Cell Death in Liver Diseases: A Review

Regulated cell death (RCD) is pivotal in directing the severity and outcome of liver injury. Hepatocyte cell death is a critical event in the progression of liver disease due to resultant inflammation leading to fibrosis. Apoptosis, necrosis, necroptosis, autophagy, and recently, pyroptosis and ferroptosis, have all been investigated in the pathogenesis of various liver diseases. These cell death subroutines display distinct features, while sharing many similar characteristics with considerable overlap and crosstalk. Multiple types of cell death modes can likely coexist, and the death of different liver cell populations may contribute to liver injury in each type of disease. This review addresses the known signaling cascades in each cell death pathway and its implications in liver disease. In this review, we describe the common findings in each disease model, as well as the controversies and the limitations of current data with a particular focus on cell death-related research in humans and in rodent models of alcoholic liver disease, non-alcoholic fatty liver disease and steatohepatitis (NASH/NAFLD), acetaminophen (APAP)-induced hepatotoxicity, autoimmune hepatitis, cholestatic liver disease, and viral hepatitis.

[1]  Xiao-hui Ma,et al.  (+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis , 2020, Cell Death & Disease.

[2]  T. Kanneganti,et al.  The regulation of the ZBP1‐NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis) , 2020, Immunological reviews.

[3]  J. Reyes,et al.  NLRP3 receptor contributes to protection against experimental antigen-mediated cholangitis , 2020, Bioscience reports.

[4]  Lanjuan Li,et al.  Autophagy regulation is an effective strategy to improve the prognosis of chemically induced acute liver injury based on experimental studies , 2020, Journal of cellular and molecular medicine.

[5]  H. Puy,et al.  Ferroptosis in Liver Diseases: An Overview , 2020, International journal of molecular sciences.

[6]  Bangmao Wang,et al.  The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope? , 2020, Cell Death & Disease.

[7]  M. Dimanche-Boitrel,et al.  Intrahepatocytic necroptosis is dispensable for hepatocyte death in murine immune-mediated hepatitis. , 2020, Journal of hepatology.

[8]  Chuanwu Zhu,et al.  Circulating Receptor-Interacting Protein Kinase 3 Are Increased in HBV Patients With Acute-on-Chronic Liver Failure and Are Associated With Clinical Outcome , 2020, Frontiers in Physiology.

[9]  T. Kanneganti,et al.  The PANoptosome: A Deadly Protein Complex Driving Pyroptosis, Apoptosis, and Necroptosis (PANoptosis) , 2020, Frontiers in Cellular and Infection Microbiology.

[10]  H. Hao,et al.  Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure , 2020, Acta Pharmacologica Sinica.

[11]  G. Gores,et al.  Lytic Cell Death in Metabolic Liver Disease. , 2020, Journal of hepatology.

[12]  P. Vogel,et al.  Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense , 2020, Cell.

[13]  Masafumi Takahashi,et al.  Role of ferroptosis in acetaminophen-induced hepatotoxicity , 2020, Archives of Toxicology.

[14]  Y. Xiong,et al.  Targeting ferroptosis alleviates methionine‐choline deficient (MCD)‐diet induced NASH by suppressing liver lipotoxicity , 2020, Liver international : official journal of the International Association for the Study of the Liver.

[15]  H. Jaeschke,et al.  Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity. , 2020, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[16]  G. Gores,et al.  Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis , 2020, Hepatology.

[17]  M. Karin,et al.  An AMPK–caspase-6 axis controls liver damage in nonalcoholic steatohepatitis , 2020, Science.

[18]  N. Sata,et al.  Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure , 2020, Cell Death & Disease.

[19]  Bei Sun,et al.  Ferroptosis: past, present and future , 2020, Cell Death & Disease.

[20]  Shan Huang,et al.  Indoleamine 2, 3-dioxygenase 1enhanceshepatocytes ferroptosis in acute immune hepatitis associated with excess nitrative stress. , 2020, Free radical biology & medicine.

[21]  Zhou Zhou,et al.  Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver Injury by Mitigating Ferroptosis. , 2020, The American journal of pathology.

[22]  J. Chan,et al.  A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. , 2019, Journal of hepatology.

[23]  W. Ding,et al.  Role of autophagy in alcohol and drug-induced liver injury. , 2019, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[24]  X. Yao,et al.  Caveolin-1 dictates ferroptosis in the execution of acute immune-mediated hepatic damage by attenuating nitrogen stress. , 2019, Free radical biology & medicine.

[25]  J. Chan,et al.  Randomized Placebo-Controlled Trial of Emricasan in Non-alcoholic Steatohepatitis (NASH) Cirrhosis with Severe Portal Hypertension. , 2019, Journal of hepatology.

[26]  Wei Zhang,et al.  Gasdermin D-mediated hepatocyte pyroptosis expands inflammatory responses that aggravate acute liver failure by upregulating monocyte chemotactic protein 1/CC chemokine receptor-2 to recruit macrophages , 2019, World journal of gastroenterology.

[27]  G. Courtois,et al.  Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease. , 2019, Journal of hepatology.

[28]  H. Jaeschke,et al.  Emerging and established modes of cell death during acetaminophen-induced liver injury , 2019, Archives of Toxicology.

