Skip to main content
SpringerLink
Log in

Consequences of Stress in the Secretary Pathway: The ER Stress Response and Its Role in the Metabolic Syndrome

  • Protocol
  • First Online:
Protein Misfolding and Cellular Stress in Disease and Aging

Part of the book series: Methods in Molecular Biology ((MIMB,volume 648))

Abstract

The unfolded protein response (UPR) was originally identified as a signaling network coordinating adaptive and apoptotic responses to accumulation of unfolded proteins in the endoplasmic reticulum (ER). More recent work has shown that UPR signaling can be triggered by a multitude of cellular events and that the UPR plays a critical role in the prevention, and also the progression, of a wide variety of diseases. Much attention has been paid to the role of the UPR in neurodegenerative diseases in the past. More recently, important roles for the UPR in diseases associated with the metabolic syndrome have been discovered. Here we review the role of the UPR in these diseases, including type 2 diabetes, atherosclerosis, fatty liver disease, and ischemia.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Schröder M (2008) Endoplasmic reticulum stress responses. Cell Mol Life Sci 65:862–894

    Article  PubMed  CAS  Google Scholar 

  2. Hidalgo C (2005) Cross talk between Ca2+ and redox signalling cascades in muscle and neurons through the combined activation of ryanodine receptors/Ca2+ release channels. Philos Trans R Soc Lond B Biol Sci 360:2237–2246

    Article  PubMed  CAS  Google Scholar 

  3. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2:326–332

    Article  PubMed  CAS  Google Scholar 

  4. Chen X, Shen J, Prywes R (2002) The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem 277:13045–13052

    Article  PubMed  CAS  Google Scholar 

  5. Shen J, Chen X, Hendershot L, Prywes R (2002) ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3:99–111

    Article  PubMed  CAS  Google Scholar 

  6. Kimata Y, Oikawa D, Shimizu Y, Ishiwata-Kimata Y, Kohno K (2004) A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1. J Cell Biol 167:445–456

    Article  PubMed  CAS  Google Scholar 

  7. Credle JJ, Finer-Moore JS, Papa FR, Stroud RM, Walter P (2005) Inaugural article: on the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc Natl Acad Sci USA 102:18773–18784

    Article  PubMed  CAS  Google Scholar 

  8. Kimata Y, Ishiwata-Kimata Y, Ito T, Hirata A, Suzuki T, Oikawa D, Takeuchi M, Kohno K (2007) Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins. J Cell Biol 179:75–86

    Article  PubMed  CAS  Google Scholar 

  9. Zhou J, Liu CY, Back SH, Clark RL, Peisach D, Xu Z, Kaufman RJ (2006) The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response. Proc Natl Acad Sci USA 103:14343–14348

    Article  PubMed  CAS  Google Scholar 

  10. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6:1355–1364

    Article  PubMed  CAS  Google Scholar 

  11. Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT, Back SH, Kaufman RJ (2006) Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124:587–599

    Article  PubMed  CAS  Google Scholar 

  12. Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274

    Article  PubMed  CAS  Google Scholar 

  13. Shi Y, An J, Liang J, Hayes SE, Sandusky GE, Stramm LE, Yang NN (1999) Characterization of a mutant pancreatic eIF-2α kinase, PEK, and co-localization with somatostatin in islet delta cells. J Biol Chem 274:5723–5730

    Article  PubMed  CAS  Google Scholar 

  14. Cullinan SB, Diehl JA (2004) PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem 279:20108–20117

    Article  PubMed  CAS  Google Scholar 

  15. 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  CAS  Google Scholar 

  16. Brewer JW, Diehl JA (2000) PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci USA 97:12625–12630

    Article  PubMed  CAS  Google Scholar 

  17. Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Harding HP, Ron D (2004) Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 24:10161–10168

    Article  PubMed  CAS  Google Scholar 

  18. Li Q, Verma IM (2002) NF-κB regulation in the immune system. Nat Rev Immunol 2:725–734

    Article  PubMed  CAS  Google Scholar 

  19. Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, Jayawardena S, De Smaele E, Cong R, Beaumont C, Torti FM, Torti SV, Franzoso G (2004) Ferritin heavy chain upregulation by NF-κB inhibits TNFα-induced apoptosis by suppressing reactive oxygen species. Cell 119:529–542

