Apoptosis in nonalcoholic fatty liver disease: Diagnostic and therapeutic implications

Expert Review of Gastroenterology and Hepatology

Volumn 5, Issue 2, 2011, Pages 201-212

  Alkhouri, Naim ^a   Carter Kent, Christine ^a   Feldstein, Ariel E ^a,b  

^a LERNER RESEARCH INSTITUTE   (United States)

^b CASE WESTERN RESERVE UNIVERSITY   (United States)

Author keywords

apoptosis; caspase inhibitor; cell death; cytokeratin 18; fibrosis; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis

Indexed keywords

APOPTOTIC PROTEASE ACTIVATING FACTOR 1; CASPASE 3; CASPASE 6; CASPASE 7; CASPASE 9; CATHEPSIN B; CATHEPSIN B INHIBITOR; CYTOKERATIN 18; DEATH RECEPTOR; DEATH RECEPTOR 5; EMRICASAN; ENZYME INHIBITOR; ETANERCEPT; FATTY ACID TRANSPORTER; GS 9450; MATRIX METALLOPROTEINASE; PENTOXIFYLLINE; PF 03491390; PLACEBO; PROTEIN BCL 2; PROTEIN BCL XL; PROTEIN MCL 1; R 3020; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 2; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR RECEPTOR 1; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND RECEPTOR; UNCLASSIFIED DRUG; VBY 376; VX 166;

ALCOHOL LIVER DISEASE; APOPTOSIS; CELL DEATH; DISEASE SEVERITY; DRUG METABOLISM; DRUG POTENCY; ENDOPLASMIC RETICULUM STRESS; ENZYME ACTIVATION; FIBROGENESIS; GASTROINTESTINAL SYMPTOM; HEPATITIS C; HUMAN; INTRAABDOMINAL FAT; LIPOTOXICITY; LIVER BIOPSY; LIVER CELL; LIVER DISEASE; LIVER INJURY; LYSOSOME; MEMBRANE DEPOLARIZATION; MITOCHONDRION; MOLECULAR DYNAMICS; NAUSEA; NONALCOHOLIC FATTY LIVER; NONHUMAN; PATHOGENESIS; PHAGOCYTOSIS; PROTEIN CLEAVAGE; PROTEIN FUNCTION; PROTEIN GLYCOSYLATION; REVIEW; SIGNAL TRANSDUCTION; UPREGULATION;

ADIPOCYTES; ANIMALS; APOPTOSIS; FATTY LIVER; HUMANS; INSULIN RESISTANCE; INTRA-ABDOMINAL FAT; LIVER; LIVER CIRRHOSIS; LYSOSOMES; MALE; MICE; MITOCHONDRIA, LIVER; RATS;

EID: 79954514102     PISSN: 17474124     EISSN: None     Source Type: Journal    
DOI: 10.1586/egh.11.6     Document Type: Review

References (123)

