非酒精性脂肪性肝病发生发展的蛋白质组学研究
|
摘要
近年来随着人们生活方式和饮食结构的改变,非酒精性脂肪性肝病(Nonalcoholic fatty liver disease,NAFLD)的患病率日益增高,成为导致慢性肝病的重要原因之一,构成日益严重的社会健康问题。NAFLD包括一系列相互联系的病理改变,从单纯性脂肪肝、脂肪性肝炎,到肝纤维化和肝硬化,甚至可以进展为肝细胞癌。目前认为,NAFLD与肥胖、糖尿病、高脂血症等代谢综合征密切相关,而高脂饮食是引起肥胖及其相关并存症高发的重要原因。摄入含过多饱和脂肪的食物可以直接导致肝细胞的脂肪浸润及氧化损伤,但其确切的分子机制尚未明确。用高脂饲料喂养SD大鼠可以成功复制不同病变程度的NAFLD动物模型。本研究采用蛋白质组学的技术手段,系统分析了高脂饮食相关的NAFLD发生发展过程中肝脏蛋白质表达谱的动态变化,发掘了一批与NAFLD疾病进程密切相关的功能蛋白质群,结合生物信息学手段系统分析差异蛋白的功能和调控网络,从而为深入探讨NAFLD发生发展的分子机制奠定了基础。
用高脂饲料喂养SD大鼠4周、12周和24周,肝脏病理分别表现为肝细胞脂肪变性、脂肪变性伴炎症细胞浸润,以及脂肪变性伴炎症细胞浸润及轻度纤维化,分别与NAFLD的单纯性脂肪肝(SS),脂肪肝合并非特异性炎症(NSI)及脂肪性肝炎(NASH)这三个阶段的病理表现相似。随后,我们利用差异凝胶电泳技术(DIGE)分析了不同造模时间的正常组和模型组大鼠肝脏蛋白质表达谱的差异,所得到的差异蛋白质点用MALDI-TOF/TOF质谱仪进行检测,共鉴定了95个差异蛋白,其中SS阶段的差异蛋白53个,NSI阶段的差异蛋白42个,NASH阶段的差异蛋白49个。这些差异蛋白在功能上具有明显的阶段特异性。其中参与脂肪酸氧化的酶在SS阶段明显下调,可能是造成该阶段肝细胞脂肪变性的重要原因;多个参与线粒体呼吸链和氧化磷酸化的酶在NSI阶段表达下调,提示线粒体功能障碍在这一阶段的重要作用;最后在NASH阶段,多个细胞骨架蛋白的表达都明显上调,很可能与该阶段肝细胞的结构和功能紊乱相关。进一步对这些差异蛋白进行相互作用网络的分析发现,多个差异蛋白的表达受到PPARα和C/EBPα这两个转录因子的调控,随后我们通过Western blot方法检测到PPARα在疾病的三个阶段都明显下调,而C/EBPα在SS和NSI阶段明显上调,提示这两个转录因子在NAFLD的发生发展中发挥了重要作用。此外,我们还发现4个内质网分子伴侣(PDI,PDIA3,GRP78和ERp29)在进展期NSI和NASH阶段明显上调。内质网分子伴侣表达上调是内质网应激的一个重要特点,资料显示内质网应激在肥胖、2型糖尿病等代谢性疾病中均发挥了重要作用,为此推测,内质网功能紊乱所造成的内质网应激是促使NAFLD病程进展的一个重要因素。上述研究结果为进一步阐明NAFLD发生发展的分子机制,发现分期分型诊断标志物和潜在的药物靶点奠定了基础。
Nonalcoholic fatty liver disease (NAFLD) has emerged as one of the most common chronic liver diseases in recent years, partly due to the lifestyle changes, including physical inactivity and high daily fat consumption. NAFLD consists of a spectrum of liver disease, ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. NAFLD is strongly associated with obesity, type 2 diabetes and hyperdyslipemia, which are the main features of the recently characterized metabolic syndrome. While a high fat diet is one of the main causes that will induce obesity and its comorbidities. Accumulate evidence suggested that a higher intake of saturated fat can directly affect hepatic fatty infiltration and oxidative damage in different types of liver disease. However, the exact role of saturated fat to the development of NAFLD remains poorly understood. By feeding Sprague-Dawley (SD) rats a high-fat diet (HFD) reproduced many key features of human NAFLD. Current study adopted proteomic approaches to systematically analyze the liver proteomes during the development of HFD-induced NAFLD which may help clarify the pathogenesis of NAFLD.
When SD rats were fed with a HFD for 4, 12 and 24 weeks, they successfully reproduced a spectrum of histological changes similar to human NAFLD: that was simple steatosis (SS) at 4 weeks, nonspecific inflammation (NSI) at 12 weeks, and steatohepatitis (NASH) at 24 weeks. Using two-dimensional difference gel electrophoresis (2-D DIGE) combined with MALDI-TOF/TOF analysis, ninety-five proteins exhibiting significant difference (ratio≥1.5 or≤-1.5, P<0.05) during the development of NAFLD were unambiguously identified. This included 53 proteins at SS stage, 42 proteins at NSI stage and 49 proteins at NASH stage. Biological functions of these proteins exhibited phase-specific characteristics during evolution of the disease: at steatosis stage, metabolic enzymes involved in lipid, carbohydrate and amino acid metabolisms were affected highlighted by depressed fatty acidβ-oxidation; by nonspecific inflammation stage, mitochondrial functions were impaired with decreasing proteins involved in mitochondrial respiratory chain and oxidative phosphorylation; up to steatohepatitis stage, cytoskeleton proteins were up-regulated, which may affect hepatocyte structural and functional integrity. Furthermore, a pathway analysis of these proteins identified PPARαand C/EBPαas key regulators that were subsequently verified by Western blot. The results showed that PPARa was decrease at all three stages of NAFLD, while C/EBPαwas increased at the earlier two stages of NAFLD. More importantly, we found that four ER chaperones, PDI, PDIA3, GRP78 and ERp29 were up-regulated especially at the more advanced stages of NAFLD. Up-regulation of ER chaperones is one of the important cellular markers of ER stress. Evidence suggested that ER stress was linked to the development of several diseases including obesity and type 2 diabetes, two major risk factors that strongly associated with NAFLD. Accordingly, we proposed that the disruption of ER function may contribute to the progression of NAFLD from steatosis to NASH. Together, these results help clarify the pathogenesis of NAFLD and identify potential targets for therapeutic interventions.