    Article  PubMed  CAS  Google Scholar 

  20. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108

    Article  PubMed  CAS  Google Scholar 

  21. Yamaguchi S, Ishihara H, Yamada T, Tamura A, Usui M, Tominaga R, Munakata Y, Satake C, Katagiri H, Tashiro F, Aburatani H, Tsukiyama-Kohara K, Miyazaki J-i, Sonenberg N, Oka Y (2008) ATF4-mediated induction of 4E-BP1 contributes to pancreatic β cell survival under endoplasmic reticulum stress. Cell Metab 7:269–276

    Article  PubMed  CAS  Google Scholar 

  22. Ma Y, Brewer JW, Diehl JA, Hendershot LM (2002) Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol 318:1351–1365

    Article  PubMed  CAS  Google Scholar 

  23. Nguyen T, Sherratt PJ, Pickett CB (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 43:233–260

    Article  PubMed  CAS  Google Scholar 

  24. Warnakulasuriyarachchi D, Cerquozzi S, Cheung HH, Holcik M (2004) Translational induction of the inhibitor of apoptosis protein HIAP2 during endoplasmic reticulum stress attenuates cell death and is mediated via an inducible internal ribosome entry site element. J Biol Chem 279:17148–17157

    Article  PubMed  CAS  Google Scholar 

  25. Yoshimura FK, Luo X, Zhao X, Gerard HC, Hudson AP (2008) Up-regulation of a cellular protein at the translational level by a retrovirus. Proc Natl Acad Sci USA 105:5543–5548

    Article  PubMed  CAS  Google Scholar 

  26. Novoa I, Zeng H, Harding HP, Ron D (2001) Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α. J Cell Biol 153:1011–1022

    Article  PubMed  CAS  Google Scholar 

  27. Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18:3066–3077

    Article  PubMed  CAS  Google Scholar 

  28. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415:92–96

    Article  PubMed  CAS  Google Scholar 

  29. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891

    Article  PubMed  CAS  Google Scholar 

  30. Shen X, Ellis RE, Lee K, Liu C-Y, Yang K, Solomon A, Yoshida H, Morimoto R, Kurnit DM, Mori K, Kaufman RJ (2001) Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell 107:893–903

    Article  PubMed  CAS  Google Scholar 

  31. Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, Yoshida H, Mori K, Kaufman RJ (2002) IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 16:452–466

    Article  PubMed  CAS  Google Scholar 

  32. Lee AH, Iwakoshi NN, Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23:7448–7459

    Article  PubMed  CAS  Google Scholar 

  33. Sriburi R, Bommiasamy H, Buldak GL, Robbins GR, Frank M, Jackowski S, Brewer JW (2007) Coordinate regulation of phospholipid biosynthesis and secretory pathway gene expression in XBP-1(S)-induced endoplasmic reticulum biogenesis. J Biol Chem 282:7024–7034

    Article  PubMed  CAS  Google Scholar 

  34. Sriburi R, Jackowski S, Mori K, Brewer JW (2004) XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol 167:35–41

    Article  PubMed  CAS  Google Scholar 

  35. Wu J, Rutkowski DT, Dubois M, Swathirajan J, Saunders T, Wang J, Song B, Yau GD-Y, Kaufman RJ (2007) ATF6α optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell 13:351–364

    Article  PubMed  CAS  Google Scholar 

  36. Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H, Harada A, Mori K (2007) Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6α and XBP1. Dev Cell 13:365–376

    Article  PubMed  CAS  Google Scholar 

  37. 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  PubMed  CAS  Google Scholar 

  38. Dempsey PW, Doyle SE, He JQ, Cheng G (2003) The signaling adaptors and pathways activated by TNF superfamily. Cytokine Growth Factor Rev 14:193–209

    Article  PubMed  CAS  Google Scholar 

  39. 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 IRE1α-mediated NF-κB activation and down-regulation of TRAF2 expression. Mol Cell Biol 26:3071–3084