1. Angulo P. Nonalcoholic fatty liver disease. N Engl. J. Med. 346, 1221-1231 (2002).
2. Wieckowska A, Feldstein AE. Nonalcoholic fatty liver disease in the pediatric population: a review. Curr. Opin. Pediatr. 17, 636-641 (2005). (Pubitemid 41406127)
3. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity Gastroenterology 116, 1413-1419 (1999). (Pubitemid 29258890)
4. Harrison SA, Neuschwander-Tetri BA. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Clin. Liver Dis. 8, 861-879, ix (2004). (Pubitemid 39311147)
5. Delhalle S, Duvoix A, Schnekenburger M, Morceau F, Dicato M, Diederich M. An introduction to the molecular mechanisms of apoptosis. Ann. NY Acad. Sci. 1010, 1-8 (2003). (Pubitemid 38264943)
6. Yuan J, Horvitz HR. A frst insight into the molecular mechanisms of apoptosis. Cell 116, S53-S56 (2004).
7. Riedl SJ, Shi Y Molecular mechanisms of caspase regulation during apoptosis. Nat Rev. Mol. Cell Biol. 5, 897-907 (2004). (Pubitemid 39486541)
8. Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev. Cancer 2, 647-656 (2002). (Pubitemid 37328916)
9. Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22, 8590-8607 (2003). (Pubitemid 38028528)
10. Antonsson B, Montessuit S, Sanchez B, Martinou JC. Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. J. Biol. Chem. 276, 11615-11623 (2001).
11. Nechushtan A, Smith CL, Lamensdorf I, Yoon SH, Youle RJ. Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J. Cell Biol. 153, 1265-1276 (2001). (Pubitemid 34289264)
12. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94, 481-490 (1998). (Pubitemid 28391864)
13. 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. 153, 999-1010 (2001).
14. Guicciardi ME, Deussing J, Miyoshi H et al. Cathepsin B contributes to TNF-α-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c J. Clin. Invest 106, 1127-1137 (2000).
15. Guicciardi ME, Bronk SF, Werneburg NW, Gores GJ. cFLIPL prevents TRAIL-induced apoptosis of hepatocellular carcinoma cells by inhibiting the lysosomal pathway of apoptosis. Am. J. Physiol. Gastrointest Liver Physiol. 292, G1337-G1346 (2007). (Pubitemid 47084667)
16. Kahraman A, Barreyro FJ, Bronk SF et al. TRAIL mediates liver injury by the innate immune system in the bile duct-ligated mouse. Hepatology 47, 1317-1330 (2008). (Pubitemid 351547918)
17. Stoka V, Turk B, Schendel SL, Kim TH et al. Lysosomal protease pathways to apoptosis. Cleavage of bid, not pro-caspases, is the most likely route. J. Biol. Chem. 276, 3149-3157 (2001).
18. Lemasters JJ. Dying a thousand deaths: redundant pathways from different organelles to apoptosis and necrosis. Gastroenterology 129, 351-360 (2005). (Pubitemid 41002067)
19. Liu CY, Kaufman RJ. The unfolded protein response. J. Cell Sci. 116, 1861-1862 (2003). (Pubitemid 36622284)
20. Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ. 11, 372-380 (2004). (Pubitemid 38489415)
21. Feldstein AE, Gores GJ. Apoptosis in alcoholic and nonalcoholic steatohepatitis. Front Biosci. 10, 3093-3099 (2005). (Pubitemid 40910547)
22. Green DR. Apoptotic pathways: ten minutes to dead. Cell 121, 671-674 (2005). (Pubitemid 40797590)
23. Guicciardi ME, Gores GJ. Apoptosis: a mechanism of acute and chronic liver injury. Gut 54, 1024-1033 (2005). (Pubitemid 40873921)
24. Malhi H, Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology 134, 1641-1654 (2008). (Pubitemid 351615416)
25. Patel T, Steer CJ, Gores GJ. Apoptosis and the liver: a mechanism of disease, growth regulation, and carcinogenesis. Hepatology 30, 811-815 (1999). (Pubitemid 29409429)
26. Rust C, Gores GJ. Apoptosis and liver disease. Am. J. Med. 108, 567-574 (2000). (Pubitemid 30249035)
27. Bataller R, Brenner DA. Liver fbrosis. J. Clin. Invest. 115, 209-218 (2005).
28. Friedman SL. Liver fbrosis-from bench to bedside. J. Hepatol. 38(Suppl. 1), S38-S53 (2003).
29. Canbay A, Friedman S, Gores GJ. Apoptosis: the nexus of liver injury and fbrosis. Hepatology 39, 273-278 (2004). (Pubitemid 38222163)