用高脂饲料喂养SD大鼠4周、12周和24周,肝脏病理分别表现为肝细胞脂肪变性、脂肪变性伴炎症细胞浸润,以及脂肪变性伴炎症细胞浸润及轻度纤维化,分别与NAFLD的单纯性脂肪肝(SS),脂肪肝合并非特异性炎症(NSI)及脂肪性肝炎(NASH)这三个阶段的病理表现相似。随后,我们利用差异凝胶电泳技术(DIGE)分析了不同造模时间的正常组和模型组大鼠肝脏蛋白质表达谱的差异,所得到的差异蛋白质点用MALDI-TOF/TOF质谱仪进行检测,共鉴定了95个差异蛋白,其中SS阶段的差异蛋白53个,NSI阶段的差异蛋白42个,NASH阶段的差异蛋白49个。这些差异蛋白在功能上具有明显的阶段特异性。其中参与脂肪酸氧化的酶在SS阶段明显下调,可能是造成该阶段肝细胞脂肪变性的重要原因;多个参与线粒体呼吸链和氧化磷酸化的酶在NSI阶段表达下调,提示线粒体功能障碍在这一阶段的重要作用;最后在NASH阶段,多个细胞骨架蛋白的表达都明显上调,很可能与该阶段肝细胞的结构和功能紊乱相关。进一步对这些差异蛋白进行相互作用网络的分析发现,多个差异蛋白的表达受到PPARα和C/EBPα这两个转录因子的调控,随后我们通过Western blot方法检测到PPARα在疾病的三个阶段都明显下调,而C/EBPα在SS和NSI阶段明显上调,提示这两个转录因子在NAFLD的发生发展中发挥了重要作用。此外,我们还发现4个内质网分子伴侣(PDI,PDIA3,GRP78和ERp29)在进展期NSI和NASH阶段明显上调。内质网分子伴侣表达上调是内质网应激的一个重要特点,资料显示内质网应激在肥胖、2型糖尿病等代谢性疾病中均发挥了重要作用,为此推测,内质网功能紊乱所造成的内质网应激是促使NAFLD病程进展的一个重要因素。上述研究结果为进一步阐明NAFLD发生发展的分子机制,发现分期分型诊断标志物和潜在的药物靶点奠定了基础。
Nonalcoholic fatty liver disease (NAFLD) has emerged as one of the most common chronic liver diseases in recent years, partly due to the lifestyle changes, including physical inactivity and high daily fat consumption. NAFLD consists of a spectrum of liver disease, ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. NAFLD is strongly associated with obesity, type 2 diabetes and hyperdyslipemia, which are the main features of the recently characterized metabolic syndrome. While a high fat diet is one of the main causes that will induce obesity and its comorbidities. Accumulate evidence suggested that a higher intake of saturated fat can directly affect hepatic fatty infiltration and oxidative damage in different types of liver disease. However, the exact role of saturated fat to the development of NAFLD remains poorly understood. By feeding Sprague-Dawley (SD) rats a high-fat diet (HFD) reproduced many key features of human NAFLD. Current study adopted proteomic approaches to systematically analyze the liver proteomes during the development of HFD-induced NAFLD which may help clarify the pathogenesis of NAFLD.
When SD rats were fed with a HFD for 4, 12 and 24 weeks, they successfully reproduced a spectrum of histological changes similar to human NAFLD: that was simple steatosis (SS) at 4 weeks, nonspecific inflammation (NSI) at 12 weeks, and steatohepatitis (NASH) at 24 weeks. Using two-dimensional difference gel electrophoresis (2-D DIGE) combined with MALDI-TOF/TOF analysis, ninety-five proteins exhibiting significant difference (ratio≥1.5 or≤-1.5, P<0.05) during the development of NAFLD were unambiguously identified. This included 53 proteins at SS stage, 42 proteins at NSI stage and 49 proteins at NASH stage. Biological functions of these proteins exhibited phase-specific characteristics during evolution of the disease: at steatosis stage, metabolic enzymes involved in lipid, carbohydrate and amino acid metabolisms were affected highlighted by depressed fatty acidβ-oxidation; by nonspecific inflammation stage, mitochondrial functions were impaired with decreasing proteins involved in mitochondrial respiratory chain and oxidative phosphorylation; up to steatohepatitis stage, cytoskeleton proteins were up-regulated, which may affect hepatocyte structural and functional integrity. Furthermore, a pathway analysis of these proteins identified PPARαand C/EBPαas key regulators that were subsequently verified by Western blot. The results showed that PPARa was decrease at all three stages of NAFLD, while C/EBPαwas increased at the earlier two stages of NAFLD. More importantly, we found that four ER chaperones, PDI, PDIA3, GRP78 and ERp29 were up-regulated especially at the more advanced stages of NAFLD. Up-regulation of ER chaperones is one of the important cellular markers of ER stress. Evidence suggested that ER stress was linked to the development of several diseases including obesity and type 2 diabetes, two major risk factors that strongly associated with NAFLD. Accordingly, we proposed that the disruption of ER function may contribute to the progression of NAFLD from steatosis to NASH. Together, these results help clarify the pathogenesis of NAFLD and identify potential targets for therapeutic interventions.
引文
1.Younossi ZM.Nonalcoholic fatty liver disease.Curr Gastroenterol Rep.1999;1(1):57-62.
2.Angulo P.Nonalcoholic fatty liver disease.N Engl J Med.2002,346(16):1221-31.
3.Ratziu V,Poynard T.Assessing the outcome of nonalcoholic steatohepatitis? It's time to get serious.Hepatology.2006,44(4):802-5.
4.Adams LA,Lymp JF,St Sauver J,et al.The natural history of nonalcoholic fatty liver disease:a population-based cohort study.Gastroenterology.2005,129(1):113-21.
5.Miele L,Forgione A,Hernandez AP,et al.The natural history and risk factors for progression of non-alcoholic fatty liver disease and steatohepatitis.Eur Rev Med Pharmacol Sci.2005,9(5):273-7.
6.Day CP,James OF.Steatohepatitis:a tale of two "hits"? Gastroenterology.1998,114(4):842-5.
7.Portincasa P,Grattagliano I,Palmieri VO,et al.Nonalcoholic steatohepatitis: recent advances from experimental models to clinical management. Clin Biochem. 2005, 38(3):203-17.
8. Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol. 2006, 290(5):G852-8.
