Metabolic therapy: Lessons from liver diseases

Current Pharmaceutical Design

Volumn 17, Issue 35, 2011, Pages 3933-3944

  Garcia Ruiz, Carmen ^a,b   Marí, Montserrat ^a,b   Colell, Anna ^a,b   Morales, Albert ^a,b   Fernandez Checa, Jose C ^a,b,c  

^a INSTITUT D INVESTIGACIONS BIOMÈDIQUES AUGUST PI I SUNYER IDIBAPS   (Spain)

^b INST D INVESTIGACIONS B   (Spain)

^c UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

Cell death; Cholesterol; Mitochondria; Oxidative stress; Sphingolipids; Steatohepatitis

Indexed keywords

4 PHENYLBUTYRIC ACID; ALCOHOL; ALPHA TOCOPHEROL; ANTIOXIDANT; ASCORBIC ACID; ATORVASTATIN; CERAMIDE; CERAMIDE GLUCOSYLTRANSFERASE INHIBITOR; CHOLESTEROL; DESIPRAMINE; EZETIMIBE; FAS ANTIGEN; GLUTATHIONE ETHYL ESTER; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IMINOSUGAR N (5' ADAMANTAN 1' YL METHOXY) PENTYL 1 DEOXYNOJIRIMYCIN; IMIPRAMINE; ISOPRENOID; MEVINOLIN; PRAVASTATIN; S ADENOSYLMETHIONINE; SPHINGOLIPID; SPHINGOMYELIN PHOSPHODIESTERASE; SQUALENE SYNTHASE INHIBITOR; TAUROURSODEOXYCHOLIC ACID; THERMOZYMOCIDIN; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG; YM 53603;

ALCOHOLIC FATTY LIVER; ARTICLE; CELL MIGRATION; DISEASE COURSE; FIBROSIS; HOMEOSTASIS; HUMAN; INFLAMMATION; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIPID STORAGE; LIPOGENESIS; LIVER; LIVER NECROSIS; METABOLISM; MITOCHONDRION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; STEATOSIS;

EID: 83455203491     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161211798357700     Document Type: Article

References (129)

