Download PDF
Z Gastroenterol 2005; 43(2): 211-217
DOI: 10.1055/s-2004-813744
Übersicht

© Karl Demeter Verlag im Georg Thieme Verlag KG Stuttgart · New York

The Relationship Between Apoptosis and Non-Alcoholic Fatty Liver Disease: An Evolutionary Cornerstone Turned Pathogenic

Apoptose in der nichtalkoholischen Steatohepatitis: Von evolutionärem Eckpfeiler zu pathogenetischem SchlüsselfaktorA. Canbay1 , R. K. Gieseler2, 3 , G. J. Gores4 , G. Gerken1
  • 1Division of Gastroenterology and Hepatology, Department of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
  • 2Laboratories of Molecular Biology, Immunology and Virology, LTBH Medical Research Institute, Beverly Hills, CA, USA
  • 3Division of Research and Development, Rodos BioTarget, Beverly Hills, CA, USA
  • 4Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, MN, USA
The authors are grateful to Michael J. Scolaro, MD, and Guido Marquitan, MS (both LTBH Medical Research Institute and Rodos BioTarget), and Maria Eugenia Guicciardi (Mayo Medical School and Foundation) for their critical reading and helpful comments. AC was supported by an institutional grant from the University of Essen (IFORES) and GJG was supported by a grant, DK41876, from the National Institutes of Health and grants from the Mayo Foundation. RKG was supported by the Buddy Taub Foundation and the Stuart Foundation and is grateful for generous private donations to LTBH Medical Research Institute.
Further Information

Publication History

manuscript received: 25.6.2004

manuscript accepted: 29.9.2004

Publication Date:
07 February 2005 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Neueste Daten favorisieren für die nichtalkoholische Fettleber ein pathogenetisches Modell, in dem der Apoptose bei der Initiierung der Leberentzündung und -fibrose eine bedeutende Rolle zukommt. Infolge primärer hepatischer und peripherer Insulinresistenz und konsekutiv alteriertem Glucose- und Fettsäuremetabolismus erfolgt in den Leberparenchymzellen eine vermehrte Akkumulation freier Fettsäuren. Diese sind in der Lage, die hepatozytäre Expression exozellulärer Death-Rezeptoren heraufzuregulieren und damit die zelluläre Vulnerabilität zu erhöhen. Damit können die Hepatozyten durch pro-apoptotische Stimuli zur Apoptose und zur Freisetzung von Entzündungsmediatoren stimuliert werden. Im chronischem Zustand führt dieser Prozess zur Aktivierung von sowohl hepatischen Sternzellen als auch Kupffer-Zellen, wodurch Apoptose und Entzündung mit Zellaktivierung im Rahmen eines circulus vitiosus aufrecht erhalten werden und letztlich zur pro-fibrotischen Kollagensynthese und -ablagerung führen.

Abstract

The data currently available favor a model for the pathogenesis of non-alcoholic fatty liver disease that is based on an apparent sequential relationship of intrahepatic apoptosis, inflammation and fibrogenesis. Based on both hepatic and peripheral insulin resistance, the hepatocellular accumulation of triglycerides, termed steatosis, initially leads to an altered metabolism of glucose and free fatty acids in the liver. In response, increased expression of death receptors in simple steatosis enhances the hepatocytes’ susceptibility for pro-apoptotic stimuli, thus eliciting excessive hepatocyte apoptosis and inflammation. Evidence indicates that these processes, if prolonged, activate both hepatic stellate and Kupffer cells, thus leading to a vicious circle in which apoptosis, inflammation, cellular activation, and collagen deposition are upregulated even further.

Schlüsselwörter

NAFLD - NASH - Apoptose - Entzündung - Fibrose - Entwicklung - Evolution

Key words

NAFLD - NASH - apoptosis - inflammation - fibrosis - development - evolution

References

  • 1 Angulo P. Nonalcoholic fatty liver disease.  N Engl J Med. 2002;  346 1221-1231
    CrossrefPubMedGoogle Scholar
  • 2 Sheth S G, Gordon F D, Chopra S. Nonalcoholic steatohepatitis.  Ann Intern Med. 1997;  126 137-145
    PubMedGoogle Scholar
  • 3 Brunt E M, Janney C G, Di Bisceglie A M. et al . Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.  Am J Gastroenterol. 1999;  94 2467-2474
    CrossrefPubMedGoogle Scholar
  • 4 Farrell G C. Drugs and steatohepatitis.  Semin Liver Dis. 2002;  22 185-194
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Ludwig J, Viggiano T R, McGill D B. et al . Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.  Mayo Clin Proc. 1980;  55 434-438
    PubMedGoogle Scholar
  • 6 Canbay A, Higuchi H, Bronk S F. et al . Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis.  Gastroenterology. 2002;  123 1323-1330
    CrossrefPubMedGoogle Scholar
  • 7 Jaeschke H. Inflammation in response to hepatocellular apoptosis.  Hepatology. 2002;  35 964-966
    CrossrefPubMedGoogle Scholar
  • 8 Canbay A, Guicciardi M E, Higuchi H. et al . Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis.  J Clin Invest. 2003;  112 152-159
    CrossrefPubMedGoogle Scholar
  • 9 Feldstein A E, Canbay A, Angulo P. et al . Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.  Gastroenterology. 2003;  125 437-443
    CrossrefPubMedGoogle Scholar
  • 10 Thornberry N A. Caspases: key mediators of apoptosis.  Chem Biol. 1998;  5 R97-103
    CrossrefPubMedGoogle Scholar
  • 11 Savill J. Apoptosis in resolution of inflammation.  Kidney Blood Press Res. 2000;  23 173-174
    PubMedGoogle Scholar
  • 12 Henson P M, Bratton D L, Fadok V A. The phosphatidylserine receptor: a crucial molecular switch?.  Nat Rev Mol Cell Biol. 2001;  2 627-633
    CrossrefPubMedGoogle Scholar
  • 13 Green D R, Reed J C. Mitochondria and apoptosis.  Science. 1998;  281 1309-1312
    CrossrefPubMedGoogle Scholar
  • 14 Guicciardi M E, Gores G J. Cheating death in the liver.  Nat Med. 2004;  10 587-588
    PubMedGoogle Scholar
  • 15 Brill A, Torchinsky A, Carp H. et al . The role of apoptosis in normal and abnormal embryonic development.  J Assist Reprod Genet. 1999;  16 512-519
    PubMedGoogle Scholar
  • 16 Guller S, LaChapelle L. The role of placental Fas ligand in maintaining immune privilege at maternal-fetal interfaces.  Semin Reprod Endocrinol. 1999;  17 39-44
    PubMedGoogle Scholar
  • 17 Joaquin A M, Gollapudi S. Functional decline in aging and disease: a role for apoptosis.  J Am Geriatr Soc. 2001;  49 1234-1240
    CrossrefPubMedGoogle Scholar
  • 18 Roubenoff R. Catabolism of aging: is it an inflammatory process?.  Curr Opin Clin Nutr Metab Care. 2003;  6 295-299
    CrossrefPubMedGoogle Scholar
  • 19 Krammer P H. CD95’s deadly mission in the immune system.  Nature. 2000;  407 789-975
    CrossrefPubMedGoogle Scholar
  • 20 Greil R, Anether G, Johrer K. et al . Tracking death dealing by Fas and TRAIL in lymphatic neoplastic disorders: pathways, targets, and therapeutic tools.  J Leukoc Biol. 2003;  74 311-330
    CrossrefPubMedGoogle Scholar
  • 21 Zeiss C J. The apoptosis-necrosis continuum: insights from genetically altered mice.  Vet Pathol. 2003;  40 481-495
    CrossrefPubMedGoogle Scholar
  • 22 Galle P R, Hofmann W J, Walczak H. et al . Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage.  J Exp Med. 1995;  182 1223-1230
    CrossrefPubMedGoogle Scholar
  • 23 Galle P R, Krammer P H. CD95-induced apoptosis in human liver disease.  Semin Liver Dis. 1998;  18 141-151
    PubMedGoogle Scholar
  • 24 Yoon J, Gores G. Death receptor-mediated apoptosis and the liver.  J Hepatol. 2002;  37 400-410
    CrossrefPubMedGoogle Scholar
  • 25 Faubion W A, Gores G J. Death receptors in liver biology and pathobiology.  Hepatology. 1999;  29 1-4
    CrossrefPubMedGoogle Scholar
  • 26 Locksley R M, Killeen N, Lenardo M J. The TNF and TNF receptor superfamilies: integrating mammalian biology.  Cell. 2001;  104 487-501
    CrossrefPubMedGoogle Scholar
  • 27 Granger S W, Butrovich K D, Houshmand P. et al . Genomic characterization of LIGHT reveals linkage to an immune response locus on chromosome 19p13.3 and distinct isoforms generated by alternate splicing or proteolysis.  J Immunol. 2001;  167 5122-5128
    PubMedGoogle Scholar
  • 28 Abi-Rached L, Gilles A, Shiina T. et al . Evidence of en bloc duplication in vertebrate genomes.  Nat Genet. 2002;  31 100-105
    PubMedGoogle Scholar
  • 29 Collette Y, Gilles A, Pontarotti P. et al . A co-evolution perspective of the TNFSF and TNFRSF families in the immune system.  Trends Immunol. 2003;  24 387-394
    CrossrefPubMedGoogle Scholar
  • 30 Ashkenazi A, Dixit V M. Death receptors: signaling and modulation.  Science. 1998;  281 1305-1308
    CrossrefPubMedGoogle Scholar
  • 31 Singh A, Ni J, Aggarwal B B. Death domain receptors and their role in cell demise.  J Interferon Cytokine Res. 1998;  18 439-450
    PubMedGoogle Scholar
  • 32 Frankel S K, Van Linden A A, Riches D W. Heterogeneity in the phosphorylation of human death receptors by p42(mapk/erk2).  Biochem Biophys Res Commun. 2001;  288 313-320
    CrossrefPubMedGoogle Scholar
  • 33 Canbay A, Friedman S, Gores G J. Apoptosis: The nexus of liver injury and fibrosis.  Hepatology. 2004;  39 273-278
    CrossrefPubMedGoogle Scholar
  • 34 Chen J J, Sun Y, Nabel G J. Regulation of the proinflammatory effects of Fas ligand (CD95L).  Science. 1998;  282 1714-1717
    CrossrefPubMedGoogle Scholar
  • 35 Guicciardi M E, Deussing J, Miyoshi H. et al . Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c.  J Clin Invest. 2000;  106 1127-1137
    PubMedGoogle Scholar
  • 36 Guicciardi M E, Miyoshi H, Bronk S F. et al . Cathepsin B knockout mice are resistant to tumor necrosis factor-alpha-mediated hepatocyte apoptosis and liver injury: implications for therapeutic applications.  Am J Pathol. 2001;  159 2045-2054
    PubMedGoogle Scholar
  • 37 Foghsgaard L, Wissing D, Mauch D. et al . Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor.  J Cell Biol. 2001;  153 999-1010
    CrossrefPubMedGoogle Scholar
  • 38 Jaeschke H, Gores G J, Cederbaum A I. et al . Mechanisms of hepatotoxicity.  Toxicol Sci. 2002;  65 166-176
    PubMedGoogle Scholar
  • 39 Maher J J, Scott M K, Saito J M. et al . Adenovirus-mediated expression of cytokine induced neutrophil chemoattractant in rat liver induces a neutrophilic hepatitis.  Hepatology. 1997;  25 624-630
    CrossrefPubMedGoogle Scholar
  • 40 Lawson J A, Fisher M A, Simmons C A. et al . Parenchymal cell apoptosis as a signal for sinusoidal sequestration and transendothelial migration of neutrophils in murine models of endotoxin and Fas-antibody-induced liver injury.  Hepatology. 1998;  28 761-767
    CrossrefPubMedGoogle Scholar
  • 41 Faouzi S, Burckhardt B E, Hanson J C. et al . Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway.  J Biol Chem. 2001;  276 49 077-49 082
    PubMedGoogle Scholar
  • 42 Lauber K, Bohn E, Krober S M. et al . Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal.  Cell. 2003;  113 717-730
    CrossrefPubMedGoogle Scholar
  • 43 Ogasawara J, Watanabe-Fukunaga R, Adachi M. et al . Lethal effect of the anti-Fas antibody in mice.  Nature. 1993;  364 806-809
    CrossrefPubMedGoogle Scholar
  • 44 Patel T, Roberts L R, Jones B A. et al . Dysregulation of apoptosis as a mechanism of liver disease: an overview.  Semin Liver Dis. 1998;  18 105-114
    PubMedGoogle Scholar
  • 45 Kiener P A, Davis P M, Starling G C. et al . Differential induction of apoptosis by Fas-Fas ligand interactions in human monocytes and macrophages.  J Exp Med. 1997;  185 1511-1516
    CrossrefPubMedGoogle Scholar
  • 46 Geske F J, Monks J, Lehman L. et al . The role of the macrophage in apoptosis: hunter, gatherer, and regulator.  Int J Hematol. 2002;  76 16-26
    PubMedGoogle Scholar
  • 47 Canbay A, Feldstein A E, Higuchi H. et al . Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression.  Hepatology. 2003;  38 1188-1198
    CrossrefPubMedGoogle Scholar
  • 48 Jaeschke H, Fisher M A, Lawson J A. et al . Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model.  J Immunol. 1998;  160 3480-3486
    PubMedGoogle Scholar
  • 49 Canbay A, Feldstein A, Baskin-Bey E. et al . The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse.  J Pharmacol Exp Ther. 2004;  308 1191-1196