9. Fishman S, Muzumdar RH, Atzmon G, et al. Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo. FASEB J. 2007, 21(1):53-60.
10. Cassader M, Gambino R, Musso G, et al. Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients. Lipids. 2001, 36(10): 111 7-24.
11. Robertson G, Leclercq I, Farrell G. Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress. Am J Physiol Gastrointest Liver Physiol. 2001,281 :G1135-9.
12. Wigg AJ, Roberts-Thomson IC, Dymock RB, et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumor necrosis factor a in the pathogenesis of nonalcoholic steatohepatitis. Gut. 2001,48:206-11.
13. Albano E, Mottaran E, Occhino G, et al. Review article: role of oxidative stress in the progression of non-alcoholic steatosis. Aliment Pharmacol Ther. 2005, 22 Suppl 2:71-3.
14. Friedman SL. Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol. 2004, 1(2):98-105.
15. Washington K, Wright K, Shyr Y, et al. Hepatic stellate cell activation in nonalcoholic steatohepatitis and fatty liver. Hum Pathol. 2000, 31(7):822-8.
16. Neuschwander-Tetri BA. Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003, 37(5): 1202-19.
17. Musso G, Gambino R. Michieli FD, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003,37:909-16.
18. Honda H, Ikejima K, Hirose M, et al. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology. 2002, 36:12-21.
19. Leclercq IA, Farrell GC, Schriemer R, et al. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J Hepatol. 2002, 37: 206-13.
20. Leclercq IA, Field J, Farrell G.C. Leptin-specific mechanisms for impaired liver regeneration in ob/ob mice after toxic injury. Gastroenterology. 2003, 124: 1451-64.
21. Zeisel SH, Blusztajn JK. Choline and human nutrition. Annu Rev Nutr. 1994, 14: 269-96.
22. Yao ZM, Vance DE. Reduction in VLDL, but not HDL, in plasma of rats deficient in choline. Biochem Cell Biol. 1990,68:552-58.
23. Weltman MD, Farrell GC, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology. 1996,111:1645-53.
24. Rinella ME, Green RM. The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol. 2004,40:47-51.
25. Lieber CS, Leo MA, Mak BCM, et al. Model of nonalcoholic steatohepatitis. Am J Clin Nutr. 2004, 79(3):502-9.
26. Svegliati-Baroni G, Candelaresi C, Saccomanno S, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol. 2006,169(3):846-60.
27. Savage DB, Choi CS, Samuel VT, et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest. 2006,116(3):817-24.
28. Diamond DL, ProU SC, Jacobs JM, et al. HepatoProteomics: applying proteomic technologies to the study of liver function and disease. Hepatology. 2006, 44(2):299-308.
29. Santamaria E, M A Avila, M U Latasa, et al. Functional proteomics of nonalcoholic steatohepatitis: Mitochondrial proteins as targets of S-adenosylmethionine. Proc Natl Acad Sci USA. 2003,100:3065-70.
30. Younossi ZM, Baranova A, Ziegler K, et al. A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease. Hepatology 2005,42:665-74.
31. Douette P, Navet R, Gerkens P, et al. Steatosis-induced proteomic changes in liver mitochondria evidenced by two-dimensional differential In-gel electrophoresis. J Proteome Res. 2005,4:2024-31.
32. Van den Bergh G, Arckens L. Fluorescent two-dimensional difference gel electrophoresis unveils the potential of gel-based proteomics. Curr Opin Biotechnol. 2004,15(1):38-43.
33. Yan JX, Devenish AT, Wait R, et al. Fluorescence two-dimensional difference gel electrophoresis and mass spectrometry based proteomic analysis of Escherichia coli. Proteomics. 2002,2(12):1682-98.
34. Dowling P, O'Driscoll L, Meleady P, et al. 2-D difference gel electrophoresis of the lung squamous cell carcinoma versus normal sera demonstrates consistent alterations in the levels of ten specific proteins. Electrophoresis. 2007, 28(23):4302-10.
35. Sun W, Xing B, Sun Y, et al. Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. Mol Cell Proteomics. 2007, 6(10): 1798-808.
36. Jin T, Hu LS, Chang M, et al. Proteomic identification of potential protein markers in cerebrospinal fluid of GBS patients. Eur J Neurol. 2007,14(5):563-8.
37. Zhang X, Guo Y, Song Y, et al. Proteomic analysis of individual variation in normal livers of human beings using difference gel electrophoresis. Proteomics. 2006,6(19):5260-8.
1.Anstee QM,Goldin RD.Mouse models in non-alcoholic fatty liver disease and steatohepatitis research.Int J Exp Pathol.2006,87(1):1-16.
2.Samaha FF.Effect of very high-fat diets on body weight,Iipoproteins,and glycemic status in the obese.Curt Atheroscler Rep.2005,7(6):412-20.
3.Denke MA.Review of human studies evaluating individual dietary responsiveness in patients with hypercholesterolemia.Am J Clin Nutr.1995,62(2):471S-477S.
4.Grynberg A.Hypertension prevention:from nutrients to(fortified)foods to dietary patterns.Focus on fatty acids.J Hum Hypertens.2005,19 Suppl 3:S25-33.
5.Musso G,Gambino R,Michieli FD,et al.Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis.Hepatotogy.2003,37:909-16.
6.Lieber CS,Leo MA,Mak KM,et al.Model of nonalcoholic steatohepatitis.Am J Clin Nutr.2004,79(3):502-9.
7.Sahai A,Malladi P,Pan X,et al.Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis:role of short-form leptin receptors and osteopontin.Am J Physiol Gastrointest Liver Physiol.2004,287(5):G1035-43.
8.Margalit M,Shalev Z,Pappo O,et al.Glucocerebroside ameliorates the metabolic syndrome in OB/OB mice.J Pharmacol Exp Ther.2006,319(1):105-10.
9.Ding X,Saxena NK,Lin S,et al.Exendin-4,a glucagon-like protein-1(OLP-1)receptor agonist,reverses hepatic steatosis in ob/ob mice.Hepatology.2006,43(1):173-81.
10.Oarcia-Ruiz I,Rodriguez-Juan C,Diaz-Sanjuan T,et al.Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice.Hepatology.2006,44(3):581-91.
11.Honda H,Ikejima K,Hirose M,et al.Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver.Hepatology.2002,36:12-21.