30. Canbay A, Feldstein A, Baskin-Bey E, Bronk SF, Gores GJ. The caspase inhibitor IDN-6556 attenuates hepatic injury and fbrosis in the bile duct ligated mouse. J. Pharmacol. Exp. Ther. 308, 1191-1196 (2004). (Pubitemid 38263997)
31. Canbay A, Guicciardi ME, Higuchi H et al. Cathepsin B inactivation attenuates hepatic injury and fbrosis during cholestasis. J. Clin. Invest. 112, 152-159 (2003). (Pubitemid 38056351)
32. Canbay A, Higuchi H, Bronk SF, Taniai M, Sebo TJ, Gores GJ. Fas enhances fbrogenesis in the bile duct ligated mouse: a link between apoptosis and fbrosis. Gastroenterology 123, 1323-1330 (2002).
33. Takehara T, Tatsumi T, Suzuki T et al. Hepatocyte-specifc disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fbrotic responses. Gastroenterology 127, 1189-1197 (2004). (Pubitemid 39345887)
34. Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profbrogenic. Lab. Invest. 83, 655-663 (2003). (Pubitemid 36618044)
35. Jiang JX, Venugopal S, Serizawa N et al. Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fbrogenesis in vivo. Gastroenterology 139, 1375-1384.
36. Watanabe A, Hashmi A, Gomes DA et al. Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via Toll-like receptor 9. Hepatology 46, 1509-1518 (2007). (Pubitemid 350155533)
37. Malhi H, Guicciardi ME, Gores GJ. Hepatocyte death: a clear and present danger. Physiol. Rev. 90, 1165-1194 (2010).
38. Kahraman A, Bronk SF, Cazanave S et al. Matrix met alloproteinase inhibitor, CTS-1027, attenuates liver injury and fbrosis in the bile duct-ligated mouse. Hepatol. Res. 39, 805-813 (2009).
39. Wielockx B, Lannoy K, Shapiro SD et al. Inhibition of matrix met alloproteinases blocks lethal hepatitis and apoptosis induced by tumor necrosis factor and allows safe antitumor therapy Nat Med. 7, 1202-1208 (2001). (Pubitemid 33063775)
40. McClain CJ, Barve S, Deaciuc I. Good fat/bad fat. Hepatology 45, 1343-1346 (2007). (Pubitemid 46918317)
41. Yamaguchi K, Yang L, McCall S et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fbrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45, 1366-1374 (2007). (Pubitemid 46918320)
42. Nolan CJ, Larter CZ. Lipotoxicity: why do saturated fatty acids cause and monounsaturates protect against it? J. Gastroenterol. Hepatol. 24, 703-706 (2009).
43. Li ZZ, Berk M, McIntyre TM, Feldstein AE. Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-CoA desaturase. J. Biol. Chem. 284, 5637-5644 (2009).
44. Bechmann LP, Gieseler RK, Sowa JP et al. Apoptosis is associated with CD36/fatty acid translocase upregulation in non-alcoholic steatohepatitis. Liver Int. 30, 850-859 (2010).
45. Akazawa Y, Gores GJ. Death receptor-mediated liver injury Semin. Liver Dis. 27, 327-338 (2007). (Pubitemid 350071834)
46. Peter ME, Krammer PH. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ. 10, 26-35 (2003). (Pubitemid 36511830)
47. Baskin-Bey ES, Gores GJ. Death by association: BH3 domain-only proteins and liver injury Am. J. Physiol. Gastrointest. Liver Physiol. 289, G987-G990 (2005). (Pubitemid 41740601)
48. Scaffdi C, Fulda S, Srinivasan A et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 17, 1675-1687 (1998). (Pubitemid 28119121)
49. Feldstein AE, Canbay A, Angulo P et al. Hepatocyte apoptosis and Fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125, 437-443 (2003). (Pubitemid 36929425)
50. Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J. Hepatol. 39, 978-983 (2003). (Pubitemid 37523769)
51. Zou C, Ma J, Wang X et al. Lack of Fas antagonism by Met in human fatty liver disease. Nat Med. 13, 1078-1085 (2007). (Pubitemid 47517506)
52. Ding WX, Yin XM. Dissection of the multiple mechanisms of TNF-α-induced apoptosis in liver injury. J. Cell Mol. Med. 8, 445-454 (2004).
53. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181-190 (2003). (Pubitemid 36936912)
54. Crespo J, Cayon A, Fernandez-Gil P et al. Gene expression of tumor necrosis factor α and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34, 1158-1163 (2001). (Pubitemid 33096588)