1. Tilg, H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. New Eng J medicine 2000; 343(20): p. 1467-76.
2. Day, CP, James OF. Steatohepatitis: a tale of two hits? Gastroenterology 1998; 114(4): p. 842-5.
3. Agulo P. Nonalcoholic fatty liver disease. New Eng J medicine 2002; 346(16): p. 1221-31.
4. 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 hepatology 2003; 39(6): p. 978-83.
5. Crespo J, Cayón A, Fernández-Gil P, et al., Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 2001; 34(6): p. 1158-63.
6. Iimuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 1997; 26(6): p. 1530-7.
7. Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 1999. 117(4): p. 942-52.
8. Lluis JM, Colell A, García-Ruiz C, Kaplowitz N, Fernández-Checa JC. Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress. Gastroenterology 2003; 124(3): p. 708-24.
9. Kaplowitz N, Than TA, Shinohara M, Ji C. Endoplasmic reticulum stress and liver injury. Seminars in liver disease 2007; 27(4): p. 367-77.
10. Browning, JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clinical Investigation 2004; 114(2): p. 147-52.
11. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J clinical Investigation 2002; 109(9): p. 1125-31.
12. Pessayre D, B Fromenty, NASH: a mitochondrial disease. J Hepatol 2005; 42(6): p. 928-40.
13. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990; 343(6257): p. 425-30.
14. Brown, MS, Goldstein JL. Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J lipid Res 1980. 21(5): p. 505-17.
15. Rawson RB, DeBose-Boyd R, Goldstein JL, Brown MS. Failure to cleave sterol regulatory element-binding proteins (SREBPs) causes cholesterol auxotrophy in Chinese hamster ovary cells with genetic absence of SREBP cleavage-activating protein. J Biological Chem 1999; 274(40): p. 28549-56.
16. Ji, C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 2003; 124(5): p. 1488-99.
17. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306(5695): p. 457-61.
18. Puri P, Mirshahi F, Cheung O, et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008; 134(2): p. 568-76.
19. Henkel AS, Elias MS, RM. Green, Homocysteine supplementation attenuates the unfolded protein response in a murine nutritional model of steatohepatitis. J Biological Chem 2009; 284(46): p. 31807-16.
20. Yang JS, Kim JT, Jeon J, et al. Changes in hepatic gene expression upon oral administration of taurine conjugated ursodeoxicoli acid in ob/ob mice. PLoS One 2010, e13858.
21. Colell A, Coll O, García-Ruiz C, et al. Tauroursodeoxycholic acid protects hepatocytes from ethanol-fed rats against tumor necrosis factor-induced cell death by replenishing mitochondrial glutathione. Hepatology 2001; 34 (5): p. 964-71.
22. Bruguera M, Bertran A, Bombi JA, Rodes J. Giant mitochondria in hepatocytes: a diagnostic hint for alcoholic liver disease. Gastroenterology 1977; 73(6): p. 1383-7.
23. Sleigh A, Raymond-Barker P, Thackray K, et al. Mitochondrial dysfunction in patients with primary congenital insulin resistance. J Clinical Investigation 2011; 121 (6):p.2457-61.
24. Castro J, Cortes JP, Guzman M. Properties of the mitochondrial membrane and carnitine palmitoyltransferase in the periportal and the perivenous zone of the liver. Effects of chronic ethanol feeding. Biochem Pharmacol 1991; 41(12): p. 1987-95.
25. Orellana-Gavaldà JM, Herrero L, Malandrino MI, et al. Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation. Hepatology 2011; 53(3): p. 821-32.
26. Feldstein AE, Werneburg NW, Canbay A, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 2004; 40(1): p. 185-94.
27. Borradaile NM, Han X, Harp JD, Gale SE, Ory DS, Schaffer JE. Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. J Lipid Research 2006; 47(12): p. 2726-37.
28. Srivastava S, Chan C. Hydrogen peroxide and hydroxyl radicals mediate palmitate-induced cytotoxicity to hepatoma cells: relation to mitochondrial permeability transition. Free Radical Res 2007; 41(1): p. 38-49.
29. Nakamura S, Takamura T, Matsuzawa-Nagata N, et al. Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. J Biological Chem 2009; 284(22): p. 14809-18.