[29]  Su Lin,et al.  Pyroptosis in Liver Disease: New Insights into Disease Mechanisms , 2019, Aging and disease.

[30]  L. Komuves,et al.  Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis , 2019, Nature.

[31]  D. Ure,et al.  A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models , 2019, The Journal of Pharmacology and Experimental Therapeutics.

[32]  Yuan He,et al.  The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation , 2019, International journal of molecular sciences.

[33]  H. Jaeschke,et al.  INFLAMMATION AND CELL DEATH DURING CHOLESTASIS: THE EVOLVING ROLE OF BILE ACIDS. , 2019, Gene expression.

[34]  T. Billiar,et al.  Gasdermin D protects against noninfectious liver injury by regulating apoptosis and necroptosis , 2019, Cell Death & Disease.

[35]  H. Nakano,et al.  Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis , 2019, Cell Death & Disease.

[36]  A. Degterev,et al.  Targeting RIPK1 for the treatment of human diseases , 2019, Proceedings of the National Academy of Sciences.

[37]  Shuai Gao,et al.  Receptor-Interacting Protein Kinase 3 (RIPK3) mRNA Levels Are Elevated in Blood Mononuclear Cells of Patients with Poor Prognosis of Acute-on-Chronic Hepatitis B Liver Failure. , 2019, The Tohoku journal of experimental medicine.

[38]  H. Malhi,et al.  Endoplasmic Reticulum Stress in Metabolic Liver Diseases and Hepatic Fibrosis , 2019, Seminars in Liver Disease.

[39]  C. Trautwein,et al.  Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis , 2019, Gut.

[40]  Zhou Zhou,et al.  Adipose‐Specific Lipin‐1 Overexpression Renders Hepatic Ferroptosis and Exacerbates Alcoholic Steatohepatitis in Mice , 2019, Hepatology communications.

[41]  T. Krech,et al.  Deletion of tumour necrosis factor α receptor 1 elicits an increased TH17 immune response in the chronically inflamed liver , 2019, Scientific Reports.

[42]  D. Vaux,et al.  Activated MLKL attenuates autophagy following its translocation to intracellular membranes , 2019, Journal of Cell Science.

[43]  Yuquan Wei,et al.  The pseudokinase MLKL regulates hepatic insulin sensitivity independently of inflammation , 2019, Molecular metabolism.

[44]  M. Dimanche-Boitrel,et al.  Depletion of RIPK1 in hepatocytes exacerbates liver damage in fulminant viral hepatitis , 2019, Cell Death & Disease.

[45]  T. Luedde,et al.  Inactivation of caspase 8 in liver parenchymal cells confers protection against murine obstructive cholestasis. , 2018, Journal of hepatology.

[46]  J. Chan,et al.  Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase 3/7 activation in subjects with non‐alcoholic fatty liver disease , 2018, Alimentary pharmacology & therapeutics.

[47]  J. Kwon,et al.  Toll-Like Receptor-7 Signaling Promotes Nonalcoholic Steatohepatitis by Inhibiting Regulatory T Cells in Mice. , 2018, The American journal of pathology.

[48]  J. Bertin,et al.  Pathogen blockade of TAK1 triggers caspase-8–dependent cleavage of gasdermin D and cell death , 2018, Science.

[49]  Xiao-Ming Yin.  Autophagy in liver diseases: A matter of what to remove and whether to keep , 2018, Liver research.

[50]  Darjus F. Tschaharganeh,et al.  TNFα sensitizes hepatocytes to FasL-induced apoptosis by NFκB-mediated Fas upregulation , 2018, Cell Death & Disease.

[51]  Jiajun Zhao,et al.  Cyclophilin D deficiency attenuates mitochondrial perturbation and ameliorates hepatic steatosis , 2018, Hepatology.

[52]  Xiaoyan Shen,et al.  SNX10 mediates alcohol-induced liver injury and steatosis by regulating the activation of chaperone-mediated autophagy. , 2018, Journal of hepatology.

[53]  A. Moles,et al.  Mitochondrial–Lysosomal Axis in Acetaminophen Hepatotoxicity , 2018, Front. Pharmacol..

[54]  Sharad Kumar,et al.  Caspases in metabolic disease and their therapeutic potential , 2018, Cell Death & Differentiation.

[55]  Y. Koyama,et al.  Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation , 2018, Journal of Molecular Medicine.

[56]  Richard D. Smith,et al.  Pyroptosis by caspase11/4‐gasdermin‐D pathway in alcoholic hepatitis in mice and patients , 2018, Hepatology.

[57]  T. Carvalho,et al.  miRNA-21 ablation protects against liver injury and necroptosis in cholestasis , 2018, Cell Death & Differentiation.

[58]  Yubin Li,et al.  NOD-Like Receptor Protein 3 Inflammasome-Dependent IL-1β Accelerated ConA-Induced Hepatitis , 2018, Front. Immunol..

[59]  J. Banales,et al.  Pyroptosis: An inflammatory link between NAFLD and NASH with potential therapeutic implications. , 2018, Journal of hepatology.

[60]  Tae Hyun Kim,et al.  Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression , 2018, Gut.

[61]  L. Dara,et al.  The Receptor Interacting Protein Kinases in the Liver , 2018, Seminars in Liver Disease.

[62]  A. Sanyal,et al.  Preclinical models of non-alcoholic fatty liver disease. , 2018, Journal of hepatology.

