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Role of Endoplasmic Reticulum Stress in Hepatic Injury

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Molecules, Systems and Signaling in Liver Injury

Part of the book series: Cell Death in Biology and Diseases ((CELLDEATH))

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Abstract

The endoplasmic reticulum (ER) is a major organelle in liver cells responsible for protein synthesis and secretion, cellular calcium homeostasis, lipid and steroid hormone metabolism, and drug detoxification. Correct folding of nascent proteins is critical for their functional maturation and secretion, and disruptions of the process will cause accumulation of misfolded/unfolded proteins, which stresses the ER and triggers the unfolded protein response (UPR). Under ER stress, the UPR can drive the liver cells into adaptive or proapoptotic responses, which has been established to be a major mechanism contributing to a spectrum of liver disorders including alcohol-induced liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), drug-induced liver injury, hepatitis virus infections, and liver cancer. In this chapter, distinct causes for the hepatic ER stress as well as molecular mechanisms and recent developments of the UPR in the pathogenesis of the liver disorders are highlighted.

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Abbreviations

AA:

Amino acid

ABCA1:

ATP-binding cassette transporter member 1, also known as the cholesterol efflux regulatory protein (CERP)

ACC:

Acetyl-CoA carboxylase

ACL:

ATP citrate lyase

ADH:

Alcohol dehydrogenase

AERR:

Alcohol-induced ER stress response

AKT:

Also known as protein kinase B (PKB), is a serine−/threonine-specific protein kinase

ALD:

Alcohol-induced liver disease

APAP:

Acetaminophen

Apo-B/E:

Apolipoprotein B/E

ARα:

Androgen receptor-α

ASK1:

Apoptosis signal-regulating kinase 1

ASMase:

Acidic sphingomyelinase

ATF:

Activating transcription factor

BAX:

bcl-2-like protein 4

BHMT:

Betaine-homocysteine methyltransferase

BiP:

Also known as GRP78, glucose-regulated protein 78

C/EBP:

CCAAT-enhancer-binding protein

CaMKII:

Calmodulin-dependent protein kinase II

CBS:

Cystathionine β-synthase

CDIPT:

CDP-diacylglycerol-inositol 3-phosphatidyltransferase

CHOP:

C/EBP homologous protein

COX:

Cyclooxygenases

CREB:

Cyclic AMP response element-binding protein

Creld2:

Cysteine rich with EGF-like domains 2

CYP2E1:

Cytochrome P4502E1

DGAT2:

Diacylglycerol acyltransferase-2

DR5:

Death receptor 5

EDEM:

ER degradation-enhancing mannosidase-like protein

eIF2α:

Eukaryotic initiation factor 2α

ER:

Endoplasmic reticulum

ERAD:

ER-associated degradation

ERK:

Extracellular signal-regulated kinases

ERO1:

ER oxidase 1

ERα:

Estrogen receptor-α

FAS:

Fatty acid synthase

GADD34:

Growth arrest and DNA damage-inducible protein 34

GGH:

Ground glass hepatocyte

GSH:

Glutathione

GSK3β:

Glycogen synthase kinase-3β

HBV:

Hepatitis B

HCA:

Hepatocellular adenomas

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C

HDL:

High-density lipoprotein

HepG2:

A perpetual cell line derived from human liver carcinoma cells

HERP:

Homocysteine-induced ER protein

HFD:

High-fat diet

HHcy:

Hyperhomocysteinemia

HIV PIs:

Anti-HIV protease inhibitors

HNF1:

Hepatocyte nuclear factor 1 α

Huh7:

A cell line derived from hepatic cellular carcinoma cells

IP10:

Interferon gamma-inducible protein 10

IRE1:

Inositol-requiring enzyme 1

JNK:

c-Jun N-terminal kinases

LDLT:

Living donor liver transplantation

LPS:

Lipopolysaccharide

MCD:

Methionine-choline deficient

MDDC:

Monocyte-derived dendritic cells

MEOS:

Microsomal ethanol oxidizing system

NADH:

Nicotinamide adenine dinucleotide

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

NF-κB:

Nuclear factor κB

NNRTI:

Non-nucleoside reverse transcriptase inhibitors

NRF2:

NF-E2-related factor 2

NRTI:

Nucleoside/nucleotide reverse transcriptase inhibitors

NSAIDs:

Nonsteroidal anti-inflammatory drugs

PERK:

PKR-like ER-localized eIF2α kinase

PGC1:

PPAR gamma co-activator 1

PP2Ac:

Protein phosphatase 2Ac

PPAR:

Peroxisome proliferator-activated receptor

PTEN:

Phosphatase and tensin homolog

RIDD:

Regulated IRE1-dependent mRNA decay

ROS:

Reactive oxygen species

S1P:

Site 1 protease

S2P:

Site 2 protease

SAH:

S-adenosylhomocysteine

SAM:

S-Adenosylmethionine

SCD:

Stearoyl-CoA desaturase

SERCA:

Sarco/ER calcium ATPase

SHP:

Small heterodimer partner

SREBP:

Sterol regulatory element-binding protein

STAT3:

Signal transducer and activator of transcription 3

sXbp1:

Unconventionally spliced Xbp1

TRAF2:

TNF receptor-associated factor 2

TRAIL:

TNF-related apoptosis-inducing ligand

TRB3:

Tribbles 3

TUDCA:

Tauroursodeoxycholic acid

UDCA:

Ursodeoxycholic acid

UPR:

The unfolded protein response

VEGF:

Vascular endothelial growth factor

VLDL:

Very low-density lipoprotein

XBP1:

X-box binding protein 1

References

  • Abdelmegeed MA, Banerjee A, Yoo SH, Jang S, Gonzalez FJ, Song BJ (2012) Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. J Hepatol 57(4):860–866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aldridge JE, Horibe T, Hoogenraad NJ (2007) Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements. PLoS One 2(9):e874