55. Ribeiro PS, Cortez-Pinto H, Sola S et al. Hepatocyte apoptosis, expression of death receptors, and activation of NF-κB in the liver of nonalcoholic and alcoholic steatohepatitis patients. Am. J. Gastroenterol. 99, 1708-1717 (2004). (Pubitemid 39237497)
56. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-α or adiponectin? Hepatology 40, 46-54 (2004). (Pubitemid 38868922)
57. Li Z, Yang S, Lin H et al. Probiotics and antibodies to TNF inhibit infammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37, 343-350 (2003). (Pubitemid 36152533)
58. Feldstein AE, Werneburg NW, Canbay A et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway Hepatology 40, 185-194 (2004). (Pubitemid 38868937)
59. Mari M, Caballero F, Colell A et al. Mitochondrial free cholesterol loading sensitizes to TNF-and Fas-mediated steatohepatitis. Cell Metab. 4, 185-198 (2006). (Pubitemid 44307975)
60. MacFarlane M. TRAIL-induced signalling and apoptosis. Toxicol. Lett 139, 89-97 (2003). (Pubitemid 36298966)
61. Sadarangani A, Kato S, Espinoza N et al. TRAIL mediates apoptosis in cancerous but not normal primary cultured cells of the human reproductive tract. Apoptosis 12, 73-85 (2007). (Pubitemid 46009505)
62. Malhi H, Barreyro FJ, Isomoto H, Bronk SF, Gores GJ. Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity Gut 56, 1124-1131 (2007). (Pubitemid 47123245)
63. Caldwell SH, Chang CY, Nakamoto RK, Krugner-Higby L. Mitochondria in nonalcoholic fatty liver disease. Clin. Liver Dis. 8, 595-617, x (2004). (Pubitemid 39141145)
64. Fromenty B, Robin MA, Igoudjil A, Mansouri A, Pessayre D. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab. 30, 121-138 (2004). (Pubitemid 38715168)
65. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest 114, 147-152 (2004). (Pubitemid 39071617)
66. Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J. Biol. Chem. 281, 12093-12101 (2006). (Pubitemid 43855473)
67. Barreyro FJ, Kobayashi S, Bronk SF, Werneburg NW, Malhi H, Gores GJ. Transcriptional regulation of Bim by FoxO3A mediates hepatocyte lipoapoptosis. J. Biol. Chem. 282, 27141-27154 (2007). (Pubitemid 47501972)
68. Cazanave SC, Mott JL, Elmi NA et al. JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis. J. Biol. Chem. 284, 26591-26602 (2009).
69. Masuoka HC, Mott J, Bronk SF et al. Mcl-1 degradation during hepatocyte lipoapoptosis. J. Biol. Chem. 284, 30039-30048 (2009).
70. Guicciardi ME, Leist M, Gores GJ. Lysosomes in cell death. Oncogene 23, 2881-2890 (2004). (Pubitemid 38638850)
71. Turk B, Bieth JG, Bjork I et al. Regulation of the activity of lysosomal cysteine proteinases by pH-induced inactivation and/or endogenous protein inhibitors, cystatins. Biol. Chem. Hoppe Seyler 376, 225-230 (1995).
72. Baskin-Bey ES, Canbay A, Bronk SF et al. Cathepsin B inactivation attenuates hepatocyte apoptosis and liver damage in steatotic livers after cold ischemia-warm reperfusion injury. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G396-G402 (2005). (Pubitemid 40129592)
73. Guicciardi ME, Miyoshi H, Bronk SF, Gores GJ. Cathepsin B knockout mice are resistant to tumor necrosis factor-alpha-mediated hepatocyte apoptosis and liver injury: implications for therapeutic applications. Am. J. Pathol. 159, 2045-2054 (2001). (Pubitemid 33104259)
74. Roberts LR, Adjei PN, Gores GJ. Cathepsins as effector proteases in hepatocyte apoptosis. Cell Biochem. Biophys. 30, 71-88 (1999). (Pubitemid 129646887)
75. Roberts LR, Kurosawa H, Bronk SF et al. Cathepsin B contributes to bile salt-induced apoptosis of rat hepatocytes. Gastroenterology 113, 1714-1726 (1997). (Pubitemid 27461261)
76. Zhao M, Antunes F, Eaton JW, Brunk UT. Lysosomal enzymes promote mitochondrial oxidant production, cytochrome c release and apoptosis. Eur. J. Biochem. 270, 3778-3786 (2003). (Pubitemid 37123249)
