Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance

Hepatocellular death is present in almost all types of human liver disease and is used as a sensitive parameter for the detection of acute and chronic liver disease of viral, toxic, metabolic, or autoimmune origin. Clinical data and animal models suggest that hepatocyte death is the key trigger of liver disease progression, manifested by the subsequent development of inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Modes of hepatocellular death differ substantially between liver diseases. Different modes of cell death such as apoptosis, necrosis, and necroptosis trigger specific cell death responses and promote progression of liver disease through distinct mechanisms. In this review, we first discuss molecular mechanisms by which different modes of cell death, damage-associated molecular patterns, and specific cell death responses contribute to the development of liver disease. We then review the clinical relevance of cell death, focusing on biomarkers; the contribution of cell death to drug-induced, viral, and fatty liver disease and liver cancer; and evidence for cell death pathways as therapeutic targets. Hepatocellular death is present in almost all types of human liver disease and is used as a sensitive parameter for the detection of acute and chronic liver disease of viral, toxic, metabolic, or autoimmune origin. Clinical data and animal models suggest that hepatocyte death is the key trigger of liver disease progression, manifested by the subsequent development of inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Modes of hepatocellular death differ substantially between liver diseases. Different modes of cell death such as apoptosis, necrosis, and necroptosis trigger specific cell death responses and promote progression of liver disease through distinct mechanisms. In this review, we first discuss molecular mechanisms by which different modes of cell death, damage-associated molecular patterns, and specific cell death responses contribute to the development of liver disease. We then review the clinical relevance of cell death, focusing on biomarkers; the contribution of cell death to drug-induced, viral, and fatty liver disease and liver cancer; and evidence for cell death pathways as therapeutic targets. The presence of hepatocyte death, reflected by increased levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), is the most widely used parameter to screen for and monitor patients with liver disease. Moreover, these markers drive therapeutic decisions; have prognostic value for patients with hepatitis B virus (HBV)1Fattovich G. Olivari N. 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Liver regeneration.Adv Biochem Eng Biotechnol. 2005; 93: 101-134Crossref PubMed Scopus (0) Google Scholar Turnover is low in the normal liver, with approximately 0.05% of hepatocytes at any given time being removed by apoptosis, mostly in zone 3.17Columbano A. Ledda-Columbano G.M. Coni P.P. et al.Occurrence of cell death (apoptosis) during the involution of liver hyperplasia.Lab Invest. 1985; 52: 670-675PubMed Google Scholar, 18Benedetti A. Jezequel A.M. Orlandi F. Preferential distribution of apoptotic bodies in acinar zone 3 of normal human and rat liver.J Hepatol. 1988; 7: 319-324Abstract Full Text PDF PubMed Google Scholar This is reflected by almost undetectable ALT levels in healthy subjects. Despite the fact that most hepatic cell types rest in G0 phase, the liver is endowed with an astounding ability to regenerate in response to massive hepatocellular death or loss of functional liver mass.19Michalopoulos G.K. DeFrances M.C. Liver regeneration.Science. 1997; 276: 60-66Crossref PubMed Scopus (2816) Google Scholar This regenerative ability not only reflects essential metabolic functions of the liver but is also directly related to its high vulnerability to insults causing massive hepatic cell death, such as food-derived toxins or infections with hepatotropic viruses, bacteria, and parasites. As such, the wide range of metabolic and detoxifying functions predisposes hepatocytes to xenobiotic- and toxin-induced injury. Rapid regeneration represents an efficient mechanism to avoid the loss of key hepatic functions in this setting. Although acute liver failure caused by foodborne poisons and infections may have posed the biggest threat in former times, the bulk of modern liver diseases result from chronic disease processes such as chronic viral hepatitis, nonalcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). In these settings, the hepatic response to cell death, which is primarily geared toward restoring hepatic architecture and function in response to an acute threat to life (by providing extracellular matrix for mechanical stability and triggering hepatocyte regeneration to restore functional liver mass), becomes maladaptive and promotes the development of tissue fibrosis, cirrhosis, and HCC. The contribution of cell death to liver disease is cell-, stage- and context-specific. Although increased cell death may be a key driver of many chronic disease processes, including fibrogenesis and hepatocarcinogenesis (Table 1), loss or malfunction of programmed cell death (PCD) induction in subsets of epithelial cells contributes to the malignant transformation and constitutes a hallmark of cancer.20Yanai H. Matsuda A. 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However, these aspects will not be covered in this review.Table 1Evidence From Animal Models for Cell Death as a Driver of Liver DiseaseExperimental evidenceMode of cell death that promotes diseaseReferencesApoptosisNecroptosisNecrosisAcetaminophenRip3 knockout protects from early liver injuryX40Ramachandran A. McGill M.R. Xie Y. et al.Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice.Hepatology. 2013; 58: 2099-2108Crossref PubMed Scopus (160) Google ScholarCyclosporin A inhibits acetaminophen hepatocyte toxicity in vitro and liver injury in vivoX36Masubuchi Y. Suda C. Horie T. Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice.J Hepatol. 2005; 42: 110-116Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 46Kon K. Kim J.S. Jaeschke H. et al.Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes.Hepatology. 2004; 40: 1170-1179Crossref PubMed Scopus (377) Google ScholarHepatic I/R injuryCyclophilin D knockout inhibits necrotic cell death in hepatocytes and cardiac ischemia-reperfusion injuryX33Nakagawa T. Shimizu S. Watanabe T. et al.Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death.Nature. 2005; 434: 652-658Crossref PubMed Scopus (1301) Google ScholarFibrosisSpontaneous fibrosis in Mcl1 hepatocyte knockout miceX54Ravichandran K.S. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways.Immunity. 2011; 35: 445-455Abstract Full Text Full Text PDF PubMed Scopus (345) Google ScholarBclx1 hepatocyte knockout develops fibrosisX55Gude D.R. Alvarez S.E. Paugh S.W. et al.Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal.FASEB J. 2008; 22: 2629-2638Crossref PubMed Scopus (234) Google ScholarNecrotic injury models (CCl4 , APAP) result in fibrosisXCommon models in the literatureTak1- and Nemo-hepatocyte-specific knockout mice develop spontaneous liver fibrosisX90Luedde T. Beraza N. Kotsikoris V. et al.Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma.Cancer Cell. 2007; 11: 119-132Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar, 152Bettermann K. Vucur M. Haybaeck J. et al.TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer.Cancer Cell. 2010; 17: 481-496Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 167Inokuchi S. Aoyama T. Miura K. et al.Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis.Proc Natl Acad Sci U S A. 2010; 107: 844-849Crossref PubMed Scopus (208) Google ScholarCaspase inhibitor IDN-6556 inhibits fibrosis after bile duct ligationX144Canbay 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: 1191-1196Crossref PubMed Scopus (188) Google ScholarNASHDecreased inflammation and fibrosis in mice with ablation of RIP3 after MCD dietX146Gautheron J. Vucur M. Reisinger F. et al.A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis.EMBO Mol Med. 2014; 6: 1062-1074Crossref PubMed Scopus (167) Google ScholarCaspase inhibitor VX-166 inhibits inflammation and fibrosis in the MCD modelX145Anstee Q.M. Concas D. Kudo H. et al.Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis.J Hepatol. 2010; 53: 542-550Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 204Witek R.P. Stone W.C. Karaca F.G. et al.Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis.Hepatology. 2009; 50: 1421-1430Crossref PubMed Scopus (168) Google ScholarALDReduced steatosis, injury, and inflammation in Rip3-deficient mice41Roychowdhury S. McMullen M.R. Pisano S.G. et al.Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury.Hepatology. 2013; 57: 1773-1783Crossref PubMed Scopus (202) Google ScholarHCCSpontaneous HCC in Mcl1 hepatocyte knockout miceX56Elliott M.R. Chekeni F.B. Trampont P.C. et al.Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance.Nature. 2009; 461: 282-286Crossref PubMed Scopus (967) Google ScholarSpontaneous HCC in mice with Mcl1 or Bclx1 hepatocyte knockout, and inhibition of hepatocarcinogenesis by additional Bak knockoutX150Canbay A. Feldstein A.E. Higuchi H. et al.Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression.Hepatology. 2003; 38: 1188-1198Crossref PubMed Scopus (356) Google ScholarSpontaneous HCC development in mice with hepatocyte-specific Nemo or Tak1 knockoutX90Luedde T. Beraza N. Kotsikoris V. et al.Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma.Cancer Cell. 2007; 11: 119-132Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar, 152Bettermann K. Vucur M. Haybaeck J. et al.TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer.Cancer Cell. 2010; 17: 481-496Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 167Inokuchi S. Aoyama T. Miura K. et al.Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis.Proc Natl Acad Sci U S A. 2010; 107: 844-849Crossref PubMed Scopus (208) Google ScholarReduced HCC development by caspase-8 ablation in Tak1 hepatocyte- specific knockout mice, increase HCC development by Rip3 knockout in Tak1 hepatocyte-specific knockout miceX105Vucur M. Reisinger F. Gautheron J. et al.RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation.Cell Rep. 2013; 4: 776-790Abstract Full Text Full Text PDF PubMed Scopus (90) Google ScholarI/R, ischemia reperfusion. Open table in a new tab I/R, ischemia reperfusion. In view of the fundamental role of cell death in virtually all hepatic diseases, precise knowledge of mechanisms regulating cell death and cell death responses is essential to understand the pathophysiology of liver disease and develop new therapeutic approaches. Cell death occurs not only as a passive response to physicochemical stress or noxious insults but may also be actively induced by the host via PCD. PCD plays an active role in development and organismal homeostasis.22Miura M. Active participation of cell death in development and organismal homeostasis.Dev Growth Differ. 2011; 53: 125-136Crossref PubMed Scopus (35) Google Scholar Accordingly, inhibition of PCD by genetic ablation of key cell death regulators leads to hepatic hyperplasia.23Adachi M. Suematsu S. 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