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Al-Rawashdeh FY, Scriven P, Cameron IC, Vergani PV, Wyld L (2010) Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 22(9):1099–1105

    Article  CAS  PubMed  Google Scholar 

  • Apostolova N, Gomez-Sucerquia LJ, Alegre F, Funes HA, Victor VM, Barrachina MD, Blas-Garcia A, Esplugues JV (2013) ER stress in human hepatic cells treated with Efavirenz: mitochondria again. J Hepatol 59(4):780–789

    Article  CAS  PubMed  Google Scholar 

  • Aubert J, Begriche K, Knockaert L, Robin MA, Fromenty B (2011) Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin Res Hepatol Gastroenterol 35(10):630–637

    Article  CAS  PubMed  Google Scholar 

  • Aubert J, Begriche K, Delannoy M, Morel I, Pajaud J, Ribault C, Lepage S, McGill MR, Lucas-Clerc C, Turlin B, Robin MA, Jaeschke H, Fromenty B (2012) Differences in early acetaminophen hepatotoxicity between obese ob/ob and db/db mice. J Pharmacol Exp Ther 342(3):676–687

    Article  CAS  PubMed  Google Scholar 

  • Barak AJ, Beckenhauer HC, Tuma DJ, Badakhsh S (1987) Effects of prolonged ethanol feeding on methionine metabolism in rat liver. Biochem Cell Biol 65(3):230–233

    Article  CAS  PubMed  Google Scholar 

  • Benali-Furet NL, Chami M, Houel L, De Giorgi F, Vernejoul F, Lagorce D, Buscail L, Bartenschlager R, Ichas F, Rizzuto R, Paterlini-Bréchot P (2005) Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion. Oncogene 24(31):4921–4933

    Article  CAS  PubMed  Google Scholar 

  • Bittremieux M, Parys JB, Pinton P, Bultynck G (2016) ER functions of oncogenes and tumor suppressors: modulators of intracellular Ca(2+) signaling. Biochim Biophys Acta 1863(6 Pt B):1364–1378

    Article  CAS  PubMed  Google Scholar 

  • Blasco C, Caballería J, Deulofeu R, Lligoña A, Parés A, Lluis JM, Gual A, Rodés J (2005) Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics. Alcohol Clin Exp Res 29(6):1044–1048

    Article  CAS  PubMed  Google Scholar 

  • Bleich S, Lenz B, Ziegenbein M, Beutler S, Frieling H, Kornhuber J, Bönsch D (2006) Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence. Alcohol Clin Exp Res 30(4):587–591

    Article  CAS  PubMed  Google Scholar 

  • Bobrovnikova-Marjon E, Hatzivassiliou G, Grigoriadou C, Romero M, Cavener DR, Thompson CB, Diehl JA (2008) PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocyte differentiation. Proc Natl Acad Sci 105(42):16314–16319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bono C, Karlin L, Harel S, Mouly E, Labaume S, Galicier L, Apcher S, Sauvageon H, Fermand JP, Bories JC, Arnulf B (2012) The human immunodeficiency virus-1 protease inhibitor nelfinavir impairs proteasome activity and inhibits the proliferation of multiple myeloma cells in vitro and in vivo. Haematologica 97(7):1101–1109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boukli NM, Saiyed ZM, Ricaurte M, Rodriguez JW, Ríos Olivares E, Cubano LA, Nair MP (2010) Implications of ER stress, the unfolded protein response, and pro- and anti-apoptotic protein fingerprints in human monocyte-derived dendritic cells treated with alcohol. Alcohol Clin Exp Res 34(12):2081–2088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bu Y, Diehl JA (2016) PERK integrates oncogenic signaling and cell survival during cancer development. J Cell Physiol. doi:10.1002/jcp.25336

  • Bulleid NJ (2012) Disulfide bond formation in the mammalian endoplasmic reticulum. Cold Spring Harb Perspect Biol 4(11). pii: a013219

    Google Scholar 

  • Burcham PC, Harman AW (1988) Effect of acetaminophen hepatotoxicity on hepatic mitochondrial and microsomal calcium contents in mice. Toxicol Lett 44(1–2):91–99

    Article  CAS  PubMed  Google Scholar 

  • Cao R, Hu Y, Wang Y, Gurley EC, Studer EJ, Wang X, Hylemon PB, Pandak WM, Sanyal AJ, Zhang L, Zhou H (2010) Prevention of HIV protease inhibitor-induced dysregulation of hepatic lipid metabolism by raltegravir via endoplasmic reticulum stress signaling pathways. J Pharmacol Exp Ther 334(2):530–539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao J, Dai DL, Yao L, Yu HH, Ning B, Zhang Q, Chen J, Cheng WH, Shen W, Yang ZX (2012) Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. Mol Cell Biochem 364(1–2):115–129

    Article  CAS  PubMed  Google Scholar 

  • Carrasco DR, Sukhdeo K, Protopopova M, Sinha R, Enos M, Carrasco DE, Zheng M, Mani M, Henderson J, Pinkus GS, Munshi N, Horner J, Ivanova EV, Protopopov A, Anderson KC, Tonon G, DePinho RA (2007) The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 11(4):349–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cazanave SC, Elmi NA, Akazawa Y, Bronk SF, Mott JL, Gores GJ (2010) CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. Am J Physiol Gastrointest Liver Physiol 299(1):G236–G243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cederbaum AI, Lu Y, Wu D (2009) Role of oxidative stress in alcohol-induced liver injury. Arch Toxicol 83(6):519–548