12.Leclercq IA,Farrell GC,Schriemer R,et al.Leptin is essential for the hepatic fibrogenic response to chronic liver injury.J Hepatol.2002,37:206-13.
13.Faggioni R,Fantuzzi G,Gabay C,et al.Leptin deficiency enhances sensitivity to endotoxin-induced lethality.Am J Physiol.1999,276:R136-42.
14.Koteish A,Dieh1 AM.Animal models of steatosis.Semin Liver Dis.2001,21:89-104.
15.Rinella ME,Green RM.The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance.J Hepatol.2004,40:47-51.
16.Svegliati-Baroni G,Candelaresi C,Saecomanno S,et al.A model of insulin resistance and nonalcoholic steatohepatitis in rats:role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury.Am J Pathol.2006,169(3):846-60.
17.Savage DB,Choi CS,Samuel VT,et al.Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2.J Clin Invest.2006,116(3):817-24.
1.Bellentani S,Saccoccio G,Masutti F,et al.Prevalence of and risk factors for hepatic steatosis in Northern Italy.Ann Intern Med.2000,132:112-7.
2.Nomura H,Kashiwagi S,Hayashi J,et al.Prevalence of fatty liver in a general population of Okinawa,Japan.Jpn J Med.1988,27:142-9.
3.Fan JG,Zhu J,Li XJ,et al.Prevalence of and risk factors for fatty liver in a general population of Shanghai,China.J Hepatol.2005,43:508-14.
4.Haynes P,Liangpunsakul S,Chalasani N.Nonalcoholic fatty liver disease in individuals with severe obesity.Clin Liver Dis.2004,8:535-47.
5.Franzese A,Vajro P,Argenziano A,et al.Liver involvement in obese children.Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population.Dig Dis Sci.1997,42:1428-32.
6.Tominaga K,Kurata JH,Chen YK,et al.Prevalence of fatty liver in Japanese children and relationship to obesity.An epidemiological ultrasonographic survey.Dig Dis Sci.1995,40:2002-9.
7.Socha P,Wierzbicka A,Neuhoff-Murawska J,et al.Nonalcoholic fatty liver disease as a feature of the metabolic syndrome.Rocz Panstw Zakl Hig.2007,58(1):129-37.
8.Adams LA,Lymp JF,St Sauver J,et al.The natural history of nonalcoholic fatty liver disease:a population-based cohort study.Gastroenterology.2005,129(1):113-21.
9.Miele L,Forgione A,Hernandez AP,et al.The natural history and risk factors for progression of non-alcoholic fatty liver disease and steatohepatitis. Eur Rev Med Pharmacol Sci. 2005, 9(5);273-7.
10. Musso G, Gambino R, Michieli FD, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003, 37:909-16.
11. Hanash S. Disease proteomics. Nature. 2003,422(6928):226-32.
12. Unlu M, Morgan ME, Minden JS. Difference gel electrophoresis: a single gel method for detecting changes in protein extracts. Electrophoresis 1997, 18:2071-7.
13. Van den Bergh G, Arckens L. Fluorescent two-dimensional difference gel electrophoresis unveils the potential of gel-based proteomics. Curr Opin Biotechnol. 2004,15(1):38-43.
14. Yan JX, Devenish AT, Wait R, et al. Fluorescence two-dimensional difference gel electrophoresis and mass spectrometry based proteomic analysis of Escherichia coli. Proteomics. 2002,2(12): 1682-98.
15. Dowling P, O'Driscoll L, Meleady P, et al. 2-D difference gel electrophoresis of the lung squamous cell carcinoma versus normal sera demonstrates consistent alterations in the levels of ten specific proteins. Electrophoresis. 2007, 28(23):4302-10.
16. Sun W, Xing B, Sun Y, et al. Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. Mol Cell Proteomics. 2007, 6(10):1798-808.
17. Jin T, Hu LS, Chang M, et al. Proteomic identification of potential protein markers in cerebrospinal fluid of GBS patients. Eur J Neurol. 2007,14(5):563-8.
18. Zhang X. Guo Y, Song Y, et al. Proteomic analysis of individual variation in normal livers of human beings using difference gel electrophoresis. Proteomics. 2006;6(19):5260-8.
19. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002,346:1221-31.
20. McCullough AJ. Update on nonalcoholic fatty liver disease. J Clin Gastroenterol. 2002,34:255-62.
21. Mulhall BP, Ong JP, Younossi ZM. Non-alcoholic fatty liver disease: an overview. J Gastroenterol Hepatol. 2002,17:1136-43.
22. Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A.. 1999, 96:7473-8.
23. Ip E, Farrell GC, Robertson G, et al. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology. 2003, 38:123-32.
24. Matsusue K, Gavrilova O, Lambert G, et al. Hepatic CCAAT/enhancer binding protein alpha mediates induction of lipogenesis and regulation of glucose homeostasis in leptin-deficient mice. Mol Endocrinol. 2002,18:2751-64.
25. Kojima H, Sakurai S, Uemura M, et al. Mitochondrial abnormality and oxidative stress in nonalcoholic steatohepatitis. Alcohol Clin Exp Res. 2007, 31(1 Suppl):S61-6.
26. Oliveira CP, Coelho AM, Barbeiro HV, et al. Liver mitochondrial dysfunction and oxidative stress in the pathogenesis of experimental nonalcoholic fatty liver disease. Braz J Med Biol Res. 2006,39(2): 189-94.
27. Begriche K, Igoudjil A, Pessayre D, et al. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it.Mitochondrion. 2006. 6(1):1-28.
28. Hensley K, Kotake Y, Sang H, et al. Dietary choline restriction causes complex I dysfunction and increased H(2)O(2) generation in liver mitochondria. Carcinogenesis. 2000,21:983-9.
29. Yang S, Zhu H, Li Y, et al. Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 2000, 378:259-68.
30. Santamaria E, Avila MA, Latasa MU, et al. Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine. Proc Natl Acad Sci U S A. 2003,100:3065-70.
31. Nakamichi I, Toivola DM, Strnad P, et al. Keratin 8 overexpression promotes mouse Mallory body formation. J Cell Biol. 2005,171:931-7.
32. Nakamichi I, Hatakeyama S, Nakayama KI. Formation of Mallory body-like inclusions and cell death induced by deregulated expression of keratin 18. Mol Biol Cell. 2002,13:3441-51.
