代谢综合征合并非酒精性脂肪肝炎小鼠模型的建立及银杏叶提取物治疗代谢综合征作用及其机制的探讨
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摘要
随着生活方式和饮食结构的改变,代谢综合征的发病率日益增高。代谢综合征是一种以肥胖、胰岛素抵抗及脂质代谢紊乱等为特征的疾病,其在肝脏的表现为非酒精性脂肪性肝病(non-alcoholic fatty liverdisease,NAFLD)。NAFLD主要包括单纯性脂肪肝、非酒精性脂肪性肝炎(non-alcoholic steatohepaitis,NASH)、以及肝硬化三个阶段,其中NASH是NAFLD发展过程中的关键阶段。对NASH的发病机制和防治措施的研究已经成为NAFLD研究的焦点。代谢综合征发病机制复杂且受多种因素调控,多需要长期的药物治疗,因此从天然产物中寻找疗效肯定、毒副作用小的预防和治疗代谢综合征的药物显得尤其重要。基于对代谢综合征的上述两方面的研究现状了解及关注,本文论文内容主要分为“代谢综合征合并非酒精性脂肪肝炎小鼠模型的建立”和“银杏叶提取物治疗代谢综合征作用及其机制的探讨”两个部分。
The prevalence of metabolic syndrome,which is characterized by obesity, insulin resistance and dyslipidaemia,has increased dramatically accompanied with the changes of life style and diet composition.As a hepatic manifestation of metabolic syndrome,non-alcoholic fatty liver disease(NAFLD) also becomes prevalent and includes simple steatosis,non-alcoholic steatohepatitis(NASH) and liver cirrhosis.Non-alcoholic steatohepatitis(NASH),a crucial stage of NAFLD,leads to liver cirrhosis.The pathogenesis and the treatment of NASH are not clear and need further research.As to the treatment of metabolic syndrome, natural products that are safe and have multiple pharmacological effects could be potential therapies,because of the complexity and chronic intervention of metabolic syndrome.Ginkgo biloba leavesare such kind of natural product and has been widely used in clinic both in and outside of China.As a standardized and well-defined product of Ginkgo biloba leaves,EGB761 not only has anti-oxidant and anti-inflammation activity but also could improve serum lipid profiles and hyperglycemia in type 1 diabetes rat model.Focused on above two aspects of metabolic syndrome,two parts of work are presented in this dissertation and named as "Establishment of a metabolic syndrome related non-alcoholic steatohepatitis mouse model" and "studies on the effects of EGB761 on metabolic syndrome and its mechanisms".
The prevalence of metabolic syndrome,which is characterized by obesity, insulin resistance and dyslipidaemia,has increased dramatically accompanied with the changes of life style and diet composition.As a hepatic manifestation of metabolic syndrome,non-alcoholic fatty liver disease(NAFLD) also becomes prevalent and includes simple steatosis,non-alcoholic steatohepatitis(NASH) and liver cirrhosis.Non-alcoholic steatohepatitis(NASH),a crucial stage of NAFLD,leads to liver cirrhosis.The pathogenesis and the treatment of NASH are not clear and need further research.As to the treatment of metabolic syndrome, natural products that are safe and have multiple pharmacological effects could be potential therapies,because of the complexity and chronic intervention of metabolic syndrome.Ginkgo biloba leavesare such kind of natural product and has been widely used in clinic both in and outside of China.As a standardized and well-defined product of Ginkgo biloba leaves,EGB761 not only has anti-oxidant and anti-inflammation activity but also could improve serum lipid profiles and hyperglycemia in type 1 diabetes rat model.Focused on above two aspects of metabolic syndrome,two parts of work are presented in this dissertation and named as "Establishment of a metabolic syndrome related non-alcoholic steatohepatitis mouse model" and "studies on the effects of EGB761 on metabolic syndrome and its mechanisms".
引文
[1]Angulo,P.,Nonalcoholic Fatty Liver Disease[J].N.Engl.J.Med.,2002,346(16):1221-1231.