    Article  CAS  PubMed  Google Scholar 

  • Chen R, Dai RY, Duan CY, Liu YP, Chen SK, Yan DM, Chen CN, Wei M, Li H (2011) Unfolded protein response suppresses cisplatin-induced apoptosis via autophagy regulation in human hepatocellular carcinoma cells. Folia Biol (Praha) 57(3):87–95

    CAS  Google Scholar 

  • Chikka MR, McCabe DD, Tyra HM, Rutkowski DT (2013) C/EBP homologous protein (CHOP) contributes to suppression of metabolic genes during endoplasmic reticulum stress in the liver. J Biol Chem 288(6):4405–4415

    Article  CAS  PubMed  Google Scholar 

  • Choukhi A, Ung S, Wychowski C, Dubuisson J (1998) Involvement of endoplasmic reticulum chaperones in the folding of hepatitis C virus glycoproteins. J Virol 72(5):3851–3858

    CAS  PubMed  PubMed Central  Google Scholar 

  • Christen V, Treves S, Duong FH, Heim MH (2007) Activation of endoplasmic reticulum stress response by hepatitis viruses up-regulates protein phosphatase 2A. Hepatology 46(2):558–565

    Article  CAS  PubMed  Google Scholar 

  • Cinti DL, Grundin R, Orrenius S (1973) The effect of ethanol on drug oxidations in vitro and the significance of ethanol-cytochrome P-450 interaction. Biochem J 134(2):367–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Claude A (1943) The constitution of protoplasm. Science 97:451–456

    Article  CAS  PubMed  Google Scholar 

  • Czaja MJ (2015) A new mechanism of lipotoxicity: calcium channel blockers as a treatment for nonalcoholic steatohepatitis? Hepatology 62(1):312–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daniele T, Schiaffino MV (2014) Organelle biogenesis and interorganellar connections: better in contact than in isolation. Commun Integr Biol 7:e29587

    Article  PubMed  PubMed Central  Google Scholar 

  • Dlugos CA (2014) ATF6 and caspase 12 expression in Purkinje neurons in acute slices from adult, ethanol-fed rats. Brain Res 1577:11–20

    Article  CAS  PubMed  Google Scholar 

  • Dubois C, Prevarskaya N, Vanden Abeele F (2016) The calcium-signaling toolkit: updates needed. Biochim Biophys Acta 1863(6 Pt B):1337–1343

    Article  CAS  PubMed  Google Scholar 

  • Egnatchik RA, Leamy AK, Jacobson DA, Shiota M, Young JD (2014) ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload. Mol Metab 3(5):544–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Esfandiari F, Villanueva JA, Wong DH et al (2005) Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs. Am J Physiol Gastrointest Liver Physiol 289(1):54–63

    Article  CAS  Google Scholar 

  • Esfandiari F, Medici V, Wong DH, Jose S, Dolatshahi M, Quinlivan E, Dayal S, Lentz SR, Tsukamoto H, Zhang YH, French SW, Halsted CH (2010) Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse. Hepatology 51(3):932–941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang C, Yi Z, Liu F, Lan S, Wang J, Lu H, Yang P, Yuan Z (2006) Proteome analysis of human liver carcinoma Huh7 cells harboring hepatitis C virus subgenomic replicon. Proteomics 6(2):519–527

    Article  CAS  PubMed  Google Scholar 

  • 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(9):781–792

    Article  CAS  PubMed  Google Scholar 

  • Fernandez A, Matias N, Fucho R, Ribas V, Von Montfort C, Nuño N, Baulies A, Martinez L, Tarrats N, Mari M, Colell A, Morales A, Dubuquoy L, Mathurin P, Bataller R, Caballeria J, Elena M, Balsinde J, Kaplowitz N, Garcia-Ruiz C, Fernandez-Checa JC (2013) ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading. J Hepatol 59(4):805–813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fournillier A, Wychowski C, Boucreux D, Baumert TF, Meunier JC, Jacobs D, Muguet S, Depla E, Inchauspé G (2001) Induction of hepatitis C virus E1 envelope protein-specific immune response can be enhanced by mutation of N-glycosylation sites. J Virol 75(24):12088–12097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franceschelli S, Moltedo O, Amodio G, Tajana G, Remondelli P (2011) In the Huh7 hepatoma cells diclofenac and indomethacin activate differently the unfolded protein response and induce ER stress apoptosis. Open Biochem J 5:45–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR, Hotamisligil GS (2011) Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473(7348):528–531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu S, Watkins SM, Hotamisligil GS (2012) The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 15(5):623–634

    Article  CAS  PubMed  Google Scholar 

  • Gardner OS, Shiau CW, Chen CS, Graves LM (2005) Peroxisome proliferator-activated receptor gamma-independent activation of p38 MAPK by thiazolidinediones involves calcium/calmodulin-dependent protein kinase II and protein kinase R: correlation with endoplasmic reticulum stress. J Biol Chem 280(11):10109–10118

    Article  CAS  PubMed  Google Scholar 

  • Gaut JR, Hendershot LM (1993) The modification and assembly of proteins in the endoplasmic reticulum. Curr Opin Cell Biol 5(4):589–595

    Article  CAS  PubMed  Google Scholar 

  • Geng W, Lo CM, Ng KT, Ling CC, Qi X, Li CX, Zhai Y, Liu XB, Ma YY, Man K (2015) Interferon-gamma inducible protein 10 (IP10) induced cisplatin resistance of HCC after liver transplantation through ER stress signaling pathway. Oncotarget 6(29):28042–28056

    Article  PubMed  PubMed Central  Google Scholar 

  • Goldstein MG, Li Z (2009) Heat-shock proteins in infection-mediated inflammation-induced tumorigenesis. J Hematol Oncol 2:5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gunawan BK, Kaplowitz N (2007) Mechanisms of drug-induced liver disease. Clin liver dis 11:459–475, v