[63]  Yitao Ding,et al.  Interleukin‐10 secreted by mesenchymal stem cells attenuates acute liver failure through inhibiting pyroptosis , 2018, Hepatology research : the official journal of the Japan Society of Hepatology.

[64]  A. Wree,et al.  NLRP3 inflammasome driven liver injury and fibrosis: Roles of IL‐17 and TNF in mice , 2018, Hepatology.

[65]  S. Lipton,et al.  Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 , 2018, Cell Death & Differentiation.

[66]  Di Chen,et al.  Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. , 2017, Journal of hepatology.

[67]  Feng Li,et al.  The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis , 2017, Nature Medicine.

[68]  Elizabeth J. Osterlund,et al.  BCL-2 family proteins: changing partners in the dance towards death , 2017, Cell Death and Differentiation.

[69]  C. Trautwein,et al.  Inhibition of Caspase-8 does not protect from alcohol-induced liver apoptosis but alleviates alcoholic hepatic steatosis in mice , 2017, Cell Death and Disease.

[70]  H. Zhang,et al.  The Activation and Function of Autophagy in Alcoholic Liver Disease. , 2017, Current molecular pharmacology.

[71]  Se-Jin Yoon,et al.  MLKL, the Protein that Mediates Necroptosis, Also Regulates Endosomal Trafficking and Extracellular Vesicle Generation , 2017, Immunity.

[72]  X. Li,et al.  TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury , 2017, The Journal of clinical investigation.

[73]  N. Kaplowitz,et al.  The role of MAP2 kinases and p38 kinase in acute murine liver injury models , 2017, Cell Death and Disease.

[74]  M. Conrad,et al.  Iron and ferroptosis: A still ill‐defined liaison , 2017, IUBMB life.

[75]  M. Bertrand,et al.  RIPK1 protects hepatocytes from Kupffer cells-mediated TNF-induced apoptosis in mouse models of PAMP-induced hepatitis. , 2017, Journal of hepatology.

[76]  Y. Iwakura,et al.  Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity , 2017, Cellular & Molecular Immunology.

[77]  K. Schroder,et al.  NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. , 2017, Journal of hepatology.

[78]  N. Kaplowitz,et al.  Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis , 2017, International journal of molecular sciences.

[79]  Xiuli Liu,et al.  Myeloid‐MyD88 Contributes to Ethanol‐Induced Liver Injury in Mice Linking Hepatocellular Death to Inflammation , 2017, Alcoholism, clinical and experimental research.

[80]  Hongliang Li,et al.  Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates , 2017, Nature Medicine.

[81]  Z. Tian,et al.  HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1β production via suppressing the NF-κB pathway and ROS production. , 2017, Journal of hepatology.

[82]  T. Karlsen,et al.  Nlrp3 Activation Induces Il-18 Synthesis and Affects the Epithelial Barrier Function in Reactive Cholangiocytes. , 2017, American Journal of Pathology.

[83]  K. Hirasawa,et al.  Hepatitis C Virus Infection of Cultured Human Hepatoma Cells Causes Apoptosis and Pyroptosis in Both Infected and Bystander Cells , 2016, Scientific Reports.

[84]  N. Kaplowitz,et al.  Questions and controversies: the role of necroptosis in liver disease , 2016, Cell Death Discovery.

[85]  Yingwei Chen,et al.  Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis , 2016, Oncotarget.

[86]  C. Croniger,et al.  Receptor interacting protein 3 protects mice from high‐fat diet‐induced liver injury , 2016, Hepatology.

[87]  P. Vandenabeele,et al.  The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis. , 2016, The Journal of clinical investigation.

[88]  N. Kaplowitz,et al.  A murder mystery in the liver: who done it and how? , 2016, The Journal of clinical investigation.

[89]  M. Bertrand,et al.  RIPK1 protects from TNF-α-mediated liver damage during hepatitis , 2016, Cell Death & Disease.

[90]  Yong-mei Song,et al.  Knockdown of RIPK1 Markedly Exacerbates Murine Immune-Mediated Liver Injury through Massive Apoptosis of Hepatocytes, Independent of Necroptosis and Inhibition of NF-κB , 2016, The Journal of Immunology.

[91]  J. Maher,et al.  Modeling fatty liver disease in animals: Is there an optimal approach, and is the effort worthwhile? , 2016, Hepatology.

[92]  Junying Yuan,et al.  Activation of necroptosis in human and experimental cholestasis , 2016, Cell Death and Disease.

[93]  Mitchell R. McGill,et al.  Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice. , 2016, Journal of hepatology.

[94]  M. Lotze,et al.  Autophagy promotes ferroptosis by degradation of ferritin , 2016, Autophagy.

[95]  T. Luedde,et al.  The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance , 2016, Nature Communications.

[96]  G. Manning,et al.  Necroptosis and Inflammation. , 2016, Annual review of biochemistry.

[97]  G. Cresci,et al.  Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes. , 2016, Gastroenterology.

[98]  N. Kaplowitz,et al.  c‐Jun N‐terminal kinase mediates mouse liver injury through a novel Sab (SH3BP5)‐dependent pathway leading to inactivation of intramitochondrial Src , 2016, Hepatology.

[99]  M. Low,et al.  Not all mice are the same: Standardization of animal research data presentation , 2016, Hepatology.