77. Boya P, Andreau K, Poncet D et al. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J. Exp. Med. 197, 1323-1334 (2003). (Pubitemid 36617779)
78. Feldstein AE, Werneburg NW, Li Z, Bronk SF, Gores GJ. Bax inhibition protects against free fatty acid-induced lysosomal permeabilization. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G1339-G1346 (2006). (Pubitemid 43788317)
79. Li Z, Berk M, McIntyre TM, Gores GJ, Feldstein AE. The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity Hepatology 47, 1495-1503 (2008). (Pubitemid 351702733)
80. Mao C, Dong D, Little E, Luo S, Lee AS. Transgenic mouse model for monitoring endoplasmic reticulum stress in vivo. Nat Med. 10, 1013-1014; author reply 1014 (2004). (Pubitemid 39424851)
81. Marciniak SJ, Yun CY, Oyadomari S et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18, 3066-3077 (2004). (Pubitemid 39658175)
82. Urano F, Wang X, Bertolotti A et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287, 664-666 (2000). (Pubitemid 30070916)
83. Wei Y, Wang D, Pagliassotti MJ. Saturated fatty acid-mediated endoplasmic reticulum stress and apoptosis are augmented by trans-10, cis-12-conjugated linoleic acid in liver cells. Mol. Cell Biochem. 303, 105-113 (2007). (Pubitemid 47261307)
84. Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am. J. Physiol. Endocrinol. Metab. 291, E275-E281 (2006). (Pubitemid 44035286)
85. Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 147, 943-951 (2006). (Pubitemid 43113013)
86. Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM, Sanyal AJ. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134, 568-576 (2008). (Pubitemid 351173040)
87. Wei Y, Wang D, Gentile CL, Pagliassotti MJ. Reduced endoplasmic reticulum luminal calcium links saturated fatty acid-mediated endoplasmic reticulum stress and cell death in liver cells. Mol. Cell Biochem. 331, 31-40 (2009).
88. Cazanave SC, Elmi NA, Akazawa Y, Bronk SF, Mott JL, Gores GJ. CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G236-G243 (2010).
89. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin. Liver Dis. 28, 370-379 (2008).
90. Wree A, Kahraman A, Gerken G, Canbay A. Obesity affects the liver-the link between adipocytes and hepatocytes. Digestion 83, 124-133 (2011).
91. Alkhouri N, Dixon LJ, Feldstein AE. Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. Expert Rev. Gastroenterol. Hepatol. 3, 445-451 (2009).
92. Neels JG, Olefsky JM. Infamed fat: what starts the fre? J. Clin. Invest 116, 33-35 (2006). (Pubitemid 43121788)
93. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest 112, 1796-1808 (2003). (Pubitemid 38063703)
94. Wellen KE, Hotamisligil GS. Infammation, stress, and diabetes. J. Clin. Invest 115, 1111-1119 (2005).
95. Alkhouri N, Gornicka A, Berk MP et al. Adipocyte apoptosis: a link between obesity, insulin resistance and hepatic steatosis. J. Biol. Chem. 285(5), 3428-3438 (2010).
96. Wueest S, Rapold RA, Schumann DM et al. Deletion of Fas in adipocytes relieves adipose tissue infammation and hepatic manifestations of obesity in mice. J. Clin. Invest 120, 191-202 (2010).
97. Caulin C, Salvesen GS, Oshima RG. Caspase cleavage of keratin 18 and reorganization of intermediate flaments during epithelial cell apoptosis. J. Cell Biol. 138, 1379-1394 (1997). (Pubitemid 27415063)
98. Ku NO, Liao J, Omary MB. Apoptosis generates stable fragments of human type I keratins. J. Biol. Chem. 272, 33197-33203 (1997). (Pubitemid 28023666)
99. Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 44, 27-33 (2006). (Pubitemid 44049136)
100. Anty R, Iannelli A, Patouraux S et al. A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients. Aliment Pharmacol. Ther. 32, 1315-1322 (2010).
101. Diab DL, Yerian L, Schauer P et al. Cytokeratin 18 fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis in bariatric surgery patients. Clin. Gastroenterol. Hepatol. 6, 1249-1254 (2008).
102. Fitzpatrick E, Mitry RR, Quaglia A, Hussain MJ, DeBruyne R, Dhawan A. Serum levels of CK18 M30 and leptin are useful predictors of steatohepatitis and fbrosis in paediatric NAFLD. J. Pediatr. Gastroenterol. Nutr. 51, 500-506 (2010).