    Google Scholar 

  • Hadziyannis S, Gerber MA, Vissoulis C, Popper H (1973) Cytoplasmic hepatitis B antigen in “ground-glass” hepatocytes of carriers. Arch Pathol 96(5):327–330

    CAS  PubMed  Google Scholar 

  • Hampton RY (2002) ER-associated degradation in protein quality control and cellular regulation. Curr Opin Cell Biol 14(4):476–482

    Article  CAS  PubMed  Google Scholar 

  • Han KL, Choi JS, Lee JY, Song J, Joe MK, Jung MH, Hwang JK (2008) Therapeutic potential of peroxisome proliferators – activated receptor-alpha/gamma dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes. Diabetes 57(3):737–745

    Article  CAS  PubMed  Google Scholar 

  • Han H, He Y, Hu J, Lau R, Lee H, Ji C (2017) Disrupted ER-to-Golgi trafficking underlies anti-HIV drugs and alcoholinduced cellular stress and hepatic injury. Hepatology Communications 1(2):122–139

    Google Scholar 

  • Han H, Hu J, Lau MY, Feng M, Petrovic LM, Ji C (2013) Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors. Front Genet 4:224

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hartman JH, Martin HC, Caro AA, Pearce AR, Miller GP (2015) Subcellular localization of rat CYP2E1 impacts metabolic efficiency toward common substrates. Toxicology 338:47–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, Brandt GS, Iwakoshi NN, Schinzel A, Glimcher LH, Korsmeyer SJ (2006) Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312(5773):572–576

    Article  CAS  PubMed  Google Scholar 

  • Hiroyuki T, Yuxia Z, Sangmin L, Rana S, Li W (2014) Circadian clock mediates ER stress signaling in alcoholic fatty liver. FASEB J 28:1116.12

    Google Scholar 

  • Horibe T, Hoogenraad NJ (2007) The chop gene contains an element for the positive regulation of the mitochondrial unfolded protein response. PLoS One 2(9):e835

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140(6):900–917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu J, Han H, Lau MY, Lee H, MacVeigh-Aloni M, Ji C (2015) Effects of combined alcohol and anti-HIV drugs on cellular stress responses in primary hepatocytes and hepatic stellate and kupffer cells. Alcohol Clin Exp Res 39(1):11–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hultberg B, Berglund M, Andersson A, Frank A (1993) Elevated plasma homocysteine in alcoholics. Alcohol Clin Exp Res 17(3):687–689

    Article  CAS  PubMed  Google Scholar 

  • Hur KY, So JS, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Iwawaki T, Glimcher LH, Lee AH (2012) IRE1α activation protects mice against acetaminophen-induced hepatotoxicity. J Exp Med 209(2):307–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ient B, Edwards R, Mould R, Hannah M, Holden-Dye L, O'Connor V (2012) HSP-4 endoplasmic reticulum (ER) stress pathway is not activated in a C. elegans model of ethanol intoxication and withdrawal. Invertebr Neurosci 12(2):93–102

    Article  CAS  Google Scholar 

  • Jaeschke H (1990) Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol. J Pharmacol Exp Ther 255(3):935–941

    CAS  PubMed  Google Scholar 

  • Ji C (2015) Advances and new concepts in alcohol-induced organelle stress, unfolded protein responses and organ damage. Biomol Ther 5(2):1099–1121

    CAS  Google Scholar 

  • Ji C, Kaplowitz N (2003) Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 124(5):1488–99

    Article  CAS  PubMed  Google Scholar 

  • Ji C, Kaplowitz N (2006) ER stress: can the liver cope? J Hepatol 45(2):321–333

    Article  CAS  PubMed  Google Scholar 

  • Ji C, Deng Q, Kaplowitz N (2004) Role of TNF-alpha in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. Hepatology 40(2):442–451

    Article  CAS  PubMed  Google Scholar 

  • 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(8):1486–1503

    Article  Google Scholar 

  • Ji C, Chan C, Kaplowitz N (2006) Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model. J Hepatol 45(5):717–724

    Article  CAS  PubMed  Google Scholar 

  • Ji C, Shinohara M, Vance D, Than TA, Ookhtens M, Chan C, Kaplowitz N (2008) Effect of transgenic extrahepatic expression of betaine-homocysteine methyltransferase on alcohol or homocysteine-induced fatty liver. Alcohol Clin Exp Res 32(6):1049–1058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji C, Kaplowitz N, Lau MY, Kao E, Petrovic LM, Lee AS (2011) Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology 54(1):229–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones M, Núñez M (2012) Liver toxicity of antiretroviral drugs. Semin Liver Dis 32(2):167–176

    Article  CAS  PubMed  Google Scholar 

  • Kalinec GM, Thein P, Parsa A, Yorgason J, Luxford W, Urrutia R, Kalinec F (2014) Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways. Hear Res 313:26–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kao E, Shinohara M, Feng M, Lau MY, Ji C (2012) Human immunodeficiency virus protease inhibitors modulate Ca2+ homeostasis and potentiate alcoholic stress and injury in mice and primary mouse and human hepatocytes. Hepatology 56(2):594–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaplowitz N (2005) Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 4(6):489–499

    Article  CAS  PubMed  Google Scholar 

  • Ke PY, Chen SS (2012) Hepatitis C virus and cellular stress response: implications to molecular pathogenesis of liver diseases. Virus 4(10):2251–2290

    Article  CAS  Google Scholar 

  • Kim S, Joe Y, Kim HJ, Kim YS, Jeong SO, Pae HO, Ryter SW, Surh YJ, Chung HT (2015) Endoplasmic reticulum stress-induced IRE1α activation mediates cross-talk of GSK-3β and XBP-1 to regulate inflammatory cytokine production. J Immunol 194(9):4498–4506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kitamura M (2011) Control of NF-κB and inflammation by the unfolded protein response. Int Rev Immunol 30(1):4–15