30. Tomita K, Tamiya G, Ando S, et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 2006; 55(3): p. 415-24.
31. Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140(2): p. 197-208.
32. Boetticher NC, Peine CJ, Kwo P, et al. A randomized, doubleblinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology 2008; 135(6): p. 1953-60.
33. Sharma P, Kumar A, Sharma BC, Sarin SK. Infliximab monotherapy for severe alcoholic hepatitis and predictors of survival: an open label trial. J Hepatol 2009; 50(3): p. 584-91.
34. Hsu H, Shu HB, Pan MG, Goeddel DV. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 1996; 84(2): p. 299-308.
35. Kischkel FC, Hellbardt S, Behrmann I, et al. Cytotoxicitydependent APO-1 (Fas/CD95)-associated proteins form a deathinducing signaling complex (DISC) with the receptor. EMBO J 1995; 14(22): p. 5579-88.
36. Scaffidi C, Medema JP, Krammer PH, Peter ME. FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b. J Biological Chem 1997; 272(43): p. 26953-8.
37. Lee SY, Reichlin A, Santana A, Sokol KA, Nussenzweig MC, Choi Y. TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival. Immunity 1997; 7(5): p. 703-13.
38. Grech AP, Amesbury M, Chan T, Gardam S, Basten A, Brink R. TRAF2 differentially regulates the canonical and noncanonical pathways of NF-kappaB activation in mature B cells. Immunity 2004; 21(5): p. 629-42.
39. Harper N, Hughes M, MacFarlane M, Cohen GM. Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. J Biological Chem 2003; 278(28): p. 25534-41.
40. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003; 114(2): p. 181-90.
41. Scaffidi C, Fulda S, Srinivasan A, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1998; 17(6): p. 1675-87.
42. Degterev A, Hitomi J, Germscheid M, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 2008; 4(5): p. 313-21.
43. Temkin V, Huang Q, Liu H, Osada H, Pope RM. Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis. Molecular Cell Biology 2006; 26(6): p. 2215-25.
44. Maxfield FR, Tabas I. Role of cholesterol and lipid organization in disease. Nature 2005; 438(7068): p. 612-21.
45. Garcia-Ruiz C, Mari M, Colell A, et al. Mitochondrial cholesterol in health and disease. Histology Histopathol 2009; 24(1): p. 117-32.
46. Ikonen E. Cellular cholesterol trafficking and compartmentalization. Nature Rev Mol Cell Biol 2008; 9(2): p. 125-38.
47. Edwards PA, Ericsson J. Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway. Ann Rev Biochem 1999; 68: p. 157-85.
48. Brusselmans K, Timmermans L, Van de Sande T, et al. Squalene synthase, a determinant of Raft-associated cholesterol and modulator of cancer cell proliferation. J Biological Chem 2007; 282(26): p. 18777-85.
49. Gil G, Faust JR, Chin DJ, Goldstein JL, Brown MS. Membranebound domain of HMG CoA reductase is required for sterolenhanced degradation of the enzyme. Cell 1985; 41(1): p. 249-58.
50. Sever N, Yang T, Brown MS, Goldstein JL, DeBose-Boyd RA. Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol Cell 2003; 11(1): p. 25-33.
51. Song BL, Sever N, DeBose-Boyd RA. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Molecular Cell 2005; 19(6): p. 829-40.
52. Hughes AL, Todd BL, Espenshade PJ. SREBP pathway responds to sterols and functions as an oxygen sensor in fission yeast. Cell 2005; 120(6): p. 831-42.
53. Mukodani J, Ishikawa Y, Fukuzaki H. Effects of hypoxia on sterol synthesis, acyl-CoA:cholesterol acyltransferase activity, and efflux of cholesterol in cultured rabbit skin fibroblasts. Arteriosclerosis 1990; 10(1): p. 106-10.
54. Nguyen AD, McDonald JG, Bruick RK, DeBose-Boyd RA. Hypoxia stimulates degradation of 3-hydroxy-3-methylglutarylcoenzyme A reductase through accumulation of lanosterol and hypoxia-inducible factor-mediated induction of insigs. J Biological Chem 2007; 282(37): p. 27436-46.
55. Ji S, Lemasters JJ, Christenson V, Thurman RG. Periportal and pericentral pyridine nucleotide fluorescence from the surface of the perfused liver: evaluation of the hypothesis that chronic treatment with ethanol produces pericentral hypoxia. Proc Nat Acad Sci USA 1982; 79(17): p. 5415-9.
56. Braeuning A, Ittrich C, Köhle C, et al. Differential gene expression in periportal and perivenous mouse hepatocytes. FEBS J 2006; 273(22): p. 5051-61.