33. Ballardini G, Fallani M, Biagini G, et al. Desmin and actin in the identification of Ito cells and in monitoring their evolution to myofibroblasts in experimental liver fibrosis. Virchows Arch B Cell Pathol Incl Mol Pathol. 1988, 56:45-9.
34. Jiroutova A, Majdiakova L, Cermakova M, et al. Expression of cytoskeletal proteins in hepatic stellate cells isolated from normal and cirrhotic rat liver. Acta Medica (Hradec Kralove) 2005,48:137-44.
35. Lai E, Teodoro T, Volchuk A. Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology (Bethesda). 2007,22:193-201.
36. Schroder M. The unfolded protein response. Mol Biotechnol. 2006;34(2):279-90.
37. Hetz CA. ER stress signaling and the BCL-2 family of proteins: from adaptation to irreversible cellular damage.Antioxid Redox Signal. 2007, 9(12):2345-55.
38. Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ. 2006,13(3):363-73.
39. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004, 306:457-61.
40. Nakatani Y, Kaneto H, Kawamori D, et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem. 2005,280:847-851.
41. Ni M, Lee AS. ER chaperones in mammalian development and human diseases. FEBS Lett. 2007, 581(19):3641-3651.
42. Hetz C, Russelakis-Carneiro M, Walchli S, et al. The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity. J Neurosci. 2005, 25(11):2793-2802.
43. Uehara T, Nakamura T, Yao D, et al. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature. 2006,441(7092):513-7.
44. Mkrtchian S, Baryshev M, Matvijenko O, et al. Oligomerization properties of ERp29, an endoplasmic reticulum stress protein. FEBS Lett. 1998,431(3):322-6.
45. Kharroubi I, Ladriere L, Cardozo AK, et al. Free fatty acids and cytokines induce pancreatic factor-kappaB and endoplasmic reticulum stress. Endocrinology 2004, 145:5087-96.
46. 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. 2006,291:E275-81.
47. Xue X, Piao JH, Nakajima A, et al. Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response(UPR)in a reactive oxygen species (ROS)-dependent fashion,and the UPR counteracts ROS accumulation by TNFalpha.J Biol Chem.2005,280:33917-25.
48.Hayashi T,Saito A,Okuno S,et al.Damage to the endoplasmic reticulum and activation of apoptotic machinery by oxidative stress in ischemic neurons.J Cereb Blood Flow Metab.2005,25(1):41-53.
1.Santamaria E,Avila MA,Latasa MU,et al.Functional proteomics of nonalcoholic steatohepatitis:Mitochondrial proteins as targets of S-adenosylmethionine.Proc Natl Acad Sci USA,2003,100:3065-3070.
2.Schmid GM,Converset V,Walter N,et al.Effect of high-fat diet on the expression of proteins in muscle,adipose tissues,and liver of C57BL/6 mice.Protiomics,2004;4:2270-2282.
3. Park JY, Seong JK . Paik YK . et al. Proteomic analysis of diet-induced hypercholesterolemic mice. Proteomics, 2004; 4:514-523.
4. Van Greevenbroek MM, Vermuelen VM, De Bruin TW, et al. Identification of novel molecular candidates for fatty liver in the hyperlipidemic mouse model, HcB19. Journal of Lipid Research, 2004,45:1148-1154.
5. Honda K, Hayashida Y, Umaki T, et al. Possible detection of pancreatic cancer by plasma protein profiling. Cancer Res, 2005, 65(22):10613-10622.
6. Hara T, Honda K, Ono M, et al. Identification of 2 serum biomarkers of renal cell carcinoma by surface enhanced laser desorption/ionization mass spectrometry. J Urol. 2005,174(4 Pt 1):1213-1217.
7. Stanley BA, Gundry RL, Cotter RJ, et al. Heart disease, clinical proteomics and mass spectrometry. Dis Markers. 2004,20(3):167-178.
8. Irizarry MC. Biomarkers of Alzheimer disease in plasma. NeuroRx. 2004, l(2):226-234.
9. Echan A, Tang HY, Ali-Khan N, et al. Depletion of multiple high-abundance proteins improves protein profiling capacities of human serum and plasma. Proteomics. 2005,5(13):3292-3303.
10. Seibert V, Ebert MP, Buschmann T. Advances in clinical cancer proteomics: SELDI-ToF-mass spectrometry and biomarker discovery. Brief Funct Genomic Proteomic. 2005,4(1): 16-26.
11. Younossi ZM, Baranova A, Ziegler K, et al. A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease. Hepatology, 2005,42(3):665-74.
12. Edvardsson U, von Lowenhielm HB, Panfilov O, et al. Hepatic protein expression of lean mice and obese diabetic mice treated with peroxisome proliferator-activated receptor activators. Proteomics, 2003, 3:468-478.
13. White IR, Man WJ, Bryant D, et al. Protein expression changes in the Sprague Dawley rat liver proteome following administration of peroxisome proliferator activated receptor a and y ligands. Proteomics, 2003,3:505-512.
14. Beranova-Giorgianni S. Proteome analysis by two dimensional gel electrophoresis and mass spectrometry: strengths and limitations. Trends in Analytical Chemistry. 2003,22(5): 273-281.
15. Nagele E, Vollmer M, Horth P, et al. 2D-LC/MS techniques for the identification of proteins in highly complex mixtures. Expert Rev Proteomics. 2004,1(1): 37-46.
16. Liu H, Zhang L, Zhang W, et al. Application in capillary electrophoresis-based two-dimensional separation system. Se Pu. 2005,23(1): 52-56.
17. Bergstrom SK, Samskog J, Markides KE. Development of a poly(dimethylsiloxane) interface for on-line capillary column liquid chromatography-capillary electrophoresis coupled to sheathless electrospray ionization time-of-flight mass spectrometry. Anal Chem. 2003,15 (20): 5461-5467.
18. Simpson DC, Smith RD. Combining capillary electrophoresis with mass spectrometry for applications in proteomics. Electrophoresis. 2005, 26(7-8):1291-1305.
2.Angulo P.Nonalcoholic fatty liver disease.N Engl J Med.2002,346(16):1221-31.
3.Ratziu V,Poynard T.Assessing the outcome of nonalcoholic steatohepatitis? It's time to get serious.Hepatology.2006,44(4):802-5.
4.Adams LA,Lymp JF,St Sauver J,et al.The natural history of nonalcoholic fatty liver disease:a population-based cohort study.Gastroenterology.2005,129(1):113-21.