[100]  N. van Bruggen,et al.  RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury , 2016, Cell Death and Differentiation.

[101]  R. D. De Lisle,et al.  A Mechanistic Review of Cell Death in Alcohol-Induced Liver Injury. , 2016, Alcoholism, clinical and experimental research.

[102]  J. Schwabe,et al.  Co-operative and Hierarchical Binding of c-FLIP and Caspase-8: A Unified Model Defines How c-FLIP Isoforms Differentially Control Cell Fate , 2016, Molecular cell.

[103]  B. Stockwell,et al.  Ferroptosis: Death by Lipid Peroxidation. , 2016, Trends in cell biology.

[104]  Neil Kaplowitz,et al.  Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury, clinical implications , 2016, Liver international : official journal of the International Association for the Study of the Liver.

[105]  M. Komatsu,et al.  Increased hepatic receptor interacting protein kinase 3 expression due to impaired proteasomal functions contributes to alcohol-induced steatosis and liver injury , 2016, Oncotarget.

[106]  N. Kaplowitz,et al.  Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity by Impairing Mitophagy , 2015, Scientific Reports.

[107]  N. Kaplowitz,et al.  Receptor interacting protein kinase 1 mediates murine acetaminophen toxicity independent of the necrosome and not through necroptosis , 2015, Hepatology.

[108]  W. Ding,et al.  Targeting Pink1-Parkin-mediated mitophagy for treating liver injury. , 2015, Pharmacological research.

[109]  J. Vince,et al.  Post-translational control of RIPK3 and MLKL mediated necroptotic cell death , 2015, F1000Research.

[110]  H. Cortez‐Pinto,et al.  Necroptosis is a key pathogenic event in human and experimental murine models of non-alcoholic steatohepatitis. , 2015, Clinical science.

[111]  R. Lerner,et al.  Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling , 2015, Nature Communications.

[112]  W. Ding,et al.  Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice. , 2015, American journal of physiology. Gastrointestinal and liver physiology.

[113]  K. Kodys,et al.  Metabolic danger signals, uric acid and ATP, mediate inflammatory cross‐talk between hepatocytes and immune cells in alcoholic liver disease , 2015, Journal of leukocyte biology.

[114]  G. Szabo,et al.  Inflammasome activation and function in liver disease , 2015, Nature Reviews Gastroenterology &Hepatology.

[115]  N. Kaplowitz,et al.  Targeting signal transduction pathways which regulate necrosis in acetaminophen hepatotoxicity. , 2015, Journal of hepatology.

[116]  Shuxia Wang,et al.  Effects of Cyclosporine on Reperfusion Injury in Patients: A Meta-Analysis of Randomized Controlled Trials , 2015, Oxidative medicine and cellular longevity.

[117]  K. Newton.  RIPK1 and RIPK3: critical regulators of inflammation and cell death. , 2015, Trends in cell biology.

[118]  Tak W. Mak,et al.  Regulation of tumour necrosis factor signalling: live or let die , 2015, Nature Reviews Immunology.

[119]  J. Mandl,et al.  Ferroptosis is Involved in Acetaminophen Induced Cell Death , 2015, Pathology & Oncology Research.

[120]  Si Ming Man,et al.  Regulation of inflammasome activation , 2015, Immunological reviews.

[121]  B. Schnabl,et al.  Alcoholic liver disease: the gut microbiome and liver cross talk. , 2015, Alcoholism, clinical and experimental research.

[122]  A. Eisenthal,et al.  Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury , 2015, Cell Death and Disease.

[123]  Min You,et al.  Sirtuin 1 signaling and alcoholic fatty liver disease. , 2015, Hepatobiliary surgery and nutrition.

[124]  F. Tacke,et al.  The concanavalin A model of acute hepatitis in mice , 2015, Laboratory animals.

[125]  H. Jaeschke,et al.  Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis. , 2015, Toxicology and applied pharmacology.

[126]  H. Jaeschke,et al.  Chronic Deletion and Acute Knockdown of Parkin Have Differential Responses to Acetaminophen-induced Mitophagy and Liver Injury in Mice* , 2015, The Journal of Biological Chemistry.

[127]  M. Dimanche-Boitrel,et al.  The chemical inhibitors of cellular death, PJ34 and Necrostatin-1, down-regulate IL-33 expression in liver , 2015, Journal of Molecular Medicine.

[128]  G. Gores,et al.  The pan‐caspase inhibitor Emricasan (IDN‐6556) decreases liver injury and fibrosis in a murine model of non‐alcoholic steatohepatitis , 2015, Liver international : official journal of the International Association for the Study of the Liver.

[129]  F. Tacke,et al.  Immune mechanisms in acetaminophen-induced acute liver failure. , 2014, Hepatobiliary surgery and nutrition.

[130]  G. Salvesen,et al.  Regulated cell death: signaling and mechanisms. , 2014, Annual review of cell and developmental biology.

[131]  A. Xu,et al.  Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice. , 2014, Journal of hepatology.

[132]  T. Luedde,et al.  Cell death and cell death responses in liver disease: mechanisms and clinical relevance. , 2014, Gastroenterology.

[133]  D Andrews,et al.  Essential versus accessory aspects of cell death: recommendations of the NCCD 2015 , 2014, Cell Death and Differentiation.