[2]Neuschwander-Tetr,B.A.and S.H.Caldwell,Nonalcoholic steatohepatitis:summary of an AASLD Single Topic Conference[J].Hepatology,2003,37(5):1202-19.
[3]Day,C.and S.Saksena,Non-alcoholic steatohepatitis:Definitions and pathogenesis[J].J Gastroenterol Hepatol,2002,17 Suppl 3:S377-S384.
[4]Rector,R.S.,et al.,Non-alcoholic fatty liver disease and the metabolic syndrome:an update[J].World J Gastroenterol,2008,14(2):185-92.
[5]Farrell,G.C.and C.Z.Larter,Nonalcoholic fatty liver disease:from steatosis to cirrhosis[J].Hepatology,2006,43(2 Suppl 1):S99-S112.
[6]Rinella,M.E.and R.M.Green,The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance[J].J Hepatol,2004,40(1):47-51.
[7]Evans,R.M.,2003 Keio Medical Science Prize commemorative lecture.PPARs and the complex journey to obesity[J].Keio J Med,2004,53(2):53-8.
[8]Forcheron,F.,et al.,Mechanisms of the triglyceride-and cholesterol-lowering effect of fenofibrate in hyperlipidemic type 2 diabetic patients[J].Diabetes,2002,51(12):3486-91.
[9]Yki-Jarvinen,H.,Thiazolidinediones[J].N Engl J Med,2004,351(11):1106-18.
[10]Harrity,T.,et al.,Muraglitazar,a Novel Dual({alpha}/{gamma}) Peroxisome Proliferator-Activated Receptor Activator,Improves Diabetes and Other Metabolic Abnormalities and Preserves{beta}-Cell Function in db/db Mice[J].Diabetes,2006,55(1):240-248.
[11]Ye,F.,et al.,Utilization of fluorescence tracer in hyperinsulinemic-euglycemic clamp test in mice[J].J Biochem Biophys Methods,2008,70(6):978-84.
[12]de Oliveira,C.P.,et al.,Hepatic gene expression profile associated with non-alcoholic steatohepatitis protection by S-nitroso-N-acetylcysteine in ob/ob mice[J].J Hepatol,2006,45(5):725-33.
[13]Day,C.P.,Non-alcoholic steatohepatitis(NASH):where are we now and where are we going?[J]Gut,2002,50(5):585-588.
[14]James,O.F.and C.P.Day,Non-alcoholic steatohepatitis(NASH):a disease of emerging identity and importance[J].J Hepatol,1998,29(3):495-501.
[15]Browning,J.D.and J.D.Horton,Molecular mediators of hepatic steatosis and liver injury[J].J Clin Invest,2004,114(2):147-52.
[16]Bradbury,M.W.and P.D.Berk,Lipid metabolism in hepatic steatosis[J].Clin Liver Dis,2004,8(3):639-71,ⅹⅰ.
[17]Schinner,S.,et al.,Molecular mechanisms of insulin resistance[J].Diabetic Medicine,2005,22(6):674-682.
[18]Postic,C.and J.Girard,Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance:lessons from genetically engineered mice[J].J Clin Invest,2008,118(3):829-38.
[19]Utzschneider,K.M.and S.E.Kahn,Review:The role of insulin resistance in nonalcoholic fatty liver disease[J].J Clin Endocrinol Metab,2006,91(12):4753-61.
[20]Marchesini,G.,et al.,Nonalcoholic Fatty Liver Disease:A Feature of the Metabolic Syndrome[J].Diabetes,2001,50(8):1844-1850.
[21]Choi,C.S.,et al.,Suppression of diacylglycerol acyltransferase-2(DGAT2),but not DGAT1,with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance[J].J Biol Chem,2007,282(31):22678-88.
[22]Tilg,H.and A.M.Diehl,Cytokines in Alcoholic and Nonalcoholic Steatohepatitis[J].N.Engl.J.Med.,2000,343(20):1467-1476.
[23]Savage,D.B.,K.F.Petersen,and G.I.Shulman,Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance[J].Physiol.Rev.,2007,87(2):507-520.