    Article  CAS  PubMed  Google Scholar 

  • Labbe G, Pessayre D, Fromenty B (2008) Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol 22(4):335–353

    Article  CAS  PubMed  Google Scholar 

  • Lake AD, Novak P, Hardwick RN, Flores-Keown B, Zhao F, Klimecki WT, Cherrington NJ (2014) The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease. Toxicol Sci 137(1):26–35

    Article  CAS  PubMed  Google Scholar 

  • Lau MY, Han H, Hu J, Ji C (2013) Association of cyclin D and estrogen receptor α36 with hepatocellular adenomas of female mice under chronic endoplasmic reticulum stress. J Gastroenterol Hepatol 28(3):576–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee WM (2003) Acute liver failure in the United States. Semin Liver Dis 23(3):217–226

    Article  CAS  PubMed  Google Scholar 

  • Lee AH, Scapa EF, Cohen DE, Glimcher LH (2008) Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320(5882):1492–1496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li B, Gao B, Ye L, Han X, Wang W, Kong L, Fang X, Zeng Y, Zheng H, Li S, Wu Z, Ye L (2007) Hepatitis B virus X protein (HBx) activates ATF6 and IRE1-XBP1 pathways of unfolded protein response. Virus Res 124(1–2):44–49

    Article  CAS  PubMed  Google Scholar 

  • Liao W, Chan L (2001) Tunicamycin induces ubiquitination and degradation of apolipoprotein B in HepG2 cells. Biochem J 353(Pt 3):493–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liberman E, Fong YL, Selby MJ, Choo QL, Cousens L, Houghton M, Yen TS (1999) Activation of the grp78 and grp94 promoters by hepatitis C virus E2 envelope protein. J Virol 73(5):3718–3722

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lieber CS (1987) Microsomal ethanol-oxidizing system. Enzyme 37(1–2):45–56

    CAS  PubMed  Google Scholar 

  • Lin RJ, Chu JS, Chien HL, Tseng CH, Ko PC, Mei YY, Tang WC, Kao YT, Cheng HY, Liang YC, Lin SY (2014) MCPIP1 suppresses hepatitis C virus replication and negatively regulates virus-induced proinflammatory cytokine responses. J Immunol 193(8):4159–4168

    Article  CAS  PubMed  Google Scholar 

  • 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(6):3077–3082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lluis JM, Colell A, García-Ruiz C, Kaplowitz N, Fernández-Checa JC (2003) Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress. Gastroenterology 124(3):708–724

    Article  CAS  PubMed  Google Scholar 

  • Longato L, Ripp K, Setshedi M, Dostalek M, Akhlaghi F, Branda M, Wands JR, de la Monte SM (2012) Insulin resistance, ceramide accumulation, and endoplasmic reticulum stress in human chronic alcohol-related liver disease. Oxidative Med Cell Longev 2012:479348

    Article  CAS  Google Scholar 

  • Lorz C, Justo P, Sanz A, Subirá D, Egido J, Ortiz A (2004) Paracetamol-induced renal tubular injury: a role for ER stress. J Am Soc Nephrol 15(2):380–389

    Article  CAS  PubMed  Google Scholar 

  • Luo B, Lee AS (2013) The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene 32(7):805–818

    Article  CAS  PubMed  Google Scholar 

  • Lutz UC (2008) Alterations in homocysteine metabolism among alcohol dependent patients – clinical, pathobiochemical and genetic aspects. Curr Drug Abuse Rev 1(1):47–55

    Article  CAS  PubMed  Google Scholar 

  • Macanas-Pirard P, Yaacob NS, Lee PC, Holder JC, Hinton RH, Kass GE (2005) Glycogen synthase kinase-3 mediates acetaminophen-induced apoptosis in human hepatoma cells. J Pharmacol Exp Ther 313(2):780–789

    Article  CAS  PubMed  Google Scholar 

  • Magne L, Blanc E, Legrand B, Lucas D, Barouki R, Rouach H, Garlatti M (2011) ATF4 and the integrated stress response are induced by ethanol and cytochrome P450 2E1 in human hepatocytes. J Hepatol 54(4):729–737

    Article  CAS  PubMed  Google Scholar 

  • Marí M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC (2014) Mitochondrial cholesterol accumulation in alcoholic liver disease: role of ASMase and endoplasmic reticulum stress. Redox Biol 3:100–108

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maurel M, Chevet E, Tavernier J, Gerlo S (2014) Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem Sci 39(5):245–254

    Article  CAS  PubMed  Google Scholar 

  • Millward CA, Heaney JD, Sinasac DS, Chu EC, Bederman IR, Gilge DA, Previs SF, Croniger CM (2007) Mice with a deletion in the gene for CCAAT/enhancer-binding protein beta are protected against diet-induced obesity. Diabetes 56(1):161–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyata S, Mizuno T, Koyama Y, Katayama T, Tohyama M (2013) The endoplasmic reticulum-resident chaperone heat shock protein 47 protects the Golgi apparatus from the effects of O-glycosylation inhibition. PLoS One 8(7):e69732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mohammad MK, Avila D, Zhang J, Barve S, Arteel G, McClain C, Joshi-Barve S (2012) Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress. Toxicol Appl Pharmacol 265(1):73–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mori K (2000) Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101(5):451–454

    Article  CAS  PubMed  Google Scholar 

  • Mori K (2015) The unfolded protein response: the dawn of a new field. Proc Jpn Acad Ser B Phys Biol Sci 91(9):469–480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagy G, Kardon T, Wunderlich L, Szarka A, Kiss A, Schaff Z, Bánhegyi G, Mandl J (2007) Acetaminophen induces ER dependent signaling in mouse liver. Arch Biochem Biophys 459(2):273–279

