Cellular and Molecular Mechanisms of Liver Injury
2008; Elsevier BV; Volume: 134; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2008.03.002
ISSN1528-0012
AutoresHarmeet Malhi, Gregory J. Gores,
Tópico(s)Hepatitis B Virus Studies
ResumoDerangements in apoptosis of liver cells are mechanistically important in the pathogenesis of end-stage liver disease. Vulnerable hepatocytes can undergo apoptosis via an extrinsic, death receptor–mediated pathway, or alternatively intracellular stress can activate the intrinsic pathway of apoptosis. Both pathways converge on mitochondria, and mitochondrial dysfunction is a prerequisite for hepatocyte apoptosis. Persistent apoptosis is a feature of chronic liver diseases, and massive apoptosis is a feature of acute liver diseases. Fibrogenesis is stimulated by ongoing hepatocyte apoptosis, eventually resulting in cirrhosis of the liver in chronic liver diseases. Endothelial cell apoptosis occurs in ischemia-reperfusion injury. Natural killer and natural killer T cells remove virus-infected hepatocytes by death receptor–mediated fibrosis. Lastly, activated stellate cell apoptosis leads to slowing and resolution of apoptosis. This review summarizes recent cellular and molecular advances in the understanding of the injury mechanisms leading to end-stage liver disease. Derangements in apoptosis of liver cells are mechanistically important in the pathogenesis of end-stage liver disease. Vulnerable hepatocytes can undergo apoptosis via an extrinsic, death receptor–mediated pathway, or alternatively intracellular stress can activate the intrinsic pathway of apoptosis. Both pathways converge on mitochondria, and mitochondrial dysfunction is a prerequisite for hepatocyte apoptosis. Persistent apoptosis is a feature of chronic liver diseases, and massive apoptosis is a feature of acute liver diseases. Fibrogenesis is stimulated by ongoing hepatocyte apoptosis, eventually resulting in cirrhosis of the liver in chronic liver diseases. Endothelial cell apoptosis occurs in ischemia-reperfusion injury. Natural killer and natural killer T cells remove virus-infected hepatocytes by death receptor–mediated fibrosis. Lastly, activated stellate cell apoptosis leads to slowing and resolution of apoptosis. This review summarizes recent cellular and molecular advances in the understanding of the injury mechanisms leading to end-stage liver disease. Gregory J. GoresView Large Image Figure ViewerDownload Hi-res image Download (PPT) Liver injury encountered in clinical practice is arbitrarily divided into acute and chronic, based on the duration or persistence of liver injury. Acute insults are mostly surmountable with rapid resolution upon elimination of the injurious agent and complete restitution of normal liver architecture and function without enduring evidence of the preceding insult. Progressive fibrosis is the hallmark of chronic liver injury; it can eventually result in cirrhosis, liver failure, or hepatocellular carcinoma. This distinction between acute and chronic liver injury is a mechanistic oversimplification. Chronic liver injury reflects, in part, continuous acute liver injury extended over time. The consequences of continuous acute liver injury are what drive hepatic fibrogenesis. This process became especially apparent when effective therapy for chronic hepatitis B became available. Many patients with end-stage liver disease thought to warrant liver transplantation for survival had significant recovery with antiviral therapy and no longer required urgent transplantation. Furthermore, with the recognition that hepatic fibrogenesis has a reversible component; inhibition of liver injury has become a potential therapeutic strategy for advanced liver disease. Thus, an understanding of the mechanisms mediating liver injury is of biomedical and clinical relevance. Recent advances in understanding the cellular processes and molecular signaling that mediate liver injury are summarized in this review. The first half focuses on mechanistic insights, and in this section references to nonliver systems serve as paradigms; the latter half focuses on select liver-specific disease processes. Nomenclature in the literature refers to apoptotic cell death and necrotic cell death in diseased livers. Apoptosis is defined morphologically on the basis of cellular rounding up, cytoplasmic shrinkage (pyknosis), chromatin condensation, and nuclear fragmentation (karyorrhexis). Effector caspase (proteases that cleave at aspartate residues) activation is required for the acquisition of this morphology. Necrotic cell death has the morphology of oncosis (cell swelling due to the inability to maintain cellular ion gradients), karyolysis, and rupture of the plasma membrane. While definitions are useful as broad categories, understanding the minute mechanisms that lead to cell death and ensuing injury are more important than allotting modes of cell death to a particular liver disease. Suffice it to say that in the liver, morphologically observed cell death can be apoptotic or necrotic or a combination of the two. Furthermore, the same stimulus can result in either morphology.1Ogasawara J. Watanabe-Fukunaga R. Adachi M. et al.Lethal effect of the anti-Fas antibody in mice.Nature. 