[24]Angulo,P.and K.D.Lindor,Treatment of non-alcoholic steatohepatitis[J].Best Pract Res Clin Gastroenterol,2002.16(5):797-810.
[25]Haque,M.and A.J.Sanyal,The metabolic abnormalities associated with non-alcoholic fatty liver disease[J].Best Pract Res Clin Gastroenterol,2002.16(5):709-31.
[26]Anstee,Q.M.and R.D.Goldin,Mouse models in non-alcoholic fatty liver disease and steatohepatitis research[J].International Journal of Experimental Pathology,2006.87(1):1-16.
[27]Nanji,A.A.,Animal models of nonalcoholic fatty liver disease and steatohepatitis[J].Clin Liver Dis,2004.8(3):559-74,ⅸ.
[28]Zou,Y.,et al.,High-fat emulsion-induced rat model of nonalcoholic steatohepatitis[J].Life Sci,2006.79(11):1100-7.
[29]Koteish,A.and A.M.Diehl,Animal models of steatosis[J].Semin Liver Dis,2001.21(1):89-104.
[30]Yu,S.,et al.,Adipocyte-specific Gene Expression and Adipogenic Steatosis in the Mouse Liver Due to Peroxisome Proliferator-activated Receptor gamma 1(PPARgamma 1) Overexpression[J].J.Biol.Chem.,2003.278(1):498-505.
[31]Araya,J.,et al.,Increase in long-chain polyunsaturated fatty acid n-6/n-3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease[J].Clin.Sci.,2004.106(6):635-643.
[32]Shimomura,I.,et al.,Nuclear Sterol Regulatory Element-binding Proteins Activate Genes Responsible for the Entire Program of Unsaturated Fatty Acid Biosynthesis in Transgenic Mouse Liver[J].J.Biol.Chem.,1998.273(52):35299-35306.
[33]Towle,H.C.,E.N.Kaytor,and H.M.Shih,Regulation of the expression of lipogenic enzyme genes by carbohydrate[J].Annu Rev Nutr,1997.17:405-33.
[34]Fukuda,H.,et al.,Transcriptional regulation of fatty acid synthase gene by insulin/glucose,polyunsaturated fatty acid and leptin in hepatocytes and adipocytes in normal and genetically obese rats [J].Eur J Biochem,1999.260(2):505-11.
[35]Xu,J.,et al.,Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids.A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats[J].J Biol Chem,1999.274(33):23577-83.
[36]Rahimian,R.,et al.,Hepatic over-expression of peroxisome proliferator activated receptor gamma2 in the ob/ob mouse model of non-insulin dependent diabetes mellitus[J].Mol Cell Biochem,2001.224(1-2):29-37.
[37]Reddy,J.K,Nonalcoholic Steatosis and Steatohepatitis:Ⅲ.Peroxisomal beta-oxidation,PPARalpha,and steatohepatitis[J].Am J Physiol Gastrointest Liver Physiol,2001.281(6):G1333-1339.
[38]den Boer,M.,et al.,Hepatic Steatosis:A Mediator of the Metabolic Syndrome.Lessons From Animal Models[J].Arterioscler.Thromb.Vasc.Biol.,2004.24(4):644-649.
[39]Nagasawa,T.,et al.,Effects of bezafibrate,PPAR pan-agonist,and GW501516,PPARdelta agonist,on development of steatohepatitis in mice fed a methionine-and choline-deficient diet[J].Eur J Pharmacol,2006.536(1-2):182-91.
[40]Ntambi,J.M.and M.Miyazaki,Regulation of stearoyl-CoA desaturases and role in metabolism[J].Prog Lipid Res,2004.43(2):91-104.
[41]Cao,J.,et al.,Molecular identification of microsomal acyl-CoA:glycerol-3-phosphate acyltransferase,a key enzyme in de novo triacylglycerol synthesis[J].Proc Natl Acad Sci U S A,2006.103(52):19695-700.
[42]Gibbons,G.F.,et al.,Synthesis and function of hepatic very-low-density lipoprotein[J].Biochem Soc Trans,2004.32(Pt 1):59-64.