    Article  PubMed  CAS  Google Scholar 

  40. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16:1345–1355

    Article  PubMed  CAS  Google Scholar 

  41. Dunn C, Wiltshire C, MacLaren A, Gillespie DA (2002) Molecular mechanism and biological functions of c-Jun N-terminal kinase signalling via the c-Jun transcription factor. Cell Signal 14:585–593

    Article  PubMed  CAS  Google Scholar 

  42. Lei K, Davis RJ (2003) JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA 100:2432–2437

    Article  PubMed  CAS  Google Scholar 

  43. Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B, Alix S, Youle RJ, LaMarche A, Maroney AC, Johnson EM Jr (2003) JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38:899–914

    Article  PubMed  CAS  Google Scholar 

  44. Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 276:13935–13940

    PubMed  CAS  Google Scholar 

  45. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 403:98–103

    Article  PubMed  CAS  Google Scholar 

  46. Fischer H, Koenig U, Eckhart L, Tschachler E (2002) Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun 293:722–726

    Article  PubMed  CAS  Google Scholar 

  47. Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y, Tohyama M (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death. J Cell Biol 165:347–356

    Article  PubMed  CAS  Google Scholar 

  48. Narin F, Atabek ME, Karakukcu M, Narin N, Kurtoglu S, Gumus H, Coksevim B, Erez R (2005) The association of plasma homocysteine levels with serum leptin and apolipoprotein B levels in childhood obesity. Ann Saudi Med 25:209–214

    PubMed  Google Scholar 

  49. Münzberg H, Björnholm M, Bates SH, Myers MG Jr (2005) Leptin receptor action and mechanisms of leptin resistance. Cell Mol Life Sci 62:642–652

    Article  PubMed  CAS  Google Scholar 

  50. Myers MG, Cowley MA, Münzberg H (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70:537–556

    Article  PubMed  CAS  Google Scholar 

  51. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D (2008) Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 135:61–73

    Article  PubMed  CAS  Google Scholar 

  52. Hosoi T, Sasaki M, Miyahara T, Hashimoto C, Matsuo S, Yoshii M, Ozawa K (2008) Endoplasmic reticulum stress induces leptin resistance. Mol Pharmacol 74:1610–1619

    Article  PubMed  CAS  Google Scholar 

  53. Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176

    Article  PubMed  CAS  Google Scholar 

  54. Groop LC (1999) Insulin resistance: the fundamental trigger of type 2 diabetes. Diab Obes Metab 1(Suppl 1):S1–S7

    Article  CAS  Google Scholar 

  55. Langin D (2006) Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome. Pharmacol Res 53:482–491

    Article  PubMed  CAS  Google Scholar 

  56. Shulman GI (1999) Cellular mechanisms of insulin resistance in humans. Am J Cardiol 84:3J–10J

    Article  PubMed  CAS  Google Scholar 

  57. Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806

    Article  PubMed  CAS  Google Scholar 

  58. Draznin B (2006) Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85alpha: the two sides of a coin. Diabetes 55:2392–2397

    Article  PubMed  CAS  Google Scholar 

  59. Özcan U, Cao Q, Yilmaz E, Lee A-H, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–461

    Article  PubMed  CAS  Google Scholar 

  60. White MF (2003) Insulin signaling in health and disease. Science 302:1710–1711

    Article  PubMed  CAS  Google Scholar 

  61. Shah OJ, Wang Z, Hunter T (2004) Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 14:1650–1656

    Article  PubMed  CAS  Google Scholar 

  62. 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

    Article  PubMed  CAS  Google Scholar 

  63. Wang D, Wei YR, Pagliassotti MJ (2006) Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 147:943–951

    Article  PubMed  CAS  Google Scholar 

  64. Bergman RN, Ader M (2000) Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol Metab 11:351–356

    Article  PubMed  CAS  Google Scholar 

  65. Haynes CM, Titus EA, Cooper AA (2004) Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell 15:767–776

    Article  PubMed  CAS  Google Scholar 

  66. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633

    Article  PubMed  CAS  Google Scholar 

  67. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120:649–661

    Article  PubMed  CAS  Google Scholar 

  68. Örd D, Örd T (2005) Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions. Biochem Biophys Res Commun 330:210–218