1993; 364: 806-809Crossref PubMed Scopus (1452) Google Scholar, 2Matsumura H. Shimizu Y. Ohsawa Y. et al.Necrotic death pathway in Fas receptor signaling.J Cell Biol. 2000; 151: 1247-1256Crossref PubMed Scopus (147) Google Scholar It is conceivable that on a cellular basis, necrosis in the liver is the result of overwhelming or dysregulated apoptosis. For example, exaggerated mitochondrial dysfunction from “apoptotic” signaling cascades can result in cellular adenosine triphosphate depletion and necrotic morphology. Hepatocytes are the most numerous cell type in the liver, and their apoptosis is prominent in liver injury.3Ribeiro P.S. Cortez-Pinto H. Sola S. et al.Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients.Am J Gastroenterol. 2004; 99: 1708-1717Crossref PubMed Scopus (170) Google Scholar, 4Feldstein A.E. Canbay A. Angulo P. et al.Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.Gastroenterology. 2003; 125: 437-443Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 5Natori S. Rust C. Stadheim L.M. et al.Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis.J Hepatol. 2001; 34: 248-253Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Councilman bodies, described by the pathologist William T. Councilman (1854–1933), in the liver of patients with yellow fever result from apoptotic death of individual hepatocytes.6Vieira W.T. Gayotto L.C. de Lima C.P. et al.Histopathology of the human liver in yellow fever with special emphasis on the diagnostic role of the Councilman body.Histopathology. 1983; 7: 195-208Crossref PubMed Google Scholar On careful examination, hepatocyte apoptosis can be identified in virtually all forms of liver injury.4Feldstein A.E. Canbay A. Angulo P. et al.Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.Gastroenterology. 2003; 125: 437-443Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 7Natori S. Higuchi H. Contreras P. et al.The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury.Liver Transpl. 2003; 9: 278-284Crossref PubMed Scopus (66) Google Scholar, 8Papakyriakou P. Tzardi M. Valatas V. et al.Apoptosis and apoptosis related proteins in chronic viral liver disease.Apoptosis. 2002; 7: 133-141Crossref PubMed Scopus (30) Google Scholar, 9Natori S. Selzner M. Valentino K.L. et al.Apoptosis of sinusoidal endothelial cells occurs during liver preservation injury by a caspase-dependent mechanism.Transplantation. 1999; 68: 89-96Crossref PubMed Google Scholar, 10Kohli V. Selzner M. Madden J.F. et al.Endothelial cell and hepatocyte deaths occur by apoptosis after ischemia-reperfusion injury in the rat liver.Transplantation. 1999; 67: 1099-1105Crossref PubMed Scopus (239) Google Scholar Apoptosis of other cellular compartments is also important. For example, sinusoidal endothelial cell apoptosis is observed in ischemia-reperfusion injury, and failure of activated stellate cell apoptosis promotes fibrosis. The M30 neoantigen is one example of an emerging clinical applicability of the apoptosis cascade.11Hetz H. Hoetzenecker K. Hacker S. et al.Caspase-cleaved cytokeratin 18 and 20 S proteasome in liver degeneration.J Clin Lab Anal. 2007; 21: 277-281Crossref PubMed Scopus (13) Google Scholar This epitope is formed by proteolytic cleavage of cytokeratin 18 by caspase 3 at Asp396 position. It is readily detectable in plasma by enzyme-linked immunosorbent assay. Circulating levels are increased in patients with chronic liver disease, and highest levels are found in patients with cholestasis or cholangitis.12Yagmur E. Trautwein C. Leers M.P. et al.Elevated apoptosis-associated cytokeratin 18 fragments (CK18Asp386) in serum of patients with chronic liver diseases indicate hepatic and biliary inflammation.Clin Biochem. 2007; 40: 651-655Crossref PubMed Scopus (20) Google Scholar Levels in hepatic graft-versus-host disease are elevated and correlate with response to therapy.13Luft T. Conzelmann M. Benner A. et al.Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease.Blood. 2007; 110: 4535-4542Crossref PubMed Scopus (29) Google Scholar In patients with steatohepatitis, serum levels of M30 correlate with liver levels and inflammation.14Wieckowska A. Zein N.N. Yerian L.M. et al.In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease.Hepatology. 2006; 44: 27-33Crossref PubMed Scopus (279) Google Scholar Thus, a biomarker reflecting hepatocyte apoptosis may eventually be important in establishing and monitoring therapy in human liver diseases. The appearance of serum cytokeratin 18 degradation products in virtually all liver diseases also highlights the role of caspases in liver tissue injury. Apoptosis can be initiated from any membrane-defined organelle in the cell. In this review, we emphasize this mechanistic concept. Mitochondrial dysfunction is the commitment step in hepatocyte cell death, and hepatocyte cell death is dependent on mitochondria.15Malhi H. Gores G.J. Lemasters J.J. Apoptosis and necrosis in the liver: a tale of two deaths?.Hepatology. 2006; 43: S31-S44Crossref PubMed Scopus (281) Google Scholar Apart from the well-recognized metabolic functions of mitochondria such as the respiratory chain, the inner and outer mitochondrial membranes also isolate a number of proapoptotic proteins within the intermembrane space. Mitochondrial outer membrane permeabilization leads to the release of these apoptosis mediators, cytochrome c, second mitochondrial activator of caspase/direct IAP binding protein with low pI (SMAC/DIABLO), HtrA2/Omi, apoptosis-inducing factor, and endonuclease G.16Green D.R. Kroemer G. The pathophysiology of mitochondrial cell death.Science. 2004; 305: 626-629Crossref PubMed Scopus (1545) Google Scholar Activation of downstream effector caspases ensues, resulting in the typical morphologic changes of apoptosis. Mitochondrial outer membrane permeabilization occurs selectively, mediated via activated Bax or Bak (vide infra) or secondary to mitochondrial permeability transition.17Green D.R. Apoptotic pathways: ten minutes to dead.Cell. 2005; 121: 671-674Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar For example, in ischemia-reperfusion injury, the mitochondrial permeability transition pore (which is composed of the voltage-dependent anion channel, adenosine nucleotide transporter, and cyclophilin D) upon activation leads to influx of solutes and ions, swelling of the mitochondrial matrix, and rupture of the outer mitochondrial membrane, releasing proapoptotic proteins into the cytosol. Of the 3 proteins that comprise the mitochondrial permeability transition pore, cyclophilin D is essential for the permeability transition pore.18Baines C.P. Kaiser R.A. Purcell N.H. et al.Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.Nature. 2005; 434: 658-662Crossref PubMed Scopus (863) Google Scholar Mitochondrial outer membrane permeabilization can occur downstream of death receptor–triggered signaling cascades (extrinsic pathway), lysosomal permeabilization, endoplasmic reticulum (ER) stress pathways, or activation of intracellular stress kinases, such as c-jun N-terminal kinase (JNK) (intrinsic pathway) (Figure 1). The Bcl-2 family proteins (Table 1) are best described as mediators of mitochondrial dysfunction.19Cory S. Huang D.C. Adams J.M. The Bcl-2 family: roles in cell survival and oncogenesis.Oncogene. 2003; 22: 8590-8607Crossref PubMed Scopus (776) Google Scholar They are divided into proapoptotic and antiapoptotic proteins. The proapoptotic proteins are structurally divided into multidomain (Bak and Bax) and BH-3 domain only (Bid, Noxa, Puma, Bim, Bmf, Bik, Hrk, and Bad), and Bcl-2, Bcl-xL, A1, and Mcl-1 are the important antiapoptotic proteins. Bax is cytosolic and Bak is located on the mitochondrial membrane; when Bax is activated, it too translocates to mitochondria. These 2 multidomain proapoptotic proteins can, on activation, form pores on the outer mitochondrial membrane, inducing mitochondrial permeabilization. Bax and Bak are either directly or indirectly activated by the BH-3–only proteins. For example, Bid is cytosolic and is activated by caspase 8–mediated cleavage, downstream of death receptor activation, and in turn activates Bax/Bak. The antiapoptotic proteins sequester Bax and Bak, preventing apoptosis. When disabled by excessive binding of BH-3–only proteins, they become overwhelmed releasing Bax and Bak and cell death ensues.Table 1The Bcl-2 Family ProteinsBcl-2 Family ProteinsAntiapoptoticProapoptoticBH3 onlyMultidomainBcl-xLBidBaxMcl-1BimBakBcl-wPumaBokBcl-2NoxaBcl-xsA1BadBooBikBmfHrk Open table in a new tab When it occurs, lysosomal involvement in cell death is an early event, observed before mitochondrial permeabilization or caspase activation. In general, lysosomes can be activated by the extrinsic or death receptor–mediated pathway or myriad intracellular stimuli, such as free fatty acids, sphingosine, ceramide, reactive oxygen species, photodamage, or lysosomotropic agents (weakly basic amines that can accumulate in lysosomes and raise intravesicular pH).20Guicciardi M.E. Leist M. Gores G.J. Lysosomes in cell death.Oncogene. 