    Article  CAS  PubMed  Google Scholar 

  • Ng DT, Randall RE, Lamb RA (1989) Intracellular maturation and transport of the SV5 type II glycoprotein hemagglutinin-neuraminidase: specific and transient association with GRP78-BiP in the endoplasmic reticulum and extensive internalization from the cell surface. J Cell Biol 109(6 Pt 2):3273–3289

    Article  CAS  PubMed  Google Scholar 

  • Núñez M, Lana R, Mendoza JL, Martín-Carbonero L, Soriano V (2001) Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 27(5):426–431

    Article  PubMed  Google Scholar 

  • Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26(24):9220–9231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ota T, Gayet C, Ginsberg HN (2008) Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest 118(1):316–332

    Article  CAS  PubMed  Google Scholar 

  • Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11(4):381–389

    Article  CAS  PubMed  Google Scholar 

  • Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D (2008) Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab 7(6):520–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ozcan L, Tabas I (2012) Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annu Rev Med 63:317–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ozcan U, Cao Q, Yilmaz E, Lee AH, 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(5695):457–461

    Article  PubMed  CAS  Google Scholar 

  • Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313(5790):1137–1140

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pajonk F, Himmelsbach J, Riess K, Sommer A, McBride WH (2002) The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. Cancer Res 62(18):5230–5235

    CAS  PubMed  Google Scholar 

  • Palade GE (1995) The endoplasmic reticulum. J Biophys Biochem Cytol 2(4 Suppl):85–98

    Google Scholar 

  • Palade GE, Siekevitz P (1956) Liver microsomes; an integrated morphological and biochemical study. J Biophys Biochem Cytol 2(2):171–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Passeri MJ, Cinaroglu A, Gao C, Sadler KC (2009) Hepatic steatosis in response to acute alcohol exposure in zebrafish requires sterol regulatory element binding protein activation. Hepatology 49(2):443–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patil C, Walter P (2001) Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals. Curr Opin Cell Biol 13(3):349–355

    Article  CAS  PubMed  Google Scholar 

  • Pfaffenbach KT, Gentile CL, Nivala AM, Wang D, Wei Y, Pagliassotti MJ (2010) Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death. Am J Physiol Endocrinol Metab 298(5):E1027–E1035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piccinini M, Rinaudo MT, Chiapello N, Ricotti E, Baldovino S, Mostert M, Tovo PA (2002) The human 26S proteasome is a target of antiretroviral agents. AIDS 16(5):693–700

    Article  PubMed  Google Scholar 

  • Pineau L, Colas J, Dupont S, Beney L, Fleurat-Lessard P, Berjeaud JM, Bergès T, Ferreira T (2009) Lipid-induced ER stress: synergistic effects of sterols and saturated fatty acids. Traffic 10(6):673–690

    Article  CAS  PubMed  Google Scholar 

  • Pinton P, Ferrari D, Rapizzi E, Di Virgilio F, Pozzan T, Rizzuto R (2001) The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J 20(11):2690–2701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Popper H (1975) Clinical pathologic correlation in viral hepatitis. The effect of the virus on the liver. Am J Pathol 81(3):609–628

    CAS  PubMed  PubMed Central  Google Scholar 

  • Porter KR, Claude A, Fullam EF (1945) A study of tissue culture cells by electron microscopy: methods and preliminary observations. J Exp Med 81(3):233–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM, Sanyal AJ (2008) Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134(2):568–576

    Article  CAS  PubMed  Google Scholar 

  • Rahman SM, Schroeder-Gloeckler JM, Janssen RC, Jiang H, Qadri I, Maclean KN, Friedman JE (2007) CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. Hepatology 45(5):1108–1117

    Article  CAS  PubMed  Google Scholar 

  • Ramirez T, Longato L, Dostalek M, Tong M, Wands JR, de la Monte SM (2013) Insulin resistance, ceramide accumulation and endoplasmic reticulum stress in experimental chronic alcohol-induced steatohepatitis. Alcohol Alcohol 48(1):39–52

    Article  CAS  PubMed  Google Scholar 

  • Röhrl C, Eigner K, Winter K, Korbelius M, Obrowsky S, Kratky D, Kovacs WJ, Stangl H (2014) Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells. J Lipid Res 55(1):94–103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee AH, Yoshida H, Mori K, Glimcher LH, Denko NC, Giaccia AJ, Le QT, Koong AC (2004) XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 64(17):5943–5947

    Article  CAS  PubMed  Google Scholar 

  • Ron D, Hubbard SR (2013) How IRE1 reacts to ER stress. Cell 132(1):24–26

    Article  CAS  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8(7):519–529

    Article  CAS  PubMed  Google Scholar 

  • Ronis MJ, Korourian S, Blackburn ML, Badeaux J, Badger TM (2010) The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat. Alcohol 44(2):157–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rutkowski DT, Wu J, Back SH, 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(6):829–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmidtke G, Holzhütter HG, Bogyo M, Kairies N, Groll M, de Giuli R, Emch S, Groettrup M (1999) How an inhibitor of the HIV-I protease modulates proteasome activity. J Biol Chem 274(50):35734–35740

    Article  CAS  PubMed  Google Scholar 

  • Schonthal AH (2012) Targeting endoplasmic reticulum stress for cancer therapy. Front Biosci (Schol Ed) 4:412–431

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Senft D, Ronai ZA (2015) UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem Sci 40(3):141–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Senior JR (2014) Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges. Drug Saf 37(Spl 1):S9–17