    Article  PubMed  CAS  Google Scholar 

  69. Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H (2005) TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 24:1243–1255

    Article  PubMed  CAS  Google Scholar 

  70. Du K, Herzig S, Kulkarni RN, Montminy M (2003) TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300:1574–1577

    Article  PubMed  CAS  Google Scholar 

  71. Lee AH, Scapa EF, Cohen DE, Glimcher LH (2008) Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320:1492–1496

    Article  PubMed  CAS  Google Scholar 

  72. Iqbal J, Dai K, Seimon T, Jungreis R, Oyadomari M, Kuriakose G, Ron D, Tabas I, Hussain MM (2008) IRE1β inhibits chylomicron production by selectively degrading MTP mRNA. Cell Metab 7:445–455

    Article  PubMed  CAS  Google Scholar 

  73. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110

    Article  PubMed  CAS  Google Scholar 

  74. Song B, Scheuner D, Ron D, Pennathur S, Kaufman RJ (2008) Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest 118:3378–3389

    Article  PubMed  CAS  Google Scholar 

  75. Ariyama Y, Shimizu H, Satoh T, Tsuchiya T, Okada S, Oyadomari S, Mori M (2007) Chop-deficient mice showed increased adiposity but no glucose intolerance. Obesity (Silver Spring) 15:1647–1656

    Article  CAS  Google Scholar 

  76. Nozaki J, Kubota H, Yoshida H, Naitoh M, Goji J, Yoshinaga T, Mori K, Koizumi A, Nagata K (2004) The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in Ins2 +/Akita pancreatic β cells. Genes Cells 9:261–270

    Article  PubMed  CAS  Google Scholar 

  77. Zuber C, Fan JY, Guhl B, Roth J (2004) Misfolded proinsulin accumulates in expanded pre-Golgi intermediates and endoplasmic reticulum subdomains in pancreatic beta cells of Akita mice. FASEB J 18:U341–U360

    Google Scholar 

  78. Wang J, Takeuchi T, Tanaka S, Kubo SK, Kayo T, Lu D, Takata K, Koizumi A, Izumi T (1999) A mutation in the insulin 2 gene induces diabetes with severe pancreatic β-cell dysfunction in the Mody mouse. J Clin Invest 103:27–37

    Article  PubMed  CAS  Google Scholar 

  79. Herbach N, Rathkolb B, Kemter E, Pichl L, Klaften M, de Angelis MH, Halban PA, Wolf E, Aigner B, Wanke R (2007) Dominant-negative effects of a novel mutated Ins2 allele causes early-onset diabetes and severe beta-cell loss in Munich Ins2 C95S mutant mice. Diabetes 56:1268–1276

    Article  PubMed  CAS  Google Scholar 

  80. Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, Araki E, Mori M (2002) Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest 109:525–532

    PubMed  CAS  Google Scholar 

  81. Colombo C, Porzio O, Liu M, Massa O, Vasta M, Salardi S, Beccaria L, Monciotti C, Toni S, Pedersen O, Hansen T, Federici L, Pesavento R, Cadario F, Federici G, Ghirri P, Arvan P, Iafusco D, Barbetti F (2008) Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J Clin Invest 118:2148–2156

    PubMed  CAS  Google Scholar 

  82. Zhang S, Liu J, Saafi EL, Cooper GJ (1999) Induction of apoptosis by human amylin in RINm5F islet β-cells is associated with enhanced expression of p53 and p21WAF1/CIP1. FEBS Lett 455:315–320

    Article  PubMed  CAS  Google Scholar 

  83. Janson J, Ashley RH, Harrison D, McIntyre S, Butler PC (1999) The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes 48:491–498

    Article  PubMed  CAS  Google Scholar 

  84. Mirzabekov TA, Lin MC, Kagan BL (1996) Pore formation by the cytotoxic islet amyloid peptide amylin. J Biol Chem 271:1988–1992