2004; 23: 2881-2890Crossref PubMed Scopus (307) Google Scholar Release of lysosomal proteases (cathepsins) mediates downstream effects. Cathepsin B (one of 11 known human cathepsins) is active at neutral pH and has been studied in several models of liver injury. Lysosomal permeabilization can result in necrotic cell death or apoptotic cell death. Massive release of cathepsins from total lysosomal permeabilization leads to necrotic cell death. Selective lysosomal permeabilization leads to apoptosis, in some instances independent of caspase activation; however, in liver injury models, caspase activation occurs downstream of lysosomal permeabilization. Lysosomal ultrastructural abnormalities are seen in many chronic liver disorders. Studies utilizing mice deficient in cathepsin B, which develop normally, show that the lysosomal pathway of apoptosis is important in steatohepatitis, cholestatic liver injury, and tumor necrosis factor (TNF)-α–mediated liver injury.21Kyaw A. Aung T. Htut T. et al.Lysosomal enzyme activities in normals and in patients with chronic liver diseases.Clin Chim Acta. 1983; 131: 317-323Crossref PubMed Google Scholar, 22Guicciardi 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: 1127-1137Crossref PubMed Google Scholar, 23Feldstein 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: 185-194Crossref PubMed Scopus (307) Google Scholar ER stress is an active area of research in the pathogenesis of chronic liver injury (Figure 2), although most of the current understanding of the known mediators of the ER stress pathway comes from other experimental systems. The stressed ER exhibits an imbalance between unfolded proteins and mature proteins, activating a series of compensatory responses, collectively termed the unfolded protein response (UPR).24Ron D. Walter P. Signal integration in the endoplasmic reticulum unfolded protein response.Nat Rev Mol Cell Biol. 2007; 8: 519-529Crossref PubMed Scopus (1602) Google Scholar ER stress can also be induced by myriad stimuli, such as calcium depletion, glycosylation inhibition (tunicamycin), UV radiation, and insulin resistance. The ER stress response is a 3-pronged attempt at correcting the accumulation of unfolded proteins, and in situations of inadequate correction or sustained ER stress, it signals cell death. There is a global reduction in protein synthesis, decreasing the amount of newly synthesized proteins that have to enter the ER, and selective induction of a set of genes referred to as UPR target genes. Three membrane sensors have been identified in the ER that function as signal transducers of ER stress: inositol-requiring protein 1 (IRE1), activating transcription factor (ATF) 6, and protein kinase RNA-like endoplasmic reticulum kinase (PERK) (Figure 2). IRE1 activation leads to endoribonucleolytic excision of an intron within X-box binding protein 1 (XBP1) messenger RNA. Uncleaved XBP1 inhibits gene transcription of a set of genes, whereas on its IRE1-mediated processing XBP1 acts as an activator of transcription of the same genes. IRE1 can also signal via JNK; this pathway is implicated in insulin resistance. ATF6 activates UPR target genes. PERK activation leads to phosphorylation of eukaryotic translation initiation factor 2α, reducing its activity and thus leading to a global decrease in protein synthesis, and selective translation of ATF4, transcription of C/EBP-homologous protein (CHOP), and activation of nuclear factor κB. ER stress can activate Bim, the potent proapoptotic BH-3–only protein, via CHOP-induced transcription, leading to its increased expression and decreasing its proteasomal degradation.25Puthalakath H. O'Reilly L.A. Gunn P. et al.ER stress triggers apoptosis by activating BH3-only protein Bim.Cell. 2007; 129: 1337-1349Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar Additionally, CHOP can also increase expression of death receptors.26He Q. Luo X. 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