Mechanisms and clinical implications of hepatocyte lipoapoptosis

Bibliography

• Angulo P, Lindor KD: Non­alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 17(Suppl.) S186–S190 (2002).
   Google Scholar
• Adams LA, Lymp JF, St Sauver J et al.: The natural history of nonalcoholic fatty liver disease: a population­based cohort study. Gastroenterology 129(1), 113–121 (2005).
   Google Scholar
• Ekstedt M, Franzen LE, Mathiesen UL et al.: Long­term follow­up of patients with NAFLD and elevated liver enzymes. Hepatology 44(4), 865–873 (2006).
   Google Scholar
• Ratziu V, Poynard T: Assessing the outcome of nonalcoholic steatohepatitis? It’s time to get serious. Hepatology 44(4), 802–805 (2006).
   Google Scholar
• Chavez­Tapia NC, Mendez­Sanchez N, Uribe M: The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann. Intern. Med. 144(5), 379; author reply 380 (2006).
   Google Scholar
• Parekh S, Anania FA: Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease. Gastroenterology 132(6), 2191–2207 (2007).
   Google Scholar
• Lee RG: Nonalcoholic steatohepatitis: tightening the morphological screws on a hepatic rambler. Hepatology 21(6), 1742–1743 (1995).
   Google Scholar
• Roden M: Mechanisms of disease: hepatic steatosis in Type 2 diabetes – pathogenesis and clinical relevance. Nat. Clin. Pract. Endocrinol. Metab. 2(6), 335–348 (2006).
   Google Scholar
• Unger RH: Lipotoxic diseases. Annu. Rev. Med. 53, 319–336 (2002).
   Google Scholar
• Kusminski CM, Shetty S, Orci L et al.: Diabetes and apoptosis: lipotoxicity. Apoptosis 14(12), 1484–1495 (2009).
   Google Scholar
• Malhi H, Bronk SF, Werneburg NW et al.: Free fatty acids induce JNK­dependent hepatocyte lipoapoptosis. J. Biol. Chem. 281(17), 12093–12101 (2006). Reports for the first time the involvement of the c-Jun N-terminal kinase (JNK) signaling pathway in lipoapoptosis processes.
   Google Scholar
• Barreyro FJ, Kobayashi S, Bronk SF et al.: Transcriptional regulation of Bim by FoxO3a mediates hepatocyte lipoapoptosis. J. Biol. Chem. 282(37), 27141–27154 (2007).
   Google Scholar
• Cazanave SC, Mott JL, Elmi NA et al.: JNK1­dependent PUMA expression contributes to hepatocyte lipoapoptosis. J. Biol. Chem. 284(39), 26591–26602(2009).
   Google Scholar
• Masuoka HC, Mott J, Bronk SF et al.: Mcl­1 degradation during hepatocyte lipoapoptosis. J. Biol. Chem. 284(44), 30039–30048 (2009).
   Google Scholar
• Wei Y, Wang D, Topczewski F et al.: Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am. J. Physiol. Endocrinol. Metab. 291(2), E275–E281 (2006).
   Google Scholar
• Wang D, Wei Y, Pagliassotti MJ: Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 147(2), 943–951 (2006). Demonstrates that the induction of an endoplasmic reticulum (ER) stress in diet-induced models of steatohepatitis depends on the free fatty acid content of the diet and not on the development of a hepatic steatosis.
   Google Scholar
• Wei Y, Wang D, Gentile CL et al.: Reduced endoplasmic reticulum luminal calcium links saturated fatty acid­mediated endoplasmic reticulum stress and cell death in liver cells. Mol. Cell. Biochem. 331(1–2), 31–40 (2009).
   Google Scholar
• Listenberger LL, Han X, Lewis SE et al.: Triglyceride accumulation protects against fatty acid­induced lipotoxicity. Proc. Natl Acad. Sci. USA 100(6), 3077–3082 (2003).
   Google Scholar
• Yamaguchi K, Yang L, McCall S et al.: Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45(6), 1366–1374 (2007).
   Google Scholar
• Larter CZ, Yeh MM, Haigh WG et al.: Hepatic free fatty acids accumulate in experimental steatohepatitis: role of adaptive pathways. J. Hepatol. 48(4), 638–647 (2008).