    Article  PubMed  CAS  Google Scholar 

  • Seo J, Fortuno ES 3rd, Suh JM, Stenesen D, Tang W, Parks EJ, Adams CM, Townes T, Graff JM (2009) Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes 58(11):2565–2573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seth D, Leo PH (2003) McGuinness et al, “Gene expression profiling of alcoholic liver disease in the baboon (Papiohamadryas) and human liver”. Am J Pathol 163(6):2303–2317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shinohara M, Ji C, Kaplowitz N (2010) Differences in betaine-homocysteine methyltransferase expression, endoplasmic reticulum stress response, and liver injury between alcohol-fed mice and rats. Hepatology 51(3):796–805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shuda M, Kondoh N, Imazeki N, Tanaka K, Okada T, Mori K, Hada A, Arai M, Wakatsuki T, Matsubara O, Yamamoto N, Yamamoto M (2003) Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 38(5):605–614

    Article  CAS  PubMed  Google Scholar 

  • Softic S, Cohen DE, Kahn CR (2016) Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig Dis Sci 61(5):1282–1293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sreejayan N, Dong F, Kandadi MR, Yang X, Ren J (2008) Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice. Obesity (Silver Spring) 16(6):1331–1337

    Article  CAS  Google Scholar 

  • Sun Q, Zhong W, Zhang W, Li Q, Sun X, Tan X, Sun X, Dong D, Zhou Z (2015) Zinc deficiency mediates alcohol-induced apoptotic cell death in the liver of rats through activating ER and mitochondrial cell death pathways. Am J Physiol Gastrointest Liver Physiol. doi:10.1152/ajpgi.00442.2014

  • Tabas I, Ron D (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13(3):184–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tai PC, Suk FM, Gerlich WH, Neurath AR, Shih C (2002) Hypermodification and immune escape of an internally deleted middle-envelope (M) protein of frequent and predominant hepatitis B virus variants. Virology 292(1):44–58

    Article  CAS  PubMed  Google Scholar 

  • Tan TC, Crawford DH, Jaskowski LA, Subramaniam VN, Clouston AD, Crane DI, Bridle KR, Anderson GJ, Fletcher LM (2013) Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury. Lab Investig 93(12):1295–1312

    Article  CAS  PubMed  Google Scholar 

  • Tardif KD, Siddiqui A (2003) Cell surface expression of major histocompatibility complex class I molecules is reduced in hepatitis C virus subgenomic replicon-expressing cells. J Virol 77(21):11644–11650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tardif KD, Mori K, Siddiqui A (2002) Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J Virol 76(15):7453–7459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tardif KD, Mori K, Kaufman RJ, Siddiqui A (2004) Hepatitis C virus suppresses the IRE1-XBP1 pathway of the unfolded protein response. J Biol Chem 279(17):17158–17164

    Article  CAS  PubMed  Google Scholar 

  • Targett-Adams P, Boulant S, Douglas MW, McLauchlan J (2010) Lipid metabolism and HCV infection. Virus 2(5):1195–1217

    Article  CAS  Google Scholar 

  • Taura M, Kariya R, Kudo E, Goto H, Iwawaki T, Amano M, Suico MA, Kai H, Mitsuya H, Okada S (2013) Comparative analysis of ER stress response into HIV protease inhibitors: lopinavir but not darunavir induces potent ER stress response via ROS/JNK pathway. Free Radic Biol Med 65:778–788

    Article  CAS  PubMed  Google Scholar 

  • Tazi KA, Bièche I, Paradis V et al (2007) In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats. J Hepatol 46(6):1075–1088

    Article  CAS  PubMed  Google Scholar 

  • Thakur PC, Stuckenholz C, Rivera MR, Davison JM, Yao JK, Amsterdam A, Sadler KC, Bahary N (2011) Lack of de novo phosphatidylinositol synthesis leads to endoplasmic reticulum stress and hepatic steatosis in cdipt-deficient zebrafish. Hepatology 54(2):452–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Touzet O, Philips A (2010) Resveratrol protects against protease inhibitor-induced reactive oxygen species production, reticulum stress and lipid raft perturbation. AIDS 24(10):1437–1447

    Article  CAS  PubMed  Google Scholar 

  • Tsuchiya M, Ji C, Kosyk O, Shymonyak S, Melnyk S, Kono H, Tryndyak V, Muskhelishvili L, Pogribny IP, Kaplowitz N, Rusyn I (2012) Interstrain differences in liver injury and one-carbon metabolism in alcohol-fed mice. Hepatology 56(1):130–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsutsumi S, Gotoh T, Tomisato W, Mima S, Hoshino T, Hwang HJ, Takenaka H, Tsuchiya T, Mori M, Mizushima T (2004) Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. Cell Death Differ 11(9):1009–1016

    Article  CAS  PubMed  Google Scholar 

  • 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(5453):664–666

    Article  CAS  PubMed  Google Scholar 

  • Usui M, Yamaguchi S, Tanji Y, Tominaga R, Ishigaki Y, Fukumoto M, Katagiri H, Mori K, Oka Y, Ishihara H (2012) Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism 61(8):1118–1128

    Article  CAS  PubMed  Google Scholar 

  • Uzi D, Barda L, Scaiewicz V, Mills M, Mueller T, Gonzalez-Rodriguez A, Valverde AM, Iwawaki T, Nahmias Y, Xavier R, Chung RT, Tirosh B, Shibolet O (2013) CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol 59(3):495–503

    Article  CAS  PubMed  Google Scholar 

  • Vandewynckel YP, Laukens D, Bogaerts E, Paridaens A, Van den Bussche A, Verhelst X, Van Steenkiste C, Descamps B, Vanhove C, Libbrecht L, De Rycke R, Lambrecht BN, Geerts A, Janssens S, Van Vlierberghe H (2014) Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy. Hepatol Int 9(1):93–104