[134]  M. Karin,et al.  ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. , 2014, Cancer cell.

[135]  H. Jaeschke,et al.  Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. , 2014, Journal of hepatology.

[136]  A. Czaja.  Targeting Apoptosis in Autoimmune Hepatitis , 2014, Digestive Diseases and Sciences.

[137]  V. Lohmann,et al.  Monocytes activate natural killer cells via inflammasome-induced interleukin 18 in response to hepatitis C virus replication. , 2014, Gastroenterology.

[138]  W. Mehal.  The Inflammasome in Liver Injury and Non-Alcoholic Fatty Liver Disease , 2014, Digestive Diseases.

[139]  A. Wree,et al.  Caspase 3 Inactivation Protects Against Hepatic Cell Death and Ameliorates Fibrogenesis in a Diet-Induced NASH Model , 2014, Digestive Diseases and Sciences.

[140]  Matthew E. Welsch,et al.  Regulation of Ferroptotic Cancer Cell Death by GPX4 , 2014, Cell.

[141]  Eric H. Baehrecke,et al.  Self-consumption: the interplay of autophagy and apoptosis , 2014, Nature Reviews Molecular Cell Biology.

[142]  Mitchell R. McGill,et al.  Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen‐induced hepatocyte necrosis in mice , 2013, Hepatology.

[143]  Yuji Ogawa,et al.  Rodent Models of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis , 2013, International journal of molecular sciences.

[144]  Fan Wang,et al.  Protective Effects of Necrostatin-1 against Concanavalin A-Induced Acute Hepatic Injury in Mice , 2013, Mediators of inflammation.

[145]  A. Strasser,et al.  The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. , 2013, Immunity.

[146]  K. Kodys,et al.  STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease , 2013, Proceedings of the National Academy of Sciences.

[147]  Hartmut Jaeschke,et al.  Zonated induction of autophagy and mitochondrial spheroids limits acetaminophen-induced necrosis in the liver☆ , 2013, Redox biology.

[148]  E. Seki,et al.  Toll‐like receptors in alcoholic liver disease, non‐alcoholic steatohepatitis and carcinogenesis , 2013, Journal of gastroenterology and hepatology.

[149]  K. Stacey,et al.  Inflammasome-mediated pyroptotic and apoptotic cell death, and defense against infection. , 2013, Current opinion in microbiology.

[150]  C. Trautwein,et al.  Hepatocyte caspase‐8 is an essential modulator of steatohepatitis in rodents , 2013, Hepatology.

[151]  Xiuli Liu,et al.  Absence of receptor interacting protein kinase 3 prevents ethanol‐induced liver injury , 2013, Hepatology.

[152]  X. Chen,et al.  Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. , 2013, Journal of hepatology.

[153]  C. Hagedorn,et al.  IL-1β Production through the NLRP3 Inflammasome by Hepatic Macrophages Links Hepatitis C Virus Infection with Liver Inflammation and Disease , 2013, PLoS pathogens.

[154]  V. Giorgio,et al.  Dimers of mitochondrial ATP synthase form the permeability transition pore , 2013, Proceedings of the National Academy of Sciences.

[155]  Yoshinori Otsuki,et al.  Elevated autophagic sequestration of mitochondria and lipid droplets in steatotic hepatocytes of chronic ethanol-treated rats: an immunohistochemical and electron microscopic study , 2013, Journal of Molecular Histology.

[156]  A. Jaeschke,et al.  Critical Role for Mixed-Lineage Kinase 3 in Acetaminophen-Induced Hepatotoxicity , 2012, Molecular Pharmacology.

[157]  P. Vandenabeele,et al.  Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models , 2012, Cell Death and Disease.

[158]  K. Kodys,et al.  IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. , 2012, The Journal of clinical investigation.

[159]  P. Vandenabeele,et al.  TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation , 2012, Cell Death and Differentiation.

[160]  A. Feldstein,et al.  Inhibition of apoptosis protects mice from ethanol-mediated acceleration of early markers of CCl4 -induced fibrosis but not steatosis or inflammation. , 2012, Alcoholism, clinical and experimental research.

[161]  S. Khaliq,et al.  Dual behavior of HCV Core gene in regulation of apoptosis is important in progression of HCC. , 2012, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[162]  R. Levine,et al.  A phase 2, randomized, double‐blind, placebo‐controlled study of GS‐9450 in subjects with nonalcoholic steatohepatitis , 2012, Hepatology.

[163]  Xiaodong Wang,et al.  Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase , 2012, Cell.

[164]  Richard A. Flavell,et al.  Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity , 2012, Nature.

[165]  H. Jaeschke,et al.  Activation of autophagy protects against acetaminophen‐induced hepatotoxicity , 2012, Hepatology.

[166]  R. Xavier,et al.  CASPASE 8 inhibits programmed necrosis by processing CYLD , 2011, Nature Cell Biology.

[167]  A. Feldstein,et al.  Identification of a Cytochrome P4502E1/Bid/C1q-dependent Axis Mediating Inflammation in Adipose Tissue after Chronic Ethanol Feeding to Mice* , 2011, The Journal of Biological Chemistry.

[168]  H. Jaeschke,et al.  Apoptosis-inducing factor modulates mitochondrial oxidant stress in acetaminophen hepatotoxicity. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[169]  R A Knight,et al.  Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 , 2011, Cell Death and Differentiation.