   Google Scholar
• Larter CZ, Yeh MM, Williams J et al.: MCD­induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes. J. Hepatol. 49(3), 407–416 (2008).
   Google Scholar
• Feldstein AE, Canbay A, Angulo P et al.: Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125(2), 437–443 (2003). Observes that the severity of nonalcoholic fatty liver disease (NAFLD) correlates with an increase in hepatocyte apoptosis, which constitutes a hallmark of nonalcoholic steatohepatitis (NASH).
   Google Scholar
• Nehra V, Angulo P, Buchman AL et al.: Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis. Dig. Dis. Sci. 46(11), 2347–2352 (2001).
   Google Scholar
• Feldstein AE, Wieckowska A, Lopez AR et al.: Cytokeratin­18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 50(4), 1072–1078 (2009).
   Google Scholar
• Lewis GF, Carpentier A, Adeli K et al.: Disordered fat storage and mobilization in the pathogenesis of insulin resistance and Type 2 diabetes. Endocr. Rev. 23(2), 201–229 (2002).
   Google Scholar
• Donnelly KL, Smith CI, Schwarzenberg SJ et al.: Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115(5), 1343–1351 (2005).
   Google Scholar
• Pohl J, Ring A, Hermann T et al.: Role of FATP in parenchymal cell fatty acid uptake. Biochim. Biophys. Acta 1686(1–2), 1–6 (2004).
   Google Scholar
• Zhou J, Febbraio M, Wada T et al.: Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPAR­g in promoting steatosis. Gastroenterology 134(2), 556–567 (2008).
   Google Scholar
• Doege H, Baillie RA, Ortegon AM et al.: Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis. Gastroenterology 130(4), 1245–1258 (2006).
   Google Scholar
• Doege H, Grimm D, Falcon A et al.: Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet­induced non­alcoholic fatty liver disease and improves hyperglycemia. J. Biol. Chem. 283(32), 22186–22192 (2008).
   Google Scholar
• Koonen DP, Jacobs RL, Febbraio M et al.: Increased hepatic CD36 expression contributes to dyslipidemia associated with diet­induced obesity. Diabetes 56(12), 2863–2871 (2007).
   Google Scholar
• Baumgardner JN, Shankar K, Hennings L et al.: A new model for nonalcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high­polyunsaturated fat diet. Am. J. Physiol. Gastrointest. Liver Physiol. 294(1), G27–G38 (2008).
   Google Scholar
• Greco D, Kotronen A, Westerbacka J et al.: Gene expression in human NAFLD. Am. J. Physiol. Gastrointest. Liver Physiol. 294(5), G1281–G1287 (2008).
   Google Scholar
• Westerbacka J, Kolak M, Kiviluoto T et al.: Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin­resistant subjects. Diabetes 56(11), 2759–2765 (2007).
   Google Scholar
• Mitsuyoshi H, Yasui K, Harano Y et al.: Analysis of hepatic genes involved in the metabolism of fatty acids and iron in nonalcoholic fatty liver disease. Hepatol. Res. 39(4), 366–373 (2009).
   Google Scholar
• Newberry EP, Xie Y, Kennedy S et al.: Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid­binding protein gene. J. Biol. Chem. 278(51), 51664–51672 (2003).
   Google Scholar
• Newberry EP, Kennedy SM, Xie Y et al.: Diet­induced alterations in intestinal and extrahepatic lipid metabolism in liver fatty acid binding protein knockout mice. Mol. Cell. Biochem. 326(1–2), 79–86 (2009).
   Google Scholar
• Charlton M, Viker K, Krishnan A et al.: Differential expression of lumican and fatty acid binding protein­1: new insights into the histologic spectrum of nonalcoholic fatty liver disease. Hepatology 49(4), 1375–1384 (2009).
   Google Scholar
• de Almeida IT, Cortez­Pinto H, Fidalgo G et al.: Plasma total and free fatty acids composition in human non­alcoholic steatohepatitis. Clin. Nutr. 21(3), 219–223 (2002).
   Google Scholar
• Diraison F, Moulin P, Beylot M: Contribution of hepatic de novo lipogenesis and re­esterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non­alcoholic fatty liver disease. Diabetes Metab. 29(5), 478–485 (2003).