    Article  PubMed  CAS  Google Scholar 

  85. Huang C-j, Lin C-y, Haataja L, Gurlo T, Butler AE, Rizza RA, Butler PC (2007) High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress-mediated β cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes 56:2016–2027

    Article  PubMed  CAS  Google Scholar 

  86. Guo F, Cavener DR (2007) The GCN2 eIF2α kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab 5:103–114

    Article  PubMed  CAS  Google Scholar 

  87. Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D (2008) Dephosphorylation of translation initiation factor 2α enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab 7:520–532

    Article  PubMed  CAS  Google Scholar 

  88. Rutkowski DT, Wu J, Back S-H, Callaghan MU, Ferris SP, Iqbal J, Clark R, Miao H, Hassler JR, Fornek J, Katze MG, Hussain MM, Song B, Swathirajan J, Wang J, Yau GD, Kaufman RJ (2008) UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell 15:829–840

    Article  PubMed  CAS  Google Scholar 

  89. Yang L, Jhaveri R, Huang J, Qi Y, Diehl AM (2007) Endoplasmic reticulum stress, hepatocyte CD1d and NKT cell abnormalities in murine fatty livers. Lab Invest 87:927–937

    Article  PubMed  CAS  Google Scholar 

  90. Guebre-Xabier M, Yang S, Lin HZ, Schwenk R, Krzych U, Diehl AM (2000) Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage. Hepatology 31:633–640

    Article  PubMed  CAS  Google Scholar 

  91. Ji C (2008) Dissection of endoplasmic reticulum stress signaling in alcoholic and non-alcoholic liver injury. J Gastroenterol Hepatol 23(Suppl 1):S16–S24

    Article  PubMed  CAS  Google Scholar 

  92. Loscalzo J (1996) The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 98:5–7

    Article  PubMed  CAS  Google Scholar 

  93. Avila MA, Berasain C, Torres L, Martin-Duce A, Corrales FJ, Yang H, Prieto J, Lu SC, Caballeria J, Rodes J, Mato JM (2000) Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol 33:907–914

    Article  PubMed  CAS  Google Scholar 

  94. Malhotra JD, Kaufman RJ (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18:716–731

    Article  PubMed  CAS  Google Scholar 

  95. Lentz SR, Sadler JE (1991) Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 88:1906–1914

    Article  PubMed  CAS  Google Scholar 

  96. Lentz SR, Sadler JE (1993) Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. Blood 81:683–689

    PubMed  CAS  Google Scholar 

  97. Austin RC, Lentz SR, Werstuck GH (2004) Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ 11(Suppl 1):S56–S64

    Article  PubMed  CAS  Google Scholar 

  98. Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, Shi YY, Zhou J, Maeda N, Krisans SK, Malinow MR, Austin RC (2001) Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 107:1263–1273

    Article  PubMed  CAS  Google Scholar 

  99. Ji C, Mehrian-Shai R, Chan C, Hsu YH, Kaplowitz N (2005) Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding. Alcohol Clin Exp Res 29:1496–1503

    Article  PubMed  CAS  Google Scholar 

  100. Lusis AJ (2000) Atherosclerosis. Nature 407:233–241

    Article  PubMed  CAS  Google Scholar 

  101. Kokame K, Kato H, Miyata T (1996) Homocysteine-respondent genes in vascular endothelial cells idenepsied by differential display analysis. GRP78/BiP and novel genes. J Biol Chem 271:29659–29665

    Article  PubMed  CAS  Google Scholar 

  102. Roybal CN, Yang SJ, Sun CW, Hurtado D, Vander Jagt DL, Townes TM, Abcouwer SF (2004) Homocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4. J Biol Chem 279:14844–14852

    Article  PubMed  CAS  Google Scholar 

  103. Zhang C, Cai Y, Adachi MT, Oshiro S, Aso T, Kaufman RJ, Kitajima S (2001) Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. J Biol Chem 276:35867–35874

    Article  PubMed  CAS  Google Scholar 

  104. Zhou J, Lhotak S, Hilditch BA, Austin RC (2005) Activation of the unfolded protein response occurs at all stages of atherosclerotic lesion development in apolipoprotein E-deficient mice. Circulation 111:1814–1821