[170]  L. Pohl,et al.  Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead to confounding results as it did in studies of JNK2 in acetaminophen and concanavalin A liver injury. , 2011, Chemical research in toxicology.

[171]  A. Dolganiuc,et al.  Mitochondrial antiviral signaling protein defect links impaired antiviral response and liver injury in steatohepatitis in mice , 2011, Hepatology.

[172]  Dominic P. Williams,et al.  Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury. , 2011, Toxicology and applied pharmacology.

[173]  N. Kaplowitz,et al.  The contribution of endoplasmic reticulum stress to liver diseases , 2011, Hepatology.

[174]  Anthony W. Purcell,et al.  Linear ubiquitination prevents inflammation and regulates immune signalling , 2011, Nature.

[175]  L. N. Valenti,et al.  Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling--a propensity score-adjusted observational study. , 2011, QJM : monthly journal of the Association of Physicians.

[176]  James E. Nelson,et al.  Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease , 2011, Hepatology.

[177]  David C. Jones,et al.  Hyponatremia in patients with acute variceal bleeding treated with terlipressin , 2011, Hepatology.

[178]  H. Jaeschke,et al.  Cyclophilin D deficiency protects against acetaminophen-induced oxidant stress and liver injury , 2011, Free radical research.

[179]  M. Saleh,et al.  The Inflammasomes: Molecular Effectors of Host Resistance Against Bacterial, Viral, Parasitic, and Fungal Infections , 2010, Front. Microbio..

[180]  D. Stolz,et al.  Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. , 2010, Gastroenterology.

[181]  J. Maher,et al.  Stress signaling in the methionine-choline-deficient model of murine fatty liver disease. , 2010, Gastroenterology.

[182]  G. Kroemer,et al.  Autophagy and the integrated stress response. , 2010, Molecular cell.

[183]  P. Vandenabeele,et al.  Molecular mechanisms of necroptosis: an ordered cellular explosion , 2010, Nature Reviews Molecular Cell Biology.

[184]  H. Jaeschke,et al.  Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury. , 2010, Toxicology and applied pharmacology.

[185]  H. Thomas,et al.  Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. , 2010, Journal of hepatology.

[186]  Bin Hu,et al.  CXC receptor‐2 knockout genotype increases X‐linked inhibitor of apoptosis protein and protects mice from acetaminophen hepatotoxicity , 2010, Hepatology.

[187]  T. Asselah,et al.  In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C , 2010, The Journal of pathology.

[188]  Elena Bisetto,et al.  Cyclophilin D in mitochondrial pathophysiology. , 2010, Biochimica et biophysica acta.

[189]  B. Neuschwander‐Tetri,et al.  Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. , 2010, The New England journal of medicine.

[190]  E. Schiff,et al.  Clinical trial: the efficacy and safety of oral PF‐03491390, a pancaspase inhibitor – a randomized placebo‐controlled study in patients with chronic hepatitis C , 2010, Alimentary pharmacology & therapeutics.

[191]  G. Gores,et al.  Mechanisms and clinical implications of hepatocyte lipoapoptosis , 2010, Clinical lipidology.

[192]  N. Kaplowitz,et al.  Silencing Glycogen Synthase Kinase-3β Inhibits Acetaminophen Hepatotoxicity and Attenuates JNK Activation and Loss of Glutamate Cysteine Ligase and Myeloid Cell Leukemia Sequence 1* , 2010, The Journal of Biological Chemistry.

[193]  Vanessa S Teaberry,et al.  Pan‐caspase inhibitor VX‐166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis , 2009, Hepatology.

[194]  F. Sutterwala,et al.  Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. , 2009, The Journal of clinical investigation.

[195]  T. Vanden Berghe,et al.  Targeted Peptidecentric Proteomics Reveals Caspase-7 as a Substrate of the Caspase-1 Inflammasomes *S , 2008, Molecular & Cellular Proteomics.

[196]  M. Karin,et al.  Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation. , 2008, Gastroenterology.

[197]  Y. Nakanuma,et al.  Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease , 2008, Proceedings of the National Academy of Sciences.

[198]  Neil Kaplowitz,et al.  Role of JNK Translocation to Mitochondria Leading to Inhibition of Mitochondria Bioenergetics in Acetaminophen-induced Liver Injury* , 2008, Journal of Biological Chemistry.

[199]  G. Gores,et al.  Cellular and molecular mechanisms of liver injury. , 2008, Gastroenterology.

[200]  M. Manns,et al.  Caspase activation is associated with spontaneous recovery from acute liver failure , 2008, Hepatology.

[201]  Alexei Degterev,et al.  Identification of RIP1 kinase as a specific cellular target of necrostatins. , 2008, Nature chemical biology.

[202]  Xiao-Ming Yin,et al.  Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome , 2008, Autophagy.

[203]  D. Klionsky,et al.  Autophagosome formation: core machinery and adaptations , 2007, Nature Cell Biology.

[204]  P. Adegboyega,et al.  Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. , 2007, Journal of hepatology.

[205]  David Hecht,et al.  Oral IDN‐6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C , 2007, Hepatology.

[206]  Y. Takei,et al.  Role of apoptosis in acetaminophen hepatotoxicity , 2007, Journal of gastroenterology and hepatology.