   Google Scholar
• Puri P, Baillie RA, Wiest MM et al.: A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46(4), 1081–1090 (2007).
   Google Scholar
• Allard JP, Aghdassi E, Mohammed S et al.: Nutritional assessment and hepatic fatty acid composition in non­alcoholic fatty liver disease (NAFLD): a cross­sectional study. J. Hepatol. 48(2), 300–307 (2008).
   Google Scholar
• Mu YM, Yanase T, Nishi Y et al.: Saturated FFAs, palmitic acid and stearic acid, induce apoptosis in human granulosa cells. Endocrinology 142(8), 3590–3597 (2001).
   Google Scholar
• Li ZZ, Berk M, McIntyre TM et al.: Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl­CoA desaturase. J. Biol. Chem. 284(9), 5637–5644 (2009).
   Google Scholar
• Akazawa Y, Cazanave S, Mott JL et al.: Palmitoleate attenuates palmitate­induced Bim and PUMA upregulation and hepatocyte lipoapoptosis. J. Hepatol. (2009) (In press).
   Google Scholar
• Ron D, Walter P: Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8(7), 519–529 (2007).
   Google Scholar
• Lu PD, Harding HP, Ron D: Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J. Cell Biol. 167(1), 27–33 (2004).
   Google Scholar
• Luo S, Baumeister P, Yang S et al.: Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements. J. Biol. Chem. 278(39), 37375–37385 (2003).
   Google Scholar
• Shaffer AL, Shapiro­Shelef M, Iwakoshi NN et al.: XBP1, downstream of Blimp­1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21(1), 81–93 (2004).
   Google Scholar
• 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(5453), 664–666 (2000).
   Google Scholar
• Yamamoto K, Sato T, Matsui T et al.: Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6a and XBP1. Dev. Cell 13(3), 365–376 (2007).
   Google Scholar
• Wu J, Rutkowski DT, Dubois M et al.: ATF6a optimizes long­term endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell 13(3), 351–364 (2007).
   Google Scholar
• Ozcan U, Cao Q, Yilmaz E et al.: Endoplasmic reticulum stress links obesity, insulin action, and Type 2 diabetes. Science 306(5695), 457–461 (2004).
   Google Scholar
• Puri P, Mirshahi F, Cheung O et al.: Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134(2), 568–576 (2008).
   Google Scholar
• Borradaile NM, Han X, Harp JD et al.: Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. J. Lipid Res. 47(12), 2726–2737 (2006).
   Google Scholar
• Ma Y, Hendershot LM: ER chaperone functions during normal and stress conditions. J. Chem. Neuroanat. 28(1–2), 51–65 (2004).
   Google Scholar
• Scorrano L, Oakes SA, Opferman JT et al.: BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300(5616), 135–139 (2003).
   Google Scholar
• Cunha DA, Hekerman P, Ladriere L et al.: Initiation and execution of lipotoxic ER stress in pancreatic b­cells. J. Cell Sci. 121(Pt 14), 2308–2318 (2008).
   Google Scholar
• Ji C, Mehrian­Shai R, Chan C et al.: Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding. Alcohol. Clin. Exp. Res. 29(8), 1496–1503 (2005).
   Google Scholar
• McCullough KD, Martindale JL, Klotz LO et al.: Gadd153 sensitizes cells to endoplasmic reticulum stress by down­regulating Bcl2 and perturbing the cellular redox state. Mol. Cell. Biol. 21(4), 1249–1259 (2001).
   Google Scholar
• Puthalakath H, O’Reilly LA, Gunn P et al.: ER stress triggers apoptosis by activating BH3­only protein Bim. Cell 129(7), 1337–1349 (2007).
   Google Scholar
• Feldstein AE, Werneburg NW, Li Z et al.: Bax inhibition protects against free fatty acid­induced lysosomal permeabilization. Am. J. Physiol. Gastrointest. Liver Physiol. 290(6), G1339–G1346 (2006).
   Google Scholar
• Yamaguchi H, Wang HG: CHOP is involved in endoplasmic reticulum stress­induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem. 279(44), 45495–45502 (2004).
   Google Scholar
• Guicciardi ME, Gores GJ: Life and death by death receptors. FASEB J. 23(6), 1625–1637 (2009).
   Google Scholar
• Malhi H, Barreyro FJ, Isomoto H et al.: Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut 56(8), 1124–1131 (2007).
