BY, Tong QY, Li ZY. Curcumin attenuates chronic ethanol-induced liver injury by inhibition of oxidative stress via mitogen-activated protein kinase/nuclear factor E2-related factor 2 pathway in mice. Pharmacogn Mag 2015; 11(44): 707–15. doi: 10.4103/0973-1296.165556

  24. Wheeler MD, Kono H, Yin M, Nakagami M, Uesugi T, Arteel GE, et al. The role of Kupffer cell oxidant production in early ethanol-induced liver disease. Free Radic Biol Med 2001; 31(12): 1544–9. doi: 10.1016/S0891-5849(01)00748-1

  25. Kurose I, Higuchi H, Kato S, Miura S, Watanabe N, Kamegaya Y, et al. Oxidative stress on mitochondria and cell membrane of cultured rat hepatocytes and perfused liver exposed to ethanol. Gastroenterology 1997; 112(4): 1331–43. doi: 10.1016/S0016-5085(97)70147-1

  26. Garcia-Ruiz C, Kaplowitz N, Fernandez-Checa JC. Role of mitochondria in alcoholic liver disease. Curr Pathobiol Rep 2013; 1: 159–68. doi: 10.1007/s40139-013-0021-z

  27. Bailey SM, Robinson G, Pinner A, Chamlee L, Ulasova E, Pompilius M, et al. S-Adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver. Am J Physiol 2006; 291: G857–67. doi: 10.1152/ajpgi.00044.2006

  28. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 2006; 127: 397–408. doi: 10.1016/j.cell.2006.09.024

  29. Cantó C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 2009; 20: 98–105. doi: 10.1097/MOL.0b013e328328d0a4

  30. Du K, Ramachandran A, McGill MR, Mansouri A, Asselah T, Farhood A, et al. Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food Chem Toxicol 2017; 108: 339–50. doi: 10.1016/j.fct.2017.08.020

  31. Wu ZD, Puigserver P, Andersson U. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999; 98(1): 115–24. doi: 10.1016/S0092-8674(00)80611-X

  32. Rasbach KA, Schnellmann RG. PGC-1alpha over-expression promotes recovery from mitochondrial dysfunction and cell injury. Biochem Bioph Res Co 2007; 355(3): 734–9. doi: 10.1016/j.bbrc.2007.02.023

  33. Rayamajhi N, Kim SK, Go H, Joe Y, Callaway Z, Kang JG, et al. Quercetin induces mitochondrial biogenesis through activation of HO-1 in HepG2 cells. Oxid Med Cell Longev 2013; 154279. doi: 10.1155/2013/154279

  34. Chaung WW, Jacob A, Ji Y, Wang P. Suppression of PGC-1α by ethanol: implications of its role in alcohol induced liver injury. Int J Clin Exp Med 2008; 2: 161–70. doi: 10.1089/hum.2007.086

  35. Wang SF, Wan T, Ye MT, Qiu Y, Pei L, Jiang R, et al. Nicotinamide riboside attenuates alcohol induced liver injuries via activation of SirT1/PGC-1α/ mitochondrial biosynthesis pathway. Redox Bio 2018; 17: 89–98. doi: 10.1016/j.redox.2018.04.006

  36. Esfandiari F, Villanueva JA, Wong DH, French SW, Halsted CH. Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs. Am J Physiol Gastrointest Liver Physiol 2005; 289(1): G54–63. doi: 10.1152/ajpgi.00542.2004

  37. Shinohara M, Cheng J, Kaplowitz N. Differences in betaine- homocysteine methyltransferase expression, ER stress response and liver injury between alcohol-fed mice and rats. Hepatology 2010; 51(3): 796–805. doi: 10.1002/hep.23391

  38. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, et al. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 2008; 453: 807–11. doi: 10.1038/nature06905

  39. Zhao L, Jiang Y, Ni Y, Zhang T, Duan C, Huang C, et al. Protective effects of Lactobacillus plantarum C88 on chronic ethanol-induced liver injury in mice. J Funct Foods 2017; 35: 97–104. doi: 10.1016/j.jff.2017.05.017

  40. Meyer M, Caselmann WH, Schlüter V, Schreck R, Hofschneider PH, Baeuerle PA. Hepatitis B virus transactivator MHBst: activation of NF-κB, selective inhibition by antioxidants and integral membrane localization. Embo J 1992; 11: 2991–3001. doi: 10.1002/j.1460-2075.1992.tb05369.x

  41. Pahl HL, Baeuerle PA. Activation of NF-κB by ER stress requires both Ca2+and reactive oxygen intermediates as messengers. FEBS Lett 1996; 392: 129–36. doi: 10.1016/0014-5793(96)00800-9

  42. Zha X, Yue Y, Dong N, Xiong S. Endoplasmic reticulum stress aggravates viral myocarditis by raising inflammation through the IRE1-associated NF-κB pathway. Can J Cardiol 2015; 31(8): 1032–40. doi: 10.1016/j.cjca.2015.03.003

  43. Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. Autocrine tumor necrosis factor a links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1α-mediated NF-κB activation and down-regulation of TRAF2 expression. Mol Cell Biol 2006; 26: 3071–84. doi: 10.1128/MCB.26.8.3071-3084.2006

  44. Yu Y, Zhang L, Liu Q, Tang L, Sun H, Guo H. Endoplasmic reticulum stress preconditioning antagonizes low-density lipoprotein-induced inflammation in human mesangial cells through upregulation of XBP1 and suppression of the IRE1α/IKK/NF-κB pathway. Mol Med Rep 2015; 11(3): 2048–54. doi: 10.3892/mmr.2014.2960

  45. Kitamura M. Control of NF-κB and inflammation by the unfolded protein response. Int Rev Immunol 2011; 30(1): 4–15. doi: 10.3109/08830185.2010.522281

  46. Wu Y, Shan B, Dai JL, Xia ZX, Cai J, Chen TW, et al. Dual role for inositol-requiring enzyme 1 in promoting the development of hepatocellular carcinoma during diet-induced obesity in mice. Hepatology 2018; 68(2): 533–46. doi: 10.1002/hep.29871

  47. Li Y, Li J, Li S, Li Y, Wang X, Liu B, et al. Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK. Toxicol Appl Pharmacol 2015; 286(1): 53–63. doi: 10.1016/j.taap.2015.03.010

  48. Barman PK, Mukherjee R, Prusty BK, Suklabaidya S, Senapati S, Ravindran B. Chitohexaose protects against acetaminophen- induced hepatotoxicity in mice. Cell Death Dis 2016; 7: e2224. doi: 10.1038/cddis.2016.131

How to Cite
Wang B, Gao X, Liu B, Li Y, Bai M, Zhang Z, Xu E, Xiong Z, Hu Y. Protective effects of curcumin against chronic alcohol-induced liver injury in mice through modulating mitochondrial dysfunction and inhibiting endoplasmic reticulum stress. fnr [Internet]. 2019Nov.1 [cited 2019Nov.21];630. Available from:
Original Articles