    Article  PubMed  CAS  Google Scholar 

  105. Zhou J, Werstuck GH, Lhoták Š, de Koning AB, Sood SK, Hossain GS, Møller J, Ritskes-Hoitinga M, Falk E, Dayal S, Lentz SR, Austin RC (2004) Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice. Circulation 110:207–213

    Article  PubMed  CAS  Google Scholar 

  106. Feng B, Yao PM, Li Y, Devlin CM, Zhang D, Harding HP, Sweeney M, Rong JX, Kuriakose G, Fisher EA, Marks AR, Ron D, Tabas I (2003) The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol 5:781–792

    Article  PubMed  CAS  Google Scholar 

  107. Li Y, Ge M, Ciani L, Kuriakose G, Westover EJ, Dura M, Covey DF, Freed JH, Maxfield FR, Lytton J, Tabas I (2004) Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages. J Biol Chem 279:37030–37039

    Article  PubMed  CAS  Google Scholar 

  108. Li Y, Schwabe RF, Devries-Seimon T, Yao PM, Gerbod-Giannone MC, Tall AR, Davis RJ, Flavell R, Brenner DA, Tabas I (2005) Free cholesterol-loaded macrophages are an abundant source of TNF-α and IL-6. Model of NF-κB- and MAP kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem 280:21763–21772

    Article  PubMed  CAS  Google Scholar 

  109. Paschen W, Mengesdorf T (2005) Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease – therapeutic potential. Pharmacol Ther 108:362–375

    Article  PubMed  CAS  Google Scholar 

  110. Paschen W, Aufenberg C, Hotop S, Mengesdorf T (2003) Transient cerebral ischemia activates processing of xbp1 messenger RNA indicative of endoplasmic reticulum stress. J Cereb Blood Flow Metab 23:449–461

    Article  PubMed  CAS  Google Scholar 

  111. Kumar R, Azam S, Sullivan JM, Owen C, Cavener DR, Zhang PC, Ron D, Harding HP, Chen JJ, Han AP, White BC, Krause GS, DeGracia DJ (2001) Brain ischemia and reperfusion activates the eukaryotic initiation factor 2α kinase, PERK. J Neurochem 77:1418–1421

    Article  PubMed  CAS  Google Scholar 

  112. Azfer A, Niu J, Rogers LM, Adamski FM, Kolattukudy PE (2006) Activation of endoplasmic reticulum stress response during the development of ischemic heart disease. Am J Physiol Heart Circ Physiol 291:H1411–H1420

    Article  PubMed  CAS  Google Scholar 

  113. Glembotski CC (2008) The role of the unfolded protein response in the heart. J Mol Cell Cardiol 44:453–459

    Article  PubMed  CAS  Google Scholar 

  114. Paschen W, Gissel C, Linden T, Althausen S, Doutheil J (1998) Activation of gadd153 expression through transient cerebral ischemia: evidence that ischemia causes endoplasmic reticulum dysfunction. Brain Res Mol Brain Res 60:115–122

    Article  PubMed  CAS  Google Scholar 

  115. Shibata M, Hattori H, Sasaki T, Gotoh J, Hamada J, Fukuuchi Y (2003) Activation of caspase-12 by endoplasmic reticulum stress induced by transient middle cerebral artery occlusion in mice. Neuroscience 118:491–499

    Article  PubMed  CAS  Google Scholar 

  116. Mouw G, Zechel JL, Gamboa J, Lust WD, Selman WR, Ratcheson RA (2003) Activation of caspase-12, an endoplasmic reticulum resident caspase, after permanent focal ischemia in rat. NeuroReport 14:183–186

    Article  PubMed  CAS  Google Scholar 

  117. Zhang PL, Lun M, Teng J, Huang J, Blasick TM, Yin L, Herrera GA, Cheung JY (2004) Preinduced molecular chaperones in the endoplasmic reticulum protect cardiomyocytes from lethal injury. Ann Clin Lab Sci 34:449–457