5.Miele L,Forgione A,Hernandez AP,et al.The natural history and risk factors for progression of non-alcoholic fatty liver disease and steatohepatitis.Eur Rev Med Pharmacol Sci.2005,9(5):273-7.
6.Day CP,James OF.Steatohepatitis:a tale of two "hits"? Gastroenterology.1998,114(4):842-5.
7.Portincasa P,Grattagliano I,Palmieri VO,et al.Nonalcoholic steatohepatitis: recent advances from experimental models to clinical management. Clin Biochem. 2005, 38(3):203-17.
8. Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol. 2006, 290(5):G852-8.
9. Fishman S, Muzumdar RH, Atzmon G, et al. Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo. FASEB J. 2007, 21(1):53-60.
10. Cassader M, Gambino R, Musso G, et al. Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients. Lipids. 2001, 36(10): 111 7-24.
11. Robertson G, Leclercq I, Farrell G. Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress. Am J Physiol Gastrointest Liver Physiol. 2001,281 :G1135-9.
12. Wigg AJ, Roberts-Thomson IC, Dymock RB, et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumor necrosis factor a in the pathogenesis of nonalcoholic steatohepatitis. Gut. 2001,48:206-11.
13. Albano E, Mottaran E, Occhino G, et al. Review article: role of oxidative stress in the progression of non-alcoholic steatosis. Aliment Pharmacol Ther. 2005, 22 Suppl 2:71-3.
14. Friedman SL. Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol. 2004, 1(2):98-105.
15. Washington K, Wright K, Shyr Y, et al. Hepatic stellate cell activation in nonalcoholic steatohepatitis and fatty liver. Hum Pathol. 2000, 31(7):822-8.
16. Neuschwander-Tetri BA. Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003, 37(5): 1202-19.
17. Musso G, Gambino R. Michieli FD, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003,37:909-16.
18. Honda H, Ikejima K, Hirose M, et al. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology. 2002, 36:12-21.
19. Leclercq IA, Farrell GC, Schriemer R, et al. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J Hepatol. 2002, 37: 206-13.
20. Leclercq IA, Field J, Farrell G.C. Leptin-specific mechanisms for impaired liver regeneration in ob/ob mice after toxic injury. Gastroenterology. 2003, 124: 1451-64.
21. Zeisel SH, Blusztajn JK. Choline and human nutrition. Annu Rev Nutr. 1994, 14: 269-96.
22. Yao ZM, Vance DE. Reduction in VLDL, but not HDL, in plasma of rats deficient in choline. Biochem Cell Biol. 1990,68:552-58.
23. Weltman MD, Farrell GC, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology. 1996,111:1645-53.
24. Rinella ME, Green RM. The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol. 2004,40:47-51.
25. Lieber CS, Leo MA, Mak BCM, et al. Model of nonalcoholic steatohepatitis. Am J Clin Nutr. 2004, 79(3):502-9.
26. Svegliati-Baroni G, Candelaresi C, Saccomanno S, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol. 2006,169(3):846-60.
27. Savage DB, Choi CS, Samuel VT, et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest. 2006,116(3):817-24.
28. Diamond DL, ProU SC, Jacobs JM, et al. HepatoProteomics: applying proteomic technologies to the study of liver function and disease. Hepatology. 2006, 44(2):299-308.
29. Santamaria E, M A Avila, M U Latasa, et al. Functional proteomics of nonalcoholic steatohepatitis: Mitochondrial proteins as targets of S-adenosylmethionine. Proc Natl Acad Sci USA. 2003,100:3065-70.
30. Younossi ZM, Baranova A, Ziegler K, et al. A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease. Hepatology 2005,42:665-74.
31. Douette P, Navet R, Gerkens P, et al. Steatosis-induced proteomic changes in liver mitochondria evidenced by two-dimensional differential In-gel electrophoresis. J Proteome Res. 2005,4:2024-31.
32. Van den Bergh G, Arckens L. Fluorescent two-dimensional difference gel electrophoresis unveils the potential of gel-based proteomics. Curr Opin Biotechnol. 2004,15(1):38-43.
33. Yan JX, Devenish AT, Wait R, et al. Fluorescence two-dimensional difference gel electrophoresis and mass spectrometry based proteomic analysis of Escherichia coli. Proteomics. 2002,2(12):1682-98.
34. Dowling P, O'Driscoll L, Meleady P, et al. 2-D difference gel electrophoresis of the lung squamous cell carcinoma versus normal sera demonstrates consistent alterations in the levels of ten specific proteins. Electrophoresis. 2007, 28(23):4302-10.
35. Sun W, Xing B, Sun Y, et al. Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. Mol Cell Proteomics. 2007, 6(10): 1798-808.
36. Jin T, Hu LS, Chang M, et al. Proteomic identification of potential protein markers in cerebrospinal fluid of GBS patients. Eur J Neurol. 2007,14(5):563-8.
37. Zhang X, Guo Y, Song Y, et al. Proteomic analysis of individual variation in normal livers of human beings using difference gel electrophoresis. Proteomics. 2006,6(19):5260-8.
1.Anstee QM,Goldin RD.Mouse models in non-alcoholic fatty liver disease and steatohepatitis research.Int J Exp Pathol.2006,87(1):1-16.
2.Samaha FF.Effect of very high-fat diets on body weight,Iipoproteins,and glycemic status in the obese.Curt Atheroscler Rep.2005,7(6):412-20.
3.Denke MA.Review of human studies evaluating individual dietary responsiveness in patients with hypercholesterolemia.Am J Clin Nutr.1995,62(2):471S-477S.
4.Grynberg A.Hypertension prevention:from nutrients to(fortified)foods to dietary patterns.Focus on fatty acids.J Hum Hypertens.2005,19 Suppl 3:S25-33.
5.Musso G,Gambino R,Michieli FD,et al.Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis.Hepatotogy.2003,37:909-16.
6.Lieber CS,Leo MA,Mak KM,et al.Model of nonalcoholic steatohepatitis.Am J Clin Nutr.2004,79(3):502-9.
7.Sahai A,Malladi P,Pan X,et al.Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis:role of short-form leptin receptors and osteopontin.Am J Physiol Gastrointest Liver Physiol.2004,287(5):G1035-43.
8.Margalit M,Shalev Z,Pappo O,et al.Glucocerebroside ameliorates the metabolic syndrome in OB/OB mice.J Pharmacol Exp Ther.2006,319(1):105-10.