[207]  G. Salvesen,et al.  The apoptosome: signalling platform of cell death , 2007, Nature Reviews Molecular Cell Biology.

[208]  W. Yeh,et al.  Ubiquitination of RIP1 Regulates an NF-κB-Independent Cell-Death Switch in TNF Signaling , 2007, Current Biology.

[209]  H. Jaeschke,et al.  Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[210]  N. Kaplowitz,et al.  c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. , 2006, Gastroenterology.

[211]  Y. Hsieh,et al.  HCV E2 may induce apoptosis of Huh-7 cells via a mitochondrial-related caspase pathway. , 2006, Biochemical and biophysical research communications.

[212]  H. Jaeschke,et al.  Role of caspases in acetaminophen-induced liver injury. , 2006, Life sciences.

[213]  H. S. Warren,et al.  Toll-like receptors. , 2005, Critical care medicine.

[214]  A. Degterev,et al.  Structure-activity relationship study of novel necroptosis inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[215]  H. Jaeschke,et al.  Peroxynitrite-Induced Mitochondrial and Endonuclease-Mediated Nuclear DNA Damage in Acetaminophen Hepatotoxicity , 2005, Journal of Pharmacology and Experimental Therapeutics.

[216]  R. Mehrian-Shai,et al.  Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding. , 2005, Alcoholism, clinical and experimental research.

[217]  H. Jaeschke,et al.  Mitochondrial permeability transition in acetaminophen‐induced necrosis and apoptosis of cultured mouse hepatocytes , 2004, Hepatology.

[218]  P. Jansen,et al.  Tauroursodeoxycholic acid protects rat hepatocytes from bile acid‐induced apoptosis via activation of survival pathways , 2004, Hepatology.

[219]  P. Kremsner,et al.  Variations in the serum concentrations of soluble Fas and soluble Fas ligand in Vietnamese patients infected with hepatitis B virus , 2004, Journal of medical virology.

[220]  P. Broët,et al.  A double‐blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis , 2004, Hepatology.

[221]  H. Saito,et al.  Bax interacts with the voltage-dependent anion channel and mediates ethanol-induced apoptosis in rat hepatocytes. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[222]  G. Gores,et al.  The Caspase Inhibitor IDN-6556 Attenuates Hepatic Injury and Fibrosis in the Bile Duct Ligated Mouse , 2004, Journal of Pharmacology and Experimental Therapeutics.

[223]  M. Singer,et al.  Hepatitis B core antigen is a potent inductor of interleukin‐18 in peripheral blood mononuclear cells of healthy controls and patients with hepatitis B infection , 2003, Journal of medical virology.

[224]  J. Kountouras,et al.  Apoptosis in hepatitis C , 2003, Journal of viral hepatitis.

[225]  M. Crabtree,et al.  Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury: roles of cytochrome c, Bax, Bid, and caspases. , 2003, Toxicology and applied pharmacology.

[226]  G. Gores,et al.  Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. , 2003, Gastroenterology.

[227]  N. Kaplowitz,et al.  Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. , 2003, Gastroenterology.

[228]  Y. J. Kang,et al.  Suppression of Fas-Mediated Signaling Pathway is Involved in Zinc Inhibition of Ethanol-Induced Liver Apoptosis , 2003, Experimental biology and medicine.

[229]  A. Costantino,et al.  Expression of HCV E1 Protein in Baculovirus-Infected Cells: Effects on Cell Viability and Apoptosis Induction , 2003, Intervirology.

[230]  C. Trautwein,et al.  Involvement of TRAIL and its receptors in viral hepatitis , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[231]  H. Jaeschke,et al.  Acetaminophen-induced inhibition of Fas receptor-mediated liver cell apoptosis: mitochondrial dysfunction versus glutathione depletion. , 2002, Toxicology and applied pharmacology.

[232]  B. Fromenty,et al.  Effects of alcohol and oxidative stress on liver pathology: the role of the mitochondrion. , 2002, Alcoholism, clinical and experimental research.

[233]  G. Gores,et al.  Bile acid-mediated hepatocyte apoptosis and cholestatic liver disease. , 2002, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[234]  E. Zuckerman,et al.  Enhanced peripheral T-cell apoptosis in chronic hepatitis C virus infection: association with liver disease severity. , 2001, Journal of hepatology.

[235]  D. Gibellini,et al.  A new route to apoptosis in hepatitis C virus infection. , 2001, Journal of hepatology.

[236]  M. Vail,et al.  Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2. , 2001, Molecular pharmacology.

[237]  C. Poremba,et al.  Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infection , 2001, Hepatology.

[238]  R. Nepomuceno,et al.  Apoptotic pathways in primary biliary cirrhosis and autoimmune hepatitis. , 2001, Liver.

[239]  G. Gores,et al.  Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis. , 2001, Journal of hepatology.

[240]  M. Manns,et al.  Tumor necrosis factor α in the pathogenesis of human and murine fulminant hepatic failure , 2000 .

[241]  Y. Shiratori,et al.  Activation of intracellular signaling by hepatitis B and C viruses: C‐viral core is the most potent signal inducer , 2000, Hepatology.

[242]  M. Lai.  Hepatitis viruses and signal transduction: True to the core? , 2000, Hepatology.

[243]  M. Lorenzi,et al.  The RIP‐like kinase, RIP3, induces apoptosis and NF‐κB nuclear translocation and localizes to mitochondria , 2000, FEBS letters.

[244]  Kenichi Kobayashi,et al.  Fas ligand expressing mononuclear cells around intrahepatic bile ducts co-express CD68 in primary biliary cirrhosis. , 2000, Liver.

[245]  T. Yen.  Nuclear factor κB and hepatitis C—is there a connection? , 2000 .

[246]  A. Wendel,et al.  Concanavalin A hepatotoxicity in mice: Tumor necrosis factor–mediated organ failure independent of caspase‐3–like protease activation , 1999, Hepatology.

[247]  G. Gores,et al.  Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas. , 1999, Gastroenterology.

[248]  V. Dixit,et al.  RIP3, a Novel Apoptosis-inducing Kinase* , 1999, The Journal of Biological Chemistry.

[249]  D. Kusewitt,et al.  Deferoxamine delays the development of the hepatotoxicity of acetaminophen in mice. , 1999, Toxicology letters.

[250]  W. Fiers,et al.  Inhibition of Caspases Increases the Sensitivity of L929 Cells to Necrosis Mediated by Tumor Necrosis Factor , 1998, The Journal of experimental medicine.

[251]  M. Manns,et al.  Concanavalin A-induced liver cell damage: activation of intracellular pathways triggered by tumor necrosis factor in mice. , 1998, Gastroenterology.

[252]  F. Capron,et al.  Plasma levels of soluble tumor necrosis factor receptors p55 and p75 in patients with alcoholic liver disease of increasing severity. , 1998, Journal of hepatology.

[253]  Y. Nakanuma,et al.  Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis , 1997, Hepatology.

[254]  K. Kharbanda,et al.  Flow cytometric analysis of vesicular pH in rat hepatocytes after ethanol administration , 1997, Hepatology.

[255]  Xiaolin Wang,et al.  In situ investigation of Fas/FasL expression in chronic hepatitis B infection and related liver diseases , 1997, Journal of viral hepatitis.

[256]  P. Nicotera,et al.  Intracellular Adenosine Triphosphate (ATP) Concentration: A Switch in the Decision Between Apoptosis and Necrosis , 1997, The Journal of experimental medicine.

[257]  P. Galle,et al.  Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage , 1995, The Journal of experimental medicine.

[258]  N. Hayashi,et al.  Role of Fas ligand in apoptosis induced by hepatitis C virus infection. , 1994, Biochemical and biophysical research communications.

[259]  T. Myers,et al.  Hepatic protein arylation, glutathione depletion, and metabolite profiles of acetaminophen and a non-hepatotoxic regioisomer, 3'-hydroxyacetanilide, in the mouse. , 1990, Drug metabolism and disposition: the biological fate of chemicals.

[260]  N. Pumford,et al.  Immunoblot analysis of protein containing 3-(cystein-S-yl)acetaminophen adducts in serum and subcellular liver fractions from acetaminophen-treated mice. , 1990, Toxicology and applied pharmacology.

[261]  M. Tirmenstein,et al.  Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3'-hydroxyacetanilide, in mouse liver. , 1989, The Journal of biological chemistry.

[262]  Y. Park,et al.  Prevention of acetaminophen-induced hepatotoxicity by dimethyl sulfoxide. , 1988, Toxicology.

[263]  B. Rumack,et al.  Treating acute acetaminophen poisoning with acetylcysteine. , 1977, JAMA.

[264]  B B Brodie,et al.  Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. , 1973, The Journal of pharmacology and experimental therapeutics.

[265]  Bumseok Kim,et al.  Ferroptosis affects the progression of non-alcoholic steatohepatitis via the modulation of lipid peroxidation-mediated cell death in mice. , 2019, The American journal of pathology.

[266]  Andrea Iorga,et al.  Cell death in drug-induced liver injury. , 2019, Advances in pharmacology.

[267]  H. Jaeschke,et al.  Acetaminophen Toxicity: Novel Insights Into Mechanisms and Future Perspectives. , 2018, Gene expression.

[268]  S-C Sun.  CYLD: a tumor suppressor deubiquitinase regulating NF-κB activation and diverse biological processes , 2010, Cell Death and Differentiation.

[269]  Michael P Holt,et al.  Drug-induced liver injury. , 2010, Handbook of experimental pharmacology.

[270]  P. Murray,et al.  Apoptosis-related proteins, BCL-2, BAX, FAS, FAS-L and PCNA in liver biopsies of patients with chronic hepatitis B virus infection , 2009, Pathology & Oncology Research.

[271]  William M. Lee,et al.  LIVER FAILURE AND LIVER DISEASE LIVER FAILURE Acetaminophen-Induced Acute Liver Failure: Results of a United States Multicenter, Prospective Study , 2005 .

[272]  Toshiharu Horie,et al.  Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice. , 2005, Journal of hepatology.

[273]  G. Gores,et al.  Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. , 1999, The Journal of clinical investigation.

[274]  M. Lai,et al.  Apoptosis and Viral Hepatitis , 1998, Seminars in liver disease.

[275]  S. Thorgeirsson,et al.  Acetaminophen-induced hepatic necrosis. VI. Metabolic disposition of toxic and nontoxic doses of acetaminophen. , 1974, Pharmacology.