57. Baumann NA, Sullivan DP, Ohvo-Rekilä H, et al. Transport of newly synthesized sterol to the sterol-enriched plasma membrane occurs via nonvesicular equilibration. Biochemistry 2005; 44(15): p. 5816-26.
58. Cruz, JC, TY. Chang, Fate of endogenously synthesized cholesterol in Niemann-Pick type C1 cells. J Biological Chem 2000; 275(52): p. 41309-16.
59. Van Meer G. Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nature Review Molecular Cell Biology 2008; 9(2): p. 112-24.
60. Stocco DM. StARTing to understand cholesterol transfer. Nature Structural Biology 2000; 7(6): p. 445-7.
61. Stravitz RT, Vlahcevic ZR, Russell TL, Heizer ML, Avadhani NG, Hylemon PB. Regulation of sterol 27-hydroxylase and an alternative pathway of bile acid biosynthesis in primary cultures of rat hepatocytes. J Steroids Biochemistry Molecular Biology 1996; 57(5-6): p. 337-47.
62. Hall EA, Ren S, Hylemon PB, et al. Detection of the steroidogenic acute regulatory protein, StAR, in human liver cells. Biochimica Biophysica Acta 2005; 1733(2-3): p. 111-9.
63. Colell A, García-Ruiz C, Lluis JM, Coll O, Mari M, Fernández- Checa JC. Cholesterol impairs the adenine nucleotide translocatormediated mitochondrial permeability transition through altered membrane fluidity. J Biological Chem 2003; 278(36): p. 33928-35.
64. Fernandez-Checa JC, Kaplowitz N. Hepatic mitochondrial glutathione: transport and role in disease and toxicity. Toxicology Applied Pharmacology 2005; 204(3): p. 263-73.
65. Rouslin W, MacGee J, Gupte S, Wesselman A, Epps DE. Mitochondrial cholesterol content and membrane properties in porcine myocardial ischemia. American J Physiology 1982; 242(2): p. H254-9.
66. Yu W, Gong JS, Ko M, Garver WS, Yanagisawa K, Michikawa M. Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function. J Biological Chem 2005; 280(12): p. 11731-9.
67. Marí M, Caballero F, Colell A, et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metabolism 2006; 4(3): p. 185-98.
68. Colell A, García-Ruiz C, Miranda M, et al. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology 1998; 115(6): p. 1541-51.
69. Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G. Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption. Gastroenterology 2004; 126(5): p. 1387-99.
70. Pastorino JG, Hoek JB. Ethanol potentiates tumor necrosis factoralpha cytotoxicity in hepatoma cells and primary rat hepatocytes by promoting induction of the mitochondrial permeability transition. Hepatology 2000; 31(5): p. 1141-52.
71. Shulga, N. JB. Hoek, JG. Pastorino, Elevated PTEN levels account for the increased sensitivity of ethanol-exposed cells to tumor necrosis factor-induced cytotoxicity. J Biological Chemistry 2005; 280(10): p. 9416-24.
72. Colell A, García-Ruiz C, Morales A, et al. Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanoltreated rats: effect of membrane physical properties and S-adenosyl- L-methionine. Hepatology 1997; 26(3): p. 699-708.
73. Coll O, Colell A, García-Ruiz C, Kaplowitz N, Fernández-Checa JC. Sensitivity of the 2-oxoglutarate carrier to alcohol intake contributes to mitochondrial glutathione depletion. Hepatology 2003; 38(3): p. 692-702.
74. Zhao P, Kalhorn TF, Slattery JT. Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver. Hepatology 2002; 36(2): p. 326-35.
75. Fernández A, Colell A, Caballero F, Matías N, García-Ruiz C, Fernández-Checa JC. Mitochondrial S-adenosyl-L-methionine transport is insensitive to alcohol-mediated changes in membrane dynamics. Alcoholism Clinical Experimental Res 2009; 33(7): p. 1169-80.
76. Wheeler MD, Nakagami M, Bradford BU, et al. Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. J Biological Chem 2001; 276(39): p. 36664-72.
77. Lamlé J, Marhenke S, Borlak J, et al. Nuclear factor-eythroid 2- related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 2008; 134(4): p. 1159-68.
78. Soccio, RE, Breslow JL. StAR-related lipid transfer (START) proteins: mediators of intracellular lipid metabolism. J Biological Chem 2003; 278(25): p. 22183-6.