9.Ding X,Saxena NK,Lin S,et al.Exendin-4,a glucagon-like protein-1(OLP-1)receptor agonist,reverses hepatic steatosis in ob/ob mice.Hepatology.2006,43(1):173-81.
10.Oarcia-Ruiz I,Rodriguez-Juan C,Diaz-Sanjuan T,et al.Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice.Hepatology.2006,44(3):581-91.
11.Honda H,Ikejima K,Hirose M,et al.Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver.Hepatology.2002,36:12-21.
12.Leclercq IA,Farrell GC,Schriemer R,et al.Leptin is essential for the hepatic fibrogenic response to chronic liver injury.J Hepatol.2002,37:206-13.
13.Faggioni R,Fantuzzi G,Gabay C,et al.Leptin deficiency enhances sensitivity to endotoxin-induced lethality.Am J Physiol.1999,276:R136-42.
14.Koteish A,Dieh1 AM.Animal models of steatosis.Semin Liver Dis.2001,21:89-104.
15.Rinella ME,Green RM.The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance.J Hepatol.2004,40:47-51.
16.Svegliati-Baroni G,Candelaresi C,Saecomanno S,et al.A model of insulin resistance and nonalcoholic steatohepatitis in rats:role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury.Am J Pathol.2006,169(3):846-60.
17.Savage DB,Choi CS,Samuel VT,et al.Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2.J Clin Invest.2006,116(3):817-24.
1.Bellentani S,Saccoccio G,Masutti F,et al.Prevalence of and risk factors for hepatic steatosis in Northern Italy.Ann Intern Med.2000,132:112-7.
2.Nomura H,Kashiwagi S,Hayashi J,et al.Prevalence of fatty liver in a general population of Okinawa,Japan.Jpn J Med.1988,27:142-9.
3.Fan JG,Zhu J,Li XJ,et al.Prevalence of and risk factors for fatty liver in a general population of Shanghai,China.J Hepatol.2005,43:508-14.
4.Haynes P,Liangpunsakul S,Chalasani N.Nonalcoholic fatty liver disease in individuals with severe obesity.Clin Liver Dis.2004,8:535-47.
5.Franzese A,Vajro P,Argenziano A,et al.Liver involvement in obese children.Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population.Dig Dis Sci.1997,42:1428-32.
6.Tominaga K,Kurata JH,Chen YK,et al.Prevalence of fatty liver in Japanese children and relationship to obesity.An epidemiological ultrasonographic survey.Dig Dis Sci.1995,40:2002-9.
7.Socha P,Wierzbicka A,Neuhoff-Murawska J,et al.Nonalcoholic fatty liver disease as a feature of the metabolic syndrome.Rocz Panstw Zakl Hig.2007,58(1):129-37.
8.Adams LA,Lymp JF,St Sauver J,et al.The natural history of nonalcoholic fatty liver disease:a population-based cohort study.Gastroenterology.2005,129(1):113-21.
9.Miele L,Forgione A,Hernandez AP,et al.The natural history and risk factors for progression of non-alcoholic fatty liver disease and steatohepatitis. Eur Rev Med Pharmacol Sci. 2005, 9(5);273-7.
10. Musso G, Gambino R, Michieli FD, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003, 37:909-16.
11. Hanash S. Disease proteomics. Nature. 2003,422(6928):226-32.
12. Unlu M, Morgan ME, Minden JS. Difference gel electrophoresis: a single gel method for detecting changes in protein extracts. Electrophoresis 1997, 18:2071-7.
13. Van den Bergh G, Arckens L. Fluorescent two-dimensional difference gel electrophoresis unveils the potential of gel-based proteomics. Curr Opin Biotechnol. 2004,15(1):38-43.
14. Yan JX, Devenish AT, Wait R, et al. Fluorescence two-dimensional difference gel electrophoresis and mass spectrometry based proteomic analysis of Escherichia coli. Proteomics. 2002,2(12): 1682-98.
15. Dowling P, O'Driscoll L, Meleady P, et al. 2-D difference gel electrophoresis of the lung squamous cell carcinoma versus normal sera demonstrates consistent alterations in the levels of ten specific proteins. Electrophoresis. 2007, 28(23):4302-10.
16. Sun W, Xing B, Sun Y, et al. Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. Mol Cell Proteomics. 2007, 6(10):1798-808.
17. Jin T, Hu LS, Chang M, et al. Proteomic identification of potential protein markers in cerebrospinal fluid of GBS patients. Eur J Neurol. 2007,14(5):563-8.
18. Zhang X. Guo Y, Song Y, et al. Proteomic analysis of individual variation in normal livers of human beings using difference gel electrophoresis. Proteomics. 2006;6(19):5260-8.
19. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002,346:1221-31.
20. McCullough AJ. Update on nonalcoholic fatty liver disease. J Clin Gastroenterol. 2002,34:255-62.
21. Mulhall BP, Ong JP, Younossi ZM. Non-alcoholic fatty liver disease: an overview. J Gastroenterol Hepatol. 2002,17:1136-43.
22. Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A.. 1999, 96:7473-8.
23. Ip E, Farrell GC, Robertson G, et al. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology. 2003, 38:123-32.
24. Matsusue K, Gavrilova O, Lambert G, et al. Hepatic CCAAT/enhancer binding protein alpha mediates induction of lipogenesis and regulation of glucose homeostasis in leptin-deficient mice. Mol Endocrinol. 2002,18:2751-64.
25. Kojima H, Sakurai S, Uemura M, et al. Mitochondrial abnormality and oxidative stress in nonalcoholic steatohepatitis. Alcohol Clin Exp Res. 2007, 31(1 Suppl):S61-6.
26. Oliveira CP, Coelho AM, Barbeiro HV, et al. Liver mitochondrial dysfunction and oxidative stress in the pathogenesis of experimental nonalcoholic fatty liver disease. Braz J Med Biol Res. 2006,39(2): 189-94.
27. Begriche K, Igoudjil A, Pessayre D, et al. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it.Mitochondrion. 2006. 6(1):1-28.
28. Hensley K, Kotake Y, Sang H, et al. Dietary choline restriction causes complex I dysfunction and increased H(2)O(2) generation in liver mitochondria. Carcinogenesis. 2000,21:983-9.
29. Yang S, Zhu H, Li Y, et al. Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 2000, 378:259-68.
30. Santamaria E, Avila MA, Latasa MU, et al. Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine. Proc Natl Acad Sci U S A. 2003,100:3065-70.