    PubMed  CAS  Google Scholar 

  118. Martindale JJ, Fernandez R, Thuerauf D, Whittaker R, Gude N, Sussman MA, Glembotski CC (2006) Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion Injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6. Circ Res 98:1186–1193

    Article  PubMed  CAS  Google Scholar 

  119. Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, Koromilas A, Wouters BG (2002) Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2α. Mol Cell Biol 22:7405–7416

    Article  PubMed  CAS  Google Scholar 

  120. Moenner M, Pluquet O, Bouchecareilh M, Chevet E (2007) Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 67:10631–10634

    Article  PubMed  CAS  Google Scholar 

  121. Bi MX, Naczki C, Koritzinsky M, Fels D, Blais J, Hu NP, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C (2005) ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 24:3470–3481

    Article  PubMed  CAS  Google Scholar 

  122. Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee A-H, Yoshida H, Mori K, Glimcher LH, Denko NC, Giaccia AJ, Le Q-T, Koong AC (2004) XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 64:5943–5947

    Article  PubMed  CAS  Google Scholar 

  123. Lee AS (2007) GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res 67:3496–3499

    Article  PubMed  CAS  Google Scholar 

  124. Abcouwer SF, Marjon PL, Loper RK, Vander Jagt DL (2002) Response of VEGF expression to amino acid deprivation and inducers of endoplasmic reticulum stress. Invest Ophthalmol Vis Sci 43:2791–2798

    PubMed  Google Scholar 

  125. Drogat B, Auguste P, Nguyen DT, Bouchecareilh M, Pineau R, Nalbantoglu J, Kaufman RJ, Chevet E, Bikfalvi A, Moenner M (2007) IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. Cancer Res 67:6700–6707

    Article  PubMed  CAS  Google Scholar 

  126. Pouysségur J, Shiu RP, Pastan I (1977) Induction of two transformation-sensitive membrane polypeptides in normal fibroblasts by a block in glycoprotein synthesis or glucose deprivation. Cell 11:941–947

    Article  PubMed  Google Scholar 

  127. Shiu RP, Pouyssegur J, Pastan I (1977) Glucose depletion accounts for the induction of two transformation-sensitive membrane proteins in Rous sarcoma virus-transformed chick embryo fibroblasts. Proc Natl Acad Sci USA 74:3840–3844

    Article  PubMed  CAS  Google Scholar 

  128. Doutheil J, Althausen S, Treiman M, Paschen W (2000) Effect of nitric oxide on endoplasmic reticulum calcium homeostasis, protein synthesis and energy metabolism. Cell Calcium 27:107–115

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We apologize to all whose work could not be cited because of space limitations. This work was supported by the Biotechnology and Biological Sciences Research Council [BB/C513418/1, BB/D01588X/1, BB/E006035/1]; the European Commission [HEALTH-F7-2007-201608]; and the Wellcome Trust [079821] to M.S. and the Biotechnology and Biological Sciences Research Council [BB/D526188/1] to L.S. and M.S. The research leading to these results has received funding from the European Community’s seventh Framework Program (FP7/2007-2013) under grant agreement n° 201608.

Author information

Authors and Affiliations

  1. School of Biological and Biomedical Sciences, Durham University, Durham, UK

    Martin Schröder & Louise Sutcliffe

Authors
  1. Martin Schröder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Louise Sutcliffe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Schröder .

Editor information

Editors and Affiliations

  1. Aarhus University Hospital, Research Unit for Molecular Medicine, University of Aarhus, Brendstrupgaardsvej 100, Aarhus N, 8200, Denmark

    Peter Bross

  2. Aarhus University Hospital, Research Unit for Molecular Medicine, University of Aarhus, Brendstrupgaardsvej 100, Aarhus N, 8200, Denmark

    Niels Gregersen

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Schröder, M., Sutcliffe, L. (2010). Consequences of Stress in the Secretary Pathway: The ER Stress Response and Its Role in the Metabolic Syndrome. In: Bross, P., Gregersen, N. (eds) Protein Misfolding and Cellular Stress in Disease and Aging. Methods in Molecular Biology, vol 648. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-756-3_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-756-3_3

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-755-6

  • Online ISBN: 978-1-60761-756-3

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation