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

A. Canbay; R. K. Gieseler; G. J. Gores; G. Gerken

doi:10.1055/s-2004-813744

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

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

Übersicht

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. Gieseler^2, 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.

Abstract

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

Volltext

Referenzen

References

1 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002; 346 1221-1231
2 Sheth S G, Gordon F D, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med. 1997; 126 137-145
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
4 Farrell G C. Drugs and steatohepatitis. Semin Liver Dis. 2002; 22 185-194
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
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
7 Jaeschke H. Inflammation in response to hepatocellular apoptosis. Hepatology. 2002; 35 964-966
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
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
10 Thornberry N A. Caspases: key mediators of apoptosis. Chem Biol. 1998; 5 R97-103
11 Savill J. Apoptosis in resolution of inflammation. Kidney Blood Press Res. 2000; 23 173-174
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
13 Green D R, Reed J C. Mitochondria and apoptosis. Science. 1998; 281 1309-1312
14 Guicciardi M E, Gores G J. Cheating death in the liver. Nat Med. 2004; 10 587-588
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
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
17 Joaquin A M, Gollapudi S. Functional decline in aging and disease: a role for apoptosis. J Am Geriatr Soc. 2001; 49 1234-1240
18 Roubenoff R. Catabolism of aging: is it an inflammatory process?. Curr Opin Clin Nutr Metab Care. 2003; 6 295-299
19 Krammer P H. CD95’s deadly mission in the immune system. Nature. 2000; 407 789-975
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
21 Zeiss C J. The apoptosis-necrosis continuum: insights from genetically altered mice. Vet Pathol. 2003; 40 481-495
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
23 Galle P R, Krammer P H. CD95-induced apoptosis in human liver disease. Semin Liver Dis. 1998; 18 141-151
24 Yoon J, Gores G. Death receptor-mediated apoptosis and the liver. J Hepatol. 2002; 37 400-410
25 Faubion W A, Gores G J. Death receptors in liver biology and pathobiology. Hepatology. 1999; 29 1-4
26 Locksley R M, Killeen N, Lenardo M J. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001; 104 487-501
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
28 Abi-Rached L, Gilles A, Shiina T. et al . Evidence of en bloc duplication in vertebrate genomes. Nat Genet. 2002; 31 100-105
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
30 Ashkenazi A, Dixit V M. Death receptors: signaling and modulation. Science. 1998; 281 1305-1308
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
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
33 Canbay A, Friedman S, Gores G J. Apoptosis: The nexus of liver injury and fibrosis. Hepatology. 2004; 39 273-278
34 Chen J J, Sun Y, Nabel G J. Regulation of the proinflammatory effects of Fas ligand (CD95L). Science. 1998; 282 1714-1717
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
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
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
38 Jaeschke H, Gores G J, Cederbaum A I. et al . Mechanisms of hepatotoxicity. Toxicol Sci. 2002; 65 166-176
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
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
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
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
43 Ogasawara J, Watanabe-Fukunaga R, Adachi M. et al . Lethal effect of the anti-Fas antibody in mice. Nature. 1993; 364 806-809
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
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
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
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
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
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
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
51 Jaeschke H. Neutrophil-mediated tissue injury in alcoholic hepatitis. Alcohol. 2002; 27 23-27
52 Friedman S L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000; 275 2247-2250
53 Maher J J. Interactions between hepatic stellate cells and the immune system. Semin Liver Dis. 2001; 21 417-426
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
55 Marra F. Hepatic stellate cells and the regulation of liver inflammation. J Hepatol. 1999; 3 1120-1130
56 Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis. 2001; 21 397-416
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
58 Gressner A M. Mediators of hepatic fibrogenesis. Hepatogastroenterology. 1996; 43 92-103
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
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
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
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
63 Denk H, Stumptner C, Fuchsbichler A. et al . [Alcoholic and nonalcoholic steatohepatitis. Histopathologic and pathogenetic considerations]. Pathologe. 2001; 22 388-398
64 Jaeschke H. Redox considerations in hepatic injury and inflammation. Antioxid Redox Signal. 2002; 4 699-700
65 Rust C, Gores G J. Apoptosis and liver disease. Am J Med. 2000; 108 567-574
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
67 Canbay A, Chen S Y, Gieseler R K. et al . Overweight patients are more susceptible for acute liver failure. Hepatogastroenterology. 2005; in press
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
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
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

Ali Canbay, MD

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

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