31. Nakamichi I, Toivola DM, Strnad P, et al. Keratin 8 overexpression promotes mouse Mallory body formation. J Cell Biol. 2005,171:931-7.
32. Nakamichi I, Hatakeyama S, Nakayama KI. Formation of Mallory body-like inclusions and cell death induced by deregulated expression of keratin 18. Mol Biol Cell. 2002,13:3441-51.
33. Ballardini G, Fallani M, Biagini G, et al. Desmin and actin in the identification of Ito cells and in monitoring their evolution to myofibroblasts in experimental liver fibrosis. Virchows Arch B Cell Pathol Incl Mol Pathol. 1988, 56:45-9.
34. Jiroutova A, Majdiakova L, Cermakova M, et al. Expression of cytoskeletal proteins in hepatic stellate cells isolated from normal and cirrhotic rat liver. Acta Medica (Hradec Kralove) 2005,48:137-44.
35. Lai E, Teodoro T, Volchuk A. Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology (Bethesda). 2007,22:193-201.
36. Schroder M. The unfolded protein response. Mol Biotechnol. 2006;34(2):279-90.
37. Hetz CA. ER stress signaling and the BCL-2 family of proteins: from adaptation to irreversible cellular damage.Antioxid Redox Signal. 2007, 9(12):2345-55.
38. Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ. 2006,13(3):363-73.
39. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004, 306:457-61.
40. Nakatani Y, Kaneto H, Kawamori D, et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem. 2005,280:847-851.
41. Ni M, Lee AS. ER chaperones in mammalian development and human diseases. FEBS Lett. 2007, 581(19):3641-3651.
42. Hetz C, Russelakis-Carneiro M, Walchli S, et al. The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity. J Neurosci. 2005, 25(11):2793-2802.
43. Uehara T, Nakamura T, Yao D, et al. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature. 2006,441(7092):513-7.
44. Mkrtchian S, Baryshev M, Matvijenko O, et al. Oligomerization properties of ERp29, an endoplasmic reticulum stress protein. FEBS Lett. 1998,431(3):322-6.
45. Kharroubi I, Ladriere L, Cardozo AK, et al. Free fatty acids and cytokines induce pancreatic factor-kappaB and endoplasmic reticulum stress. Endocrinology 2004, 145:5087-96.
46. 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. 2006,291:E275-81.
47. Xue X, Piao JH, Nakajima A, et al. Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response(UPR)in a reactive oxygen species (ROS)-dependent fashion,and the UPR counteracts ROS accumulation by TNFalpha.J Biol Chem.2005,280:33917-25.
48.Hayashi T,Saito A,Okuno S,et al.Damage to the endoplasmic reticulum and activation of apoptotic machinery by oxidative stress in ischemic neurons.J Cereb Blood Flow Metab.2005,25(1):41-53.
1.Santamaria E,Avila MA,Latasa MU,et al.Functional proteomics of nonalcoholic steatohepatitis:Mitochondrial proteins as targets of S-adenosylmethionine.Proc Natl Acad Sci USA,2003,100:3065-3070.
2.Schmid GM,Converset V,Walter N,et al.Effect of high-fat diet on the expression of proteins in muscle,adipose tissues,and liver of C57BL/6 mice.Protiomics,2004;4:2270-2282.
3. Park JY, Seong JK . Paik YK . et al. Proteomic analysis of diet-induced hypercholesterolemic mice. Proteomics, 2004; 4:514-523.
4. Van Greevenbroek MM, Vermuelen VM, De Bruin TW, et al. Identification of novel molecular candidates for fatty liver in the hyperlipidemic mouse model, HcB19. Journal of Lipid Research, 2004,45:1148-1154.
5. Honda K, Hayashida Y, Umaki T, et al. Possible detection of pancreatic cancer by plasma protein profiling. Cancer Res, 2005, 65(22):10613-10622.
6. Hara T, Honda K, Ono M, et al. Identification of 2 serum biomarkers of renal cell carcinoma by surface enhanced laser desorption/ionization mass spectrometry. J Urol. 2005,174(4 Pt 1):1213-1217.
7. Stanley BA, Gundry RL, Cotter RJ, et al. Heart disease, clinical proteomics and mass spectrometry. Dis Markers. 2004,20(3):167-178.
8. Irizarry MC. Biomarkers of Alzheimer disease in plasma. NeuroRx. 2004, l(2):226-234.
9. Echan A, Tang HY, Ali-Khan N, et al. Depletion of multiple high-abundance proteins improves protein profiling capacities of human serum and plasma. Proteomics. 2005,5(13):3292-3303.
10. Seibert V, Ebert MP, Buschmann T. Advances in clinical cancer proteomics: SELDI-ToF-mass spectrometry and biomarker discovery. Brief Funct Genomic Proteomic. 2005,4(1): 16-26.
11. Younossi ZM, Baranova A, Ziegler K, et al. A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease. Hepatology, 2005,42(3):665-74.
12. Edvardsson U, von Lowenhielm HB, Panfilov O, et al. Hepatic protein expression of lean mice and obese diabetic mice treated with peroxisome proliferator-activated receptor activators. Proteomics, 2003, 3:468-478.
13. White IR, Man WJ, Bryant D, et al. Protein expression changes in the Sprague Dawley rat liver proteome following administration of peroxisome proliferator activated receptor a and y ligands. Proteomics, 2003,3:505-512.
14. Beranova-Giorgianni S. Proteome analysis by two dimensional gel electrophoresis and mass spectrometry: strengths and limitations. Trends in Analytical Chemistry. 2003,22(5): 273-281.
15. Nagele E, Vollmer M, Horth P, et al. 2D-LC/MS techniques for the identification of proteins in highly complex mixtures. Expert Rev Proteomics. 2004,1(1): 37-46.
16. Liu H, Zhang L, Zhang W, et al. Application in capillary electrophoresis-based two-dimensional separation system. Se Pu. 2005,23(1): 52-56.
17. Bergstrom SK, Samskog J, Markides KE. Development of a poly(dimethylsiloxane) interface for on-line capillary column liquid chromatography-capillary electrophoresis coupled to sheathless electrospray ionization time-of-flight mass spectrometry. Anal Chem. 2003,15 (20): 5461-5467.
18. Simpson DC, Smith RD. Combining capillary electrophoresis with mass spectrometry for applications in proteomics. Electrophoresis. 2005, 26(7-8):1291-1305.