103. Malik R, Chang M, Bhaskar K et al. The clinical utility of biomarkers and the nonalcoholic steatohepatitis CRN liver biopsy scoring system in patients with nonalcoholic fatty liver disease. J. Gastroenterol. Hepatol. 24, 564-568 (2009).
104. Yilmaz Y, Dolar E, Ulukaya E et al. Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis. World J. Gastroenterol. 13, 837-844 (2007). (Pubitemid 46470292)
105. Younossi ZM, Jarrar M, Nugent C et al. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes. Surg. 18, 1430-1437 (2008).
106. Musso G, Gambino R, Durazzo M, Cassader M. Noninvasive assessment of liver disease severity with liver fat score and CK-18 in NAFLD: prognostic value of liver fat equation goes beyond hepatic fat estimation. Hepatology 51, 715-717 (2010).
107. Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 50, 1072-1078 (2009).
108. Tamimi TA, Berk MP, Alkhouri N et al. An apoptosis panel for nonalcoholic steatohepatitis diagnosis. Gastroenterology 136, A89 (2009).
109. Yan X, Xu L, Qi J, Liang X et al. sTRAIL levels and TRAIL gene polymorphisms in Chinese patients with fatty liver disease. Immunogenetics 61, 551-556 (2009).
110. Holsinger L, Coakley D, Dener J, Green M, Booth R, Dalrymple S. Effcacy of a reversible cathepsin B inhibitor in a rodent model of liver fbrosis and human pharmacokinetic profle. Hepatology 52, 1128A (2010).
111. Wu X, Zhang L, Gurley E et al. Prevention of free fatty acid-induced hepatic lipotoxicity by 18ß-glycyrrhetinic acid through lysosomal and mitochondrial pathways. Hepatology 47, 1905-1915 (2008). (Pubitemid 351945558)
112. Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am. J. Gastroenterol. 99, 2365-2368 (2004). (Pubitemid 40039367)
113. Satapathy SK, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Benefcial effects of pentoxifylline on hepatic steatosis, fbrosis and necroinfammation in patients with non-alcoholic steatohepatitis. J. Gastroenterol. Hepatol. 22, 634-638 (2007). (Pubitemid 46608380)
114. Zein CO, Gogate P, Yerian L, Kirwan J, McCullough A. Pentoxifylline improves nonalcoholic steatohepatitis: results of a double-blinded, randomized, placebo-controlled trial. Am. J. Gastroenterol. 105, S114 (2010).
115. Boetticher NC, Peine CJ, Kwo P et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology 135, 1953-1960 (2008).
116. Valentino KL, Gutierrez M, Sanchez R, Winship MJ, Shapiro DA. First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes. Int. J. Clin. Pharmacol. Ther. 41, 441-449 (2003). (Pubitemid 37258860)
117. Dixon L, Berk M, Thapaliya S, Feldstein A. Caspase 1-mediated regulation of fbrogenesis in diet-induced steatohepatitis. Hepatology 52, A351 (2010).
118. Witek RP, Stone WC, Karaca FG et al. Pan-caspase inhibitor VX-166 reduces fbrosis in an animal model of nonalcoholic steatohepatitis. Hepatology 50, 1421-1430 (2009).
119. Anstee QM, Concas D, Kudo H et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J. Hepatol. 53, 542-550 (2010).
120. Pockros PJ, Schiff ER, Shiffman ML et al. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C Hepatology 46, 324-329 (2007). (Pubitemid 47344766)
121. Shiffman ML, Pockros P, McHutchison JG, Schiff ER, Morris M, Burgess G. Clinical trial: the effcacy and safety of oral PF-03491390, a pancaspase inhibitor - A randomized placebo-controlled study in patients with chronic hepatitis C Aliment. Pharmacol. Ther. 31, 969-978 (2010).
122. Barreyro F, Holod S, Finocchietto P et al. PF-03491390 Pan-caspase inhibitor decreases liver injury and fbrosis in a murine model of non-alcoholic steatohepatitis (NASH). J. Hepatol. 52, S303 (2010).
123. Ratziu V, Chojkier M, Sheikh M et al. Safety, tolerability and preliminary activity of GS-9450, a selective caspase inhibitor, in patients with non-alcoholic steatohepatitis (NASH). J. Hepatol. 52, S38 (2010).