79. Kishida T, Kostetskii I, Zhang Z, et al. Targeted mutation of the MLN64 START domain causes only modest alterations in cellular sterol metabolism. J Biological Chem 2004; 279(18): p. 19276-85.
80. Tichauer JE, Morales MG, Amigo L, et al. Overexpression of the cholesterol-binding protein MLN64 induces liver damage in the mouse. World J Gastroenterol 2007; 13(22): p. 3071-9.
81. Charman M. Kennedy BE, Osborne N, Karten B. MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein. J Lipid Research 2011; 51(5): p. 1023-34.
82. Miller, WL. Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochimica Biophysica Acta 2007; 1771(6): p. 663-76.
83. Pandak WM, Ren S, Marques D, et al. Transport of cholesterol into mitochondria is rate-limiting for bile acid synthesis via the alternative pathway in primary rat hepatocytes. J Biological Chem 2002; 277(50): p. 48158-64.
84. Ren S, Hylemon P, Marques D, Hall E, Redford K, Gil G, Pandak WM. Effect of increasing the expression of cholesterol transporters (StAR, MLN64, and SCP-2) on bile acid synthesis. J Lipid Res 2004; 45(11): p. 2123-31.
85. Okamoto T, Schlegel A, Scherer PE, Lisanti MP. Caveolins, a family of scaffolding proteins for organizing preassembled signaling complexes at the plasma membrane. J Biological Chemistry 1998; 273(10): p. 5419-22.
86. Murata M, Peränen J, Schreiner R, Wieland F, Kurzchalia TV, Simons K. VIP21/caveolin is a cholesterol-binding protein. Proc Nat Acad Sci USA 1995; 92(22): p. 10339-43.
87. Smart EJ, Ying Y, Donzell WC, Anderson RG. A role for caveolin in transport of cholesterol from endoplasmic reticulum to plasma membrane. J Biological Chem 1996; 271(46): p. 29427-35.
88. Li WP, Liu P, Pilcher BK, Anderson RG. Cell-specific targeting of caveolin-1 to caveolae, secretory vesicles, cytoplasm or mitochondria. J Cell Sci 2001; 114(Pt 7): p. 1397-408.
89. Sano R, Annunziata I, Patterson A, et al. GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis. Molecular Cell 2009; 36(3): p. 500-11.
90. Bosch M, Marí M, Herms A, et al. Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility. Curr Biology 2011; 21(8): p. 681-6.
91. Morales A, Lee H, Goñi FM, Kolesnick R, Fernandez-Checa JC. Sphingolipids and cell death. Apoptosis 2007; 12(5): p. 923-39.
92. Kolesnick RN, Kronke M. Regulation of ceramide production and apoptosis. Ann Rev Physiol 1998; 60: p. 643-65.
93. Hannun YA, Luberto C. Ceramide in the eukaryotic stress response. Trends Cell Biol 2000; 10(2): p. 73-80.
94. García-Ruiz C, Colell A, Marí M, Morales A, Fernández-Checa JC. Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J Biological Chem 1997; 272(17): p. 11369-77.
95. Gudz TI, Tserng KY, Hoppel CL Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biological Chem 1997; 272(39): p. 24154-8.
96. Cremesti AE, Goni FM, Kolesnick R. Role of sphingomyelinase and ceramide in modulating rafts: do biophysical properties determine biologic outcome? FEBS Letters 2002; 531(1): p. 47-53.
97. Edelmann B, Bertsch U, Tchikov V, et al. Caspase-8 and caspase-7 sequentially mediate proteolytic activation of acid sphingomyelinase in TNF-R1 receptosomes. EMBO J 30(2): p. 379-94.
98. Jenkins RW, Idkowiak-Baldys J, Simbari F, et al. A novel mechanism of lysosomal acid sphingomyelinase maturation: requirement for carboxyl-terminal proteolytic processing. J Biological Chem 2011; 286(5): p. 3777-88.
99. Moles A, Tarrats N, Morales A, et al. Acidic sphingomyelinase controls hepatic stellate cell activation and in vivo liver fibrogenesis. Am J Pathol 2011; 177(3): p. 1214-24.
100. Schutze SV, Tchikov W. Schneider-Brachert, Regulation of TNFR1 and CD95 signalling by receptor compartmentalization. Nat Rev Mol Cell Biol 2008; 9(8): p. 655-62.
101. García-Ruiz C, Colell A, Marí M, et al, Defective TNF-alphamediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J Clinical Investigation 2003; 111(2): p. 197-208.
102. Ségui B, Cuvillier O, Adam-Klages S, et al. Involvement of FAN in TNF-induced apoptosis. J Clinical Investigation 2001; 108(1): p. 143-51.
103. Heinrich M, Neumeyer J, Jakob M, et al. Cathepsin D links TNFinduced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differentiation 2004; 11(5): p. 550-63.