   Google Scholar
• Volkmann X, Fischer U, Bahr MJ et al.: Increased hepatotoxicity of tumor necrosis factor­related apoptosis­inducing ligand in diseased human liver. Hepatology 46(5), 1498–1508 (2007).
   Google Scholar
• Ribeiro PS, Cortez­Pinto H, Sola S et al.: Hepatocyte apoptosis, expression of death receptors, and activation of NF­kB in the liver of nonalcoholic and alcoholic steatohepatitis patients. Am. J. Gastroenterol. 99(9), 1708–1717 (2004).
   Google Scholar
• Feldstein AE, Canbay A, Guicciardi ME et al.: Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J. Hepatol. 39(6), 978–983 (2003).
   Google Scholar
• Siebler J, Schuchmann M, Strand S et al.: Enhanced sensitivity to CD95­induced apoptosis in ob/ob mice. Dig. Dis. Sci. 52(9), 2396–2402 (2007).
   Google Scholar
• Schattenberg JM, Singh R, Wang Y et al.: JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 43(1), 163–172 (2006).
   Google Scholar
• Singh R, Wang Y, Xiang Y et al.: Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology 49(1), 87–96 (2009). Characterizes the proapoptotic effects of JNK1 isoform and the antiapoptotic functions of JNK2 isoform in murine model of steatohepatitis.
   Google Scholar
• Wang Y, Ausman LM, Russell RM et al.: Increased apoptosis in high­fat diet­induced nonalcoholic steatohepatitis in rats is associated with c­Jun NH2­terminal kinase activation and elevated proapoptotic Bax. J. Nutr. 138(10), 1866–1871 (2008).
   Google Scholar
• Jaeschke A, Davis RJ: Metabolic stress signaling mediated by mixed­lineage kinases. Mol. Cell 27(3), 498–508 (2007).
   Google Scholar
• Czaja MJ: The future of GI and liver research: editorial perspectives. III. JNK/AP­1 regulation of hepatocyte death. Am. J. Physiol. Gastrointest. Liver Physiol. 284(6), G875–G8759 (2003).
   Google Scholar
• Czaja MJ: Cell signaling in oxidative stress­induced liver injury. Semin. Liver Dis. 27(4), 378–389 (2007).
   Google Scholar
• Davis RJ: Signal transduction by the JNK group of MAP kinases. Cell 103(2), 239–252 (2000).
   Google Scholar
• Kodama Y, Taura K, Miura K et al.: Antiapoptotic effect of c­Jun N­terminal kinase­1 through Mcl­1 stabilization in TNF­induced hepatocyte apoptosis. Gastroenterology 136(4), 1423–1434 (2009).
   Google Scholar
• Sabapathy K, Hochedlinger K, Nam SY et al.: Distinct roles for JNK1 and JNK2 in regulating JNK activity and c­Jun­dependent cell proliferation. Mol. Cell 15(5), 713–725 (2004).
   Google Scholar
• Videla LA, Tapia G, Rodrigo R et al.: Liver NF­kB and AP­1 DNA binding in obese patients. Obesity (Silver Spring) 17(5), 973–979 (2009).
   Google Scholar
• Yamamoto K, Ichijo H, Korsmeyer SJ: BCL­2 is phosphorylated and inactivated by an ASK1/Jun N­terminal protein kinase pathway normally activated at G(2)/M. Mol. Cell. Biol. 19(12), 8469–8478 (1999).
   Google Scholar
• Donovan N, Becker EB, Konishi Y et al.: JNK phosphorylation and activation of BAD couples the stress­activated signaling pathway to the cell death machinery. J. Biol. Chem. 277(43), 40944–40949 (2002).
   Google Scholar
• Lei K, Davis RJ: JNK phosphorylation of Bim­related members of the Bcl2 family induces Bax­dependent apoptosis. Proc. Natl Acad. Sci. USA 100(5), 2432–2437 (2003).
   Google Scholar
• Kim BJ, Ryu SW, Song BJ: JNK­ and p38 kinase­mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J. Biol. Chem. 281(30), 21256–21265 (2006).