    CrossrefPubMedGoogle Scholar
  • 50 Ziol M, Tepper M, Lohez M. et al . Clinical and biological relevance of hepatocyte apoptosis in alcoholic hepatitis.  J Hepatol. 2001;  34 254-260
    CrossrefPubMedGoogle Scholar
  • 51 Jaeschke H. Neutrophil-mediated tissue injury in alcoholic hepatitis.  Alcohol. 2002;  27 23-27
    CrossrefPubMedGoogle Scholar
  • 52 Friedman S L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.  J Biol Chem. 2000;  275 2247-2250
    CrossrefPubMedGoogle Scholar
  • 53 Maher J J. Interactions between hepatic stellate cells and the immune system.  Semin Liver Dis. 2001;  21 417-426
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 Knittel T, Dinter C, Kobold D. et al . Expression and regulation of cell adhesion molecules by hepatic stellate cells (HSC) of rat liver: involvement of HSC in recruitment of inflammatory cells during hepatic tissue repair.  Am J Pathol. 1999;  154 153-167
    PubMedGoogle Scholar
  • 55 Marra F. Hepatic stellate cells and the regulation of liver inflammation.  J Hepatol. 1999;  3 1120-1130
    PubMedGoogle Scholar
  • 56 Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells.  Semin Liver Dis. 2001;  21 397-416
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Paik Y H, Schwabe R F, Bataller R. et al . Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells.  Hepatology. 2003;  37 1043-1055
    CrossrefPubMedGoogle Scholar
  • 58 Gressner A M. Mediators of hepatic fibrogenesis.  Hepatogastroenterology. 1996;  43 92-103
    PubMedGoogle Scholar
  • 59 Saile B, DiRocco P, Dudas J. et al . IGF-I induces DNA synthesis and apoptosis in rat liver hepatic stellate cells (HSC) but DNA synthesis and proliferation in rat liver myofibroblasts (rMF).  Lab Invest. 2004;  84 1037-1049
    CrossrefPubMedGoogle Scholar
  • 60 Klaunig J E, Babich M A, Baetcke K P. et al . PPARalpha agonist-induced rodent tumors: modes of action and human relevance.  Crit Rev Toxicol. 2003;  33 655-780
    PubMedGoogle Scholar
  • 61 Feldstein A, Canbay A, Guicciardi M E. et al . Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice.  J Hepatol. 2003;  39 978-983
    CrossrefPubMedGoogle Scholar
  • 62 Papathanassoglou E D, Moynihan J A, Ackerman M H. Does programmed cell death (apoptosis) play a role in the development of multiple organ dysfunction in critically ill patients? a review and a theoretical framework.  Crit Care Med. 2000;  28 537-549
    PubMedGoogle Scholar
  • 63 Denk H, Stumptner C, Fuchsbichler A. et al . [Alcoholic and nonalcoholic steatohepatitis. Histopathologic and pathogenetic considerations].  Pathologe. 2001;  22 388-398
    CrossrefPubMedGoogle Scholar
  • 64 Jaeschke H. Redox considerations in hepatic injury and inflammation.  Antioxid Redox Signal. 2002;  4 699-700
    CrossrefPubMedGoogle Scholar
  • 65 Rust C, Gores G J. Apoptosis and liver disease.  Am J Med. 2000;  108 567-574
    CrossrefPubMedGoogle Scholar
  • 66 Tinel M, Berson A, Vadrot N. et al . Subliminal Fas stimulation increases the hepatotoxicity of acetaminophen and bromobenzene in mice.  Hepatology. 2004;  39 655-666
    CrossrefPubMedGoogle Scholar
  • 67 Canbay A, Chen S Y, Gieseler R K. et al . Overweight patients are more susceptible for acute liver failure.  Hepatogastroenterology. 2005;  in press
    PubMedGoogle Scholar
  • 68 Feldstein A E, Werneburg N W, Canbay A. et al . Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway.  Hepatology. 2004;  40 185-194
    CrossrefPubMedGoogle Scholar
  • 69 Valentino K L, Gutierrez M, Sanchez R. et al . First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes.  Int J Clin Pharmacol Ther. 2003;  41 441-449
    CrossrefPubMedGoogle Scholar
  • 70 Eichhorst S T, Krueger A, Muerkoster S. et al . Suramin inhibits death receptor-induced apoptosis in vitro and fulminant apoptotic liver damage in mice.  Nat Med. 2004;  10 602-609
    PubMedGoogle Scholar

Ali Canbay, MD

Division of Gastroenterology and Hepatology, Department of Medicine, University Hospital, University of Duisburg-Essen

Hufelandstr. 55

45122 Essen

Germany

Phone: ++ 49/2 01/7 23-36 11

Fax: ++ 49/2 01/7 23-59 70

Email: Ali.Canbay@Uni-Essen.de

      >