104. Heinrich M, Wickel M, Schneider-Brachert W, et al. Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J 1999; 18(19): p. 5252-63.
105. Cifone MG, De Maria R, Roncaioli P, et al. Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase. J Experimental Medicine 1994; 180(4): p. 1547-52.
106. Brenner B, Ferlinz K, Grassmé H, et al. Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases. Cell Death Differentiation 1998; 5(1): p. 29-37.
107. Dumitru CA, Gulbins E. TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene 2006; 25(41): p. 5612-25.
108. García-Ruiz C, Colell A, París R, Fernández-Checa JC. Direct interaction of GD3 ganglioside with mitochondria generates reactive oxygen species followed by mitochondrial permeability transition, cytochrome c release, and caspase activation. FASEB J 2000; 14(7): p. 847-58.
109. Marí M, Colell A, Morales A, et al, Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis. J Clinical Investigation 2004; 113(6): p. 895-904.
110. Colell A, García-Ruiz C, Roman J, Ballesta A, Fernández-Checa JC. Ganglioside GD3 enhances apoptosis by suppressing the nuclear factor-kappa B-dependent survival pathway. FASEB J 2001; 15(6): p. 1068-70.
111. Garofalo T, Giammarioli AM, Misasi R, et al. Lipid microdomains contribute to apoptosis-associated modifications of mitochondria in T cells. Cell Death Differentiation 2005; 12(11): p. 1378-89.
112. Sorice M, Manganelli V, Matarrese P, et al. Cardiolipin-enriched raft-like microdomains are essential activating platforms for apoptotic signals on mitochondria. FEBS Letters 2009; 583(15): p. 2447-50.
113. Hotamisligil GS. The role of TNFalpha and TNF receptors in obesity and insulin resistance. J Internal Medicine 1999; 245(6): p. 621-5.
114. Holland WL, Brozinick JT, Wang LP, et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesityinduced insulin resistance. Cell Metabolism 2007; 5(3): p. 167-79.
115. Monetti M, Levin MC, Watt MJ, et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metabolism 2007; 6(1): p. 69-78.
116. Ruvolo PP, Deng X, Ito T, Carr BK, May WS. Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. The J biological chemistry 1999; 274(29): p. 20296-300.
117. Deevska GM, Rozenova KA, Giltiay NV, et al. Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice. The J biological chemistry 2009; 284(13): p. 8359-68.
118. Bijl N, Sokolović M, Vrins C, et al. Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice. Hepatology 2009; 50(5): p. 1431-41.
119. Wang ZT Yao Z Song, Chronic alcohol consumption disrupted cholesterol homeostasis in rats: down-regulation of low-density lipoprotein receptor and enhancement of cholesterol biosynthesis pathway in the liver. Alcoholism Clinical Experimental Research 2010; 34(3): p. 471-8.
120. Matsuzawa N, Takamura T, Kurita S, et al. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 2007; 46(5): p. 1392-403.
121. Wouters K, van Gorp PJ, Bieghs V, et al. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology 2008; 48(2): p. 474-86.
122. Puri P, Wiest MM, Cheung O, et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology 2009; 50(6): p. 1827-38.
123. Ogawa T, Fujii H, Yoshizato K, Kawada N. A human-type nonalcoholic steatohepatitis model with advanced fibrosis in rabbits. American J Pathology 2010; 177(1): p. 153-65.
124. Llacuna L, Fernández A, Montfort CV, et al. Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury. J hepatology 2011; 54(5): p. 1002-10.
125. Kiyici M, Gulten M, Gurel S, et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Canadian J Gastroenterology 2003; 17(12): p. 713-8.
126. Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004; 174(1): p. 193-6.
127. Lewis JH, Mortensen ME, Zweig S, et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with wellcompensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007; 46(5): p. 1453-63.
128. Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD. Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. American J Gastroenterology 2011; 106(1): p. 71-7.
129. Llacuna L, Marí M, Garcia-Ruiz C, Fernandez-Checa JC, Morales A. Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. Hepatology 2006; 44(3): p. 561-72.