    Article  PubMed  PubMed Central  Google Scholar 

  • Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334(6059):1081–1086

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Kaufman RJ (2012) The impact of the unfolded protein response on human disease. J Cell Biol 197(7):857–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang D, Wei Y, Schmoll D, Maclean KN, Pagliassotti MJ (2006a) Endoplasmic reticulum stress increases glucose-6-phosphatase and glucose cycling in liver cells. Endocrinology 147(1):350–358

    Article  CAS  PubMed  Google Scholar 

  • Wang HC, Huang W, Lai MD, Su IJ (2006b) Hepatitis B virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis. Cancer Sci 97(8):683–688

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Huang Z, Du Y, Cheng Y, Chen S, Guo F (2010) ATF4 regulates lipid metabolism and thermogenesis. Cell Res 20(2):174–184

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Chen Z, Lam V, Han J, Hassler J, Finck BN, Davidson NO, Kaufman RJ (2012) IRE1α-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. Cell Metab 16(4):473–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Zhang L, Wu X, Gurley EC, Kennedy E, Hylemon PB, Pandak WM, Sanyal AJ, Zhou H (2013a) The role of CCAAT enhancer-binding protein homologous protein in human immunodeficiency virus protease-inhibitor-induced hepatic lipotoxicity in mice. Hepatology 57(3):1005–1016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang C, Jiang K, Gao D, Kang X, Sun C, Zhang Q, Li Y, Sun L, Zhang S, Guo K, Liu Y (2013b) Clusterin protects hepatocellular carcinoma cells from endoplasmic reticulum stress induced apoptosis through GRP78. PLoS One 8(2):e55981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Z, Jiang C, Chen W, Zhang G, Luo D, Cao Y, Wu J, Ding Y, Liu B (2014) Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma cells. Biomed Res Int 2014:732516

    PubMed  PubMed Central  Google Scholar 

  • 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(2):E275–E281

    Article  CAS  PubMed  Google Scholar 

  • Weston RT, Puthalakath H (2010) Endoplasmic reticulum stress and BCL-2 family members. Adv Exp Med Biol 687:65–77

    Article  CAS  PubMed  Google Scholar 

  • Xiao G, Zhang T, Yu S, Lee S, Calabuig-Navarro V, Yamauchi J, Ringquist S, Dong HH (2013) ATF4 protein deficiency protects against high fructose-induced hypertriglyceridemia in mice. J Biol Chem 288(35):25350–25361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie Q, Khaoustov VI, Chung CC, Sohn J, Krishnan B, Lewis DE, Yoffe B (2002) Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation. Hepatology 36(3):592–601

    Article  CAS  PubMed  Google Scholar 

  • Xu Z, Yen TS (1996) Intracellular retention of surface protein by a hepatitis B virus mutant that releases virion particles. J Virol 70(1):133–140

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu J, Lai KK, Verlinsky A et al (2011) Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK. J Hepatol 55(3):673–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto K, Takahara K, Oyadomari S, Okada T, Sato T, Harada A, Mori K (2010) Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol Biol Cell 21(17):2975–2986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 Investig 87(9):927–937

    Article  CAS  PubMed  Google Scholar 

  • Ye J, Rawson RB, Komuro R, Chen X, Davé 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(6):1355–1364

    Article  CAS  PubMed  Google Scholar 

  • Yi Z, Fang C, Pan T, Wang J, Yang P, Yuan Z (2006) Subproteomic study of hepatitis C virus replicon reveals Ras-GTPase-activating protein binding protein 1 as potential HCV RC component. Biochem Biophys Res Commun 350(1):174–178

    Article  CAS  PubMed  Google Scholar 

  • Zeng L, Lu M, Mori K, Luo S, Lee AS, Zhu Y, Shyy JY (2004) ATF6 modulates SREBP2-mediated lipogenesis. EMBO J 23(4):950–958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, Wang G, Chang L, Xu W, Miao H, Leonardi R, Chen YE, Jackowski S, Kaufman RJ (2011) The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis. EMBO J 30(7):1357–1375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Singh N, Robinson-Taylor KS, Dorsett-Martin WA, Morris MW Jr, Earl TM, Anderson CD (2015) Hepatocyte autophagy is linked to C/EBP-homologous protein, Bcl2-interacting mediator of cell death, and BH3-interacting domain death agonist gene expression. J Surg Res 195(2):588–595

    Article  CAS  PubMed  Google Scholar 

  • Zheng Y, Gao B, Ye L, Kong L, Jing W, Yang X, Wu Z, Ye L (2005) Hepatitis C virus non-structural protein NS4B can modulate an unfolded protein response. J Microbiol 43(6):529–536

    CAS  PubMed  Google Scholar 

  • Zhu G, Lee AS (2015) Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis. J Cell Physiol 230(7):1413–1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work is supported by the US National Institutes of Health (NIH) grants R01AA018612 (NCE), R21AA023952, and R01DA042632 (to C. Ji). H. Han is a PhD student in Ji’s lab. Dr. Ji is grateful to the graduate students and postdoctoral fellows who contributed to the studies in the lab. The USC Research Center for Liver Diseases (P30DK48522) and the Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis (P50AA011999-20) provided technical assistance for the studies.

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  1. Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA

    Cheng Ji, Neil Kaplowitz & Hui Han

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  1. Cheng Ji
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Correspondence to Cheng Ji .

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  1. Department of Pharmacology Toxicology and Therapy, The University of Kansas Medical Center, Kansas City, Kansas, USA

    Wen-Xing Ding

  2. Health Pathology Laboratory, Indiana University, Indianapolis, Indiana, USA

    Xiao-Ming Yin

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Ji, C., Kaplowitz, N., Han, H. (2017). Role of Endoplasmic Reticulum Stress in Hepatic Injury. In: Ding, WX., Yin, XM. (eds) Molecules, Systems and Signaling in Liver Injury. Cell Death in Biology and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-58106-4_10

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