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Oxidative Stress and the Unfolded Protein Response in the Liver

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Studies on Hepatic Disorders

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Abstract

Several liver and biliary diseases are characterized by oxidative and endoplasmic reticulum stress, both of which can lead to inflammation, disruption of hormone signaling, and cell death. Endoplasmic reticulum stress results from the accumulation of unfolded proteins in the lumen and is linked to the unfolded protein response (UPR), a signaling pathway that reduces global protein synthesis and upregulates folding and degradation machinery. Protein folding in the endoplasmic reticulum lumen can also generate reactive oxygen species and oxidative stress can influence the UPR. In this chapter, the interactions between the endoplasmic reticulum, UPR, and oxidative stress will be discussed with special emphasis placed on these events in the liver.

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References

  1. van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9:112–124. doi:10.1038/nrm2330

    Article  PubMed Central  PubMed  Google Scholar 

  2. Gentile CL, Frye M, Pagliassotti MJ (2011) Endoplasmic reticulum stress and the unfolded protein response in nonalcoholic fatty liver disease. Antioxid Redox Signal 15:505–521. doi:10.1089/ars.2010.3790

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Gentile CL, Pagliassotti MJ (2008) The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem 19:567–576. doi:10.1016/j.jnutbio.2007.10.001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Marciniak S, Ron D (2006) Endoplasmic reticulum stress signaling in disease. Physiol Rev 86:1133–1149

    Article  CAS  PubMed  Google Scholar 

  5. Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569:29–63. doi:10.1016/j.mrfmmm.2004.06.056

    Article  PubMed  Google Scholar 

  6. Guerriero CJ, Brodsky JL (2012) The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiol Rev 92:537–576. doi:10.1152/physrev.00027.2011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Rutkowski DT, Kaufman RJ (2004) A trip to the ER: coping with stress. Trends Cell Biol 14:20–28

    Article  CAS  PubMed  Google Scholar 

  8. Wu J, Kaufman RJ (2006) From acute ER stress to physiological roles of the Unfolded Protein Response. Cell Death Differ 13:374–384

    Article  CAS  PubMed  Google Scholar 

  9. Zhang K, Kaufman RJ (2008) From endoplasmic reticulum stress to the inflammatory response. Nature 454:455–462

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Kaufman RJ (2002) Orchestrating the unfolded protein response in health and disease. J Clin Invest 110:1389–1398

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789

    Article  PubMed  Google Scholar 

  12. Trusina A, Papa FR, Tang C (2008) Rationalizing translation attenuation in the network architecture of the unfolded protein response. Proc Natl Acad Sci U S A 105:20280–20285. doi:10.1073/pnas.0803476105

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233

    Article  CAS  PubMed  Google Scholar 

  14. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198–7209

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666

    Article  CAS  PubMed  Google Scholar 

  16. Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH (2006) Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kB activation and down-regulation of TRAF2 expression. Mol Cell Biol 26:3071–3084

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Nguyen DT, Kebache S, Fazel A, Wong HN, Jenna S, Emadali A, Lee EH, Bergeron JJ, Kaufman RJ, Larose L, Chevet E (2004) Nck-dependent activation of extracellular signal-regulated kinase-1 and regulation of cell survival during endoplasmic reticulum stress. Mol Biol Cell 15:4248–4260

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Hetz C, Glimcher LH (2009) Fine-tuning of the unfolded protein response: assembling the IRE1alpha interactome. Mol Cell 35:551–561

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Hollien J, Weissman JS (2006) Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313:104–107. doi:10.1126/science.1129631

    Article  CAS  PubMed  Google Scholar 

  20. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS (2009) Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 186:323–331. doi:10.1083/jcb.200903014

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Santos CX, Tanaka LY, Wosniak J, Laurindo FR (2009) Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase. Antioxid Redox Signal 11:2409–2427. doi:10.1089/ARS.2009.2625

    Article  CAS  PubMed  Google Scholar 

  22. Shimizu Y, Hendershot LM (2009) Oxidative folding: cellular strategies for dealing with the resultant equimolar production of reactive oxygen species. Antioxid Redox Signal 11:2317–2331

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Hanada S, Harada M, Kumemura H, Omary MB, Koga H, Kawaguchi T, Taniguchi E, Yoshida T, Hisamoto T, Yanagimoto C, Maeyama M, Ueno T, Sata M (2007) Oxidative stress induces the endoplasmic reticulum stress and facilitates inclusion formation in cultured cells. J Hepatol 47:93–102

    Article  CAS  PubMed  Google Scholar 

  24. Yokouchi M, Hiramatsu N, Hayakawa K, Okamura M, Du S, Kasai A, Takano Y, Shitamura A, Shimada T, Yao J, Kitamura M (2008) Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response. J Biol Chem 283:4252–4260

    Article  CAS  PubMed  Google Scholar 

  25. Xue X, Piao JH, Nakajima A, Sakon-Komazawa S, Kojima Y, Mori K, Yagita H, Okumura K, Harding H, Nakano H (2005) Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha. J Biol Chem 280:33917–33925. doi:10.1074/jbc.M505818200

    Article  CAS  PubMed  Google Scholar 

  26. Cullinan SB, Diehl JA (2006) Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38:317–332

    Article  CAS  PubMed  Google Scholar 

  27. Moi P, Chan K, Asunis I, Cao A, Kan YW (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A 91:9926–9930

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Sugimoto H, Okada K, Shoda J, Warabi E, Ishige K, Ueda T, Taguchi K, Yanagawa T, Nakahara A, Hyodo I, Ishii T, Yamamoto M (2010) Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol 298:G283–G294

    Article  CAS  PubMed  Google Scholar 

  29. Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, Biswal S (2006) Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 116:984–995

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Liu Y, Adachi M, Zhao S, Hareyama M, Koong AC, Luo D, Rando TA, Imai K, Shinomura Y (2009) Preventing oxidative stress: a new role for XBP1. Cell Death Differ 16:847–857

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Hwang C, Sinskey AJ, Lodish HF (1992) Oxidized redox state of glutathione in the endoplasmic reticulum. Science 257:1496–1502

    Article  CAS  PubMed  Google Scholar 

  32. Tu BP, Weissman JS (2004) Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol 164:341–346. doi:10.1083/jcb.200311055

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Szaraz P, Banhegyi G, Benedetti A (2010) Altered redox state of luminal pyridine nucleotides facilitates the sensitivity towards oxidative injury and leads to endoplasmic reticulum stress dependent autophagy in HepG2 cells. Int J Biochem Cell Biol 42:157–166. doi:10.1016/j.biocel.2009.10.004

    Article  CAS  PubMed  Google Scholar 

  34. Haynes CM, Titus EA, Cooper AA (2004) Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell 15:767–776. doi:10.1016/j.molcel.2004.08.025

    Article  CAS  PubMed  Google Scholar 

  35. Malhotra JD, Miao H, Zhang K, Wolfson A, Pennathur S, Pipe SW, Kaufman RJ (2008) Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc Natl Acad Sci U S A 105:18525–18530. doi:10.1073/pnas.0809677105

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Malhotra JD, Kaufman RJ (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 9:2277–2293. doi:10.1089/ars.2007.1782

    Article  CAS  PubMed  Google Scholar 

  37. Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE (2003) Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 100:3077–3082. doi:10.1073/pnas.0630588100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Unger RH, Zhou YT (2001) Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50(Suppl 1):S118–S121

    Article  CAS  PubMed  Google Scholar 

  39. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ (2004) Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 40:185–194. doi:10.1002/hep.20283

    Article  CAS  PubMed  Google Scholar 

  40. Wei Y, Wang D, Topczewski F, Pagliassotti MJ (2006) Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 291:E275–E281. doi:10.1152/ajpendo.00644.2005

    Article  CAS  PubMed  Google Scholar 

  41. Gentile CL, Nivala AM, Gonzales JC, Pfaffenbach KT, Wang D, Wei Y, Jiang H, Orlicky DJ, Petersen DR, Pagliassotti MJ, Maclean KN (2011) Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease. Am J Physiol Regul Integr Comp Physiol 301:R1710–R1722. doi:10.1152/ajpregu.00677.2010

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Howarth DL, Vacaru AM, Tsedensodnom O, Mormone E, Nieto N, Costantini LM, Snapp EL, Sadler KC (2012) Alcohol disrupts endoplasmic reticulum function and protein secretion in hepatocytes. Alcohol Clin Exp Res 36:14–23. doi:10.1111/j.1530-0277.2011.01602.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Howarth DL, Passeri M, Sadler KC (2011) Drinks like a fish: using zebrafish to understand alcoholic liver disease. Alcohol Clin Exp Res 35:826–829. doi:10.1111/j.1530-0277.2010.01407.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Tsedensodnom O, Vacaru AM, Howarth DL, Yin C, Sadler KC (2013) Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease. Dis Model Mech 6:1213–1226. doi:10.1242/dmm.012195

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Marchi S, Patergnani S, Pinton P (2013) The endoplasmic reticulum-mitochondria connection: one touch, multiple functions. Biochim Biophys Acta. doi:10.1016/j.bbabio.2013.10.015

    Google Scholar 

  46. Hayashi T, Rizzuto R, Hajnoczky G, Su TP (2009) MAM: more than just a housekeeper. Trends Cell Biol 19:81–88. doi:10.1016/j.tcb.2008.12.002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Pizzo P, Pozzan T (2007) Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol 17:511–517. doi:10.1016/j.tcb.2007.07.011

    Article  CAS  PubMed  Google Scholar 

  48. Bravo R, Gutierrez T, Paredes F, Gatica D, Rodriguez AE, Pedrozo Z, Chiong M, Parra V, Quest AF, Rothermel BA, Lavandero S (2012) Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics. Int J Biochem Cell Biol 44:16–20. doi:10.1016/j.biocel.2011.10.012

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Bravo R, Vicencio JM, Parra V, Troncoso R, Munoz JP, Bui M, Quiroga C, Rodriguez AE, Verdejo HE, Ferreira J, Iglewski M, Chiong M, Simmen T, Zorzano A, Hill JA, Rothermel BA, Szabadkai G, Lavandero S (2011) Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress. J Cell Sci 124:2143–2152. doi:10.1242/jcs.080762

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610. doi:10.1038/nature07534

    Article  PubMed  Google Scholar 

  51. Sebastian D, Hernandez-Alvarez MI, Segales J, Sorianello E, Munoz JP, Sala D, Waget A, Liesa M, Paz JC, Gopalacharyulu P, Oresic M, Pich S, Burcelin R, Palacin M, Zorzano A (2012) Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci U S A 109:5523–5528. doi:10.1073/pnas.1108220109

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Shen T, Zheng M, Cao C, Chen C, Tang J, Zhang W, Cheng H, Chen KH, Xiao RP (2007) Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis. J Biol Chem 282:23354–23361. doi:10.1074/jbc.M702657200

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Food Science and Human Nutrition, Colorado State University, Gifford 234, Fort Collins, CO, USA, 80523-1571

    William M. Hudson & Michael J. Pagliassotti

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  1. William M. Hudson
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  2. Michael J. Pagliassotti
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Correspondence to Michael J. Pagliassotti .

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Editors and Affiliations

  1. Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy

    Emanuele Albano

  2. Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, School of Medicine, University of Torino, Torino, Italy

    Maurizio Parola

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Hudson, W.M., Pagliassotti, M.J. (2015). Oxidative Stress and the Unfolded Protein Response in the Liver. In: Albano, E., Parola, M. (eds) Studies on Hepatic Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15539-5_5

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