   Google Scholar
• Eichhorst ST, Muller M, Li­Weber M et al.: A novel AP­1 element in the CD95 ligand promoter is required for induction of apoptosis in hepatocellular carcinoma cells upon treatment with anticancer drugs. Mol. Cell. Biol. 20(20), 7826–7837 (2000).
   Google Scholar
• Erlacher M, Labi V, Manzl C et al.: Puma cooperates with Bim, the rate­limiting BH3­only protein in cell death during lymphocyte development, in apoptosis induction. J. Exp. Med. 203(13), 2939–2951 (2006).
   Google Scholar
• Yamaguchi H, Wang HG: Bcl­xL protects BimEL­induced Bax conformational change and cytochrome C release independent of interacting with Bax or BimEL. J. Biol. Chem. 277(44), 41604–41612 (2002).
   Google Scholar
• Adams JM, Cory S: The Bcl­2 apoptotic switch in cancer development and therapy. Oncogene 26(9), 1324–1337 (2007).
   Google Scholar
• Gallenne T, Gautier F, Oliver L et al.: Bax activation by the BH3­only protein Puma promotes cell dependence on antiapoptotic Bcl­2 family members. J. Cell Biol. 185(2), 279–290 (2009).
   Google Scholar
• Chipuk JE, Fisher JC, Dillon CP et al.: Mechanism of apoptosis induction by inhibition of the anti­apoptotic BCL­2 proteins. Proc. Natl Acad. Sci. USA 105(51), 20327–20332 (2008).
   Google Scholar
• Jabbour AM, Heraud JE, Daunt CP et al.: Puma indirectly activates Bax to cause apoptosis in the absence of Bid or Bim. Cell Death Differ. 16(4), 555–563 (2009).
   Google Scholar
• Taylor RC, Cullen SP, Martin SJ: Apoptosis: controlled demolition at the cellular level. Nat. Rev. Mol. Cell Biol. 9(3), 231–241 (2008).
   Google Scholar
• Li Z, Berk M, McIntyre TM et al.: The lysosomal­mitochondrial axis in free fatty acid­induced hepatic lipotoxicity. Hepatology 47(5), 1495–1503 (2008).
   Google Scholar
• Sanyal AJ, Campbell­Sargent C, Mirshahi F et al.: Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120(5), 1183–1192 (2001).
   Google Scholar
• Caldwell SH, Swerdlow RH, Khan EM et al.: Mitochondrial abnormalities in non­alcoholic steatohepatitis. J. Hepatol. 31(3), 430–434 (1999).
   Google Scholar
• Caldwell SH, Chang CY, Nakamoto RK et al.: Mitochondria in nonalcoholic fatty liver disease. Clin. Liver Dis. 8(3), 595–617, (2004).
   Google Scholar
• Summers SA: Ceramides in insulin resistance and lipotoxicity. Prog. Lipid Res. 45(1), 42–72 (2006).
   Google Scholar
• Holland WL, Brozinick JT, Wang LP et al.: Inhibition of ceramide synthesis ameliorates glucocorticoid­, saturated­fat­, and obesity­ induced insulin resistance. Cell Metab. 5(3), 167–179 (2007).
   Google Scholar
• Shimabukuro M, Zhou YT, Levi M et al.: Fatty acid­induced b cell apoptosis: a link between obesity and diabetes. Proc. Natl Acad. Sci. USA 95(5), 2498–2502 (1998).
   Google Scholar
• Unger RH, Orci L: Lipoapoptosis: its mechanism and its diseases. Biochim. Biophys. Acta 1585(2–3), 202–212 (2002).
   Google Scholar
• Paumen MB, Ishida Y, Muramatsu M et al.: Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate­induced apoptosis. J. Biol. Chem. 272(6), 3324–3329 (1997).
   Google Scholar
• Shah C, Yang G, Lee I et al.: Protection from high fat diet­induced increase in ceramide in mice lacking plasminogen activator inhibitor 1. J. Biol. Chem. 283(20), 13538–13548 (2008).
   Google Scholar
• Kolak M, Westerbacka J, Velagapudi VR et al.: Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity. Diabetes 56(8), 1960–1968 (2007).
   Google Scholar
• Paris F, Grassme H, Cremesti A et al.: Natural ceramide reverses Fas resistance of acid sphingomyelinase­/­ hepatocytes. J. Biol. Chem. 276(11), 8297–8305 (2001).
   Google Scholar
• Kotronen A, Seppanen­Laakso T, Westerbacka J et al.: Hepatic stearoyl­CoA desaturase (SCD)­1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver. Diabetes 58(1), 203–208 (2009).
   Google Scholar
• Mari M, Caballero F, Colell A et al.: Mitochondrial free cholesterol loading sensitizes to TNF­ and Fas­mediated steatohepatitis. Cell Metab. 4(3), 185–198 (2006).
   Google Scholar
• Ichi I, Nakahara K, Kiso K et al.: Effect of dietary cholesterol and high fat on ceramide concentration in rat tissues. Nutrition 23(7–8), 570–574 (2007).
   Google Scholar
• Feng B, Yao PM, Li Y et al.: The endoplasmic reticulum is the site of cholesterol­induced cytotoxicity in macrophages. Nat. Cell Biol. 5(9), 781–792 (2003).
   Google Scholar
• Devries­Seimon T, Li Y, Yao PM et al.: Cholesterol­induced macrophage apoptosis requires ER stress pathways and engagement of the Type A scavenger receptor. J. Cell Biol. 171(1), 61–73 (2005).
   Google Scholar
• Calamita G, Portincasa P: Present and future therapeutic strategies in non­alcoholic fatty liver disease. Expert Opin. Ther. Targets. 11(9), 1231–1249 (2007).
   Google Scholar
• Lin HZ, Yang SQ, Chuckaree C et al.: Metformin reverses fatty liver disease in obese, leptin­deficient mice. Nat. Med. 6(9), 998–1003 (2000).
   Google Scholar
• Nair S, Diehl AM, Wiseman M et al.: Metformin in the treatment of non­alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol. Ther. 20(1), 23–28 (2004).
   Google Scholar
• Witek RP, Stone WC, Karaca FG et al.: Pan­caspase inhibitor VX­166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology 50(5), 1421–1430 (2009).
   Google Scholar
• Fromenty B, Robin MA, Igoudjil A et al.: The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab. 30(2), 121–138 (2004).
   Google Scholar
• Feldstein AE, Werneburg NW, Canbay A et al.: Free fatty acids promote hepatic lipotoxicity by stimulating TNF­a expression via a lysosomal pathway. Hepatology 40(1), 185–194 (2004).
   Google Scholar
• Svegliati­Baroni G, Candelaresi C, Saccomanno S et al.: A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator­activated receptor­a and n­3 polyunsaturated fatty acid treatment on liver injury. Am. J. Pathol. 169(3), 846–860 (2006).
   Google Scholar
• Araya J, Rodrigo R, Videla LA et al.: Increase in long­chain polyunsaturated fatty acid n­6/n­3 ratio in relation to hepatic steatosis in patients with non­alcoholic fatty liver disease. Clin. Sci. (Lond). 106(6), 635–643 (2004).
   Google Scholar
• Videla LA, Rodrigo R, Araya J et al.: Oxidative stress and depletion of hepatic long­chain polyunsaturated fatty acids may contribute to nonalcoholic fatty liver disease. Free Radic. Biol. Med. 37(9), 1499–1507 (2004).
   Google Scholar
• Capanni M, Calella F, Biagini MR et al.: Prolonged n­3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non­alcoholic fatty liver disease: a pilot study. Aliment Pharmacol. Ther. 23(8), 1143–1151 (2006).
   Google Scholar
• Spadaro L, Magliocco O, Spampinato D et al.: Effects of n­3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig. Liver Dis. 40(3), 194–199 (2008).
   Google Scholar
• Ozcan U, Yilmaz E, Ozcan L et al.: Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of Type 2 diabetes. Science 313(5790), 1137–1140 (2006). Reports that chemical chaperones, which enhance the adaptative capacity of the ER, may have therapeutic potential in the treatment of obesity and NAFLD.
   Google Scholar
• Lindor KD, Kowdley KV, Heathcote EJ et al.: Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39(3), 770–778 (2004).
   Google Scholar
• Cnop M, Igoillo­Esteve M, Cunha DA et al.: An update on lipotoxic endoplasmic reticulum stress in pancreatic b­cells. Biochem. Soc. Trans. 36(Pt 5), 909–915 (2008).
   Google Scholar