[43]Wetterau,J.R.,et al.,Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia[J].Science,1992.258(5084):999-1001.
[44]Letteron,P.,et al.,Inhibition of microsomal triglyceride transfer protein:another mechanism for drug-induced steatosis in mice[J].Hepatology,2003.38(1):133-40.
[45]Bugianesi,E.,et al.,Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease:sites and mechanisms[J].Diabetologia,2005.48(4):634-42.
[46]Seppala-Lindroos,A.,et al.,Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men[J].J Clin Endocrinol Metab,2002.87(7):3023-8.
[47]Marchesini,G.,et al.,Association of nonalcoholic fatty liver disease with insulin resistance[J].Am J Med,1999.107(5):450-5.
[48]Abdul-Ghani,M.A.,D.Tripathy,and R.A.DeFronzo,Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose[J].Diabetes Care,2006.29(5):1130-9.
[49]Dong,X.,et al.,Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth [J].J Clin Invest,2006.116(1):101-14.
[50]Tonks,N.K.,Protein tyrosine phosphatases:from genes,to function,to disease[J].Nat Rev Mol Cell Biol,2006.7(11):833-46.
[51]Klaman,L.D.,et al.,Increased Energy Expenditure,Decreased Adiposity,and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice[J].Mol.Cell.Biol.,2000.20(15):5479-5489.
[1]Rader,D.J.,Effect of Insulin Resistance,Dyslipidemia,and Intra-abdominal Adiposity on the Development of Cardiovascular Disease and Diabetes Mellitus[J].The American Journal of Medicine,2007.120(3,Supplement 1):S12-S18.
[2]Smith,J.V.and Y.Luo,Studies on molecular mechanisms of Ginkgo biloba extract[J].Appl Microbiol Biotechnol,2004.64(4):465-72.
[3]Coskun,O.,et al.,Protection of endotoxin-induced oxidative renal tissue damage of rats by vitamin E or/and EGb 761 treatment[J].J Appl Toxicol,2005.25(1):8-12.
[4] Kudolo, G.B., D. Delaney, and J. Blodgett, Short-term oral ingestion of Ginkgo biloba extract (EGb 761) reduces malondialdehyde levels in washed platelets of type 2 diabetic subjects [J] . Diabetes Research and Clinical Practice, 2005. 68(1): 29-38.
[5] Abdel-Salam, O.M., et al., Evaluation of the anti-inflammatory, anti-nociceptive and gastric effects of Ginkgo biloba in the rat [J] . Pharmacol Res, 2004. 49(2): 133-42.
[6] Yao, Z.X., et al., Ginkgo biloba extract (Egb 761) inhibits beta-amyloid production by lowering free cholesterol levels [J] . J Nutr Biochem, 2004. 15(12): 749-56.
[7] Van Gaal, L.F., I.L Mertens, and C.E. De Block, Mechanisms linking obesity with cardiovascular disease [J] . Nature, 2006. 444(7121): 875-80.
[8] Long, Y.C. and J.R. Zierath, AMP-activated protein kinase signaling in metabolic regulation [J] . J Clin Invest, 2006. 116(7): 1776-83.
[9] Abdul-Ghani, M.A., D. Tripathy, and R.A. DeFronzo, Contributions of {beta}-Cell Dysfunction and Insulin Resistance to the Pathogenesis of Impaired Glucose Tolerance and Impaired Fasting Glucose [J] . Diabetes Care, 2006. 29(5): 1130-1139.
[10] Taniguchi, C.M., B. Emanuelli, and C.R. Kahn, Critical nodes in signalling pathways: insights into insulin action [J] . Nat Rev Mol Cell Biol, 2006. 7(2): 85-96.
[11] Qiu, W, et al., Hepatic PTP-1B expression regulates the assembly and secretion of apolipoprotein B-containing lipoproteins: evidence from protein tyrosine phosphatase-1B overexpression, knockout, and RNAi studies [J] . Diabetes, 2004. 53(12): 3057-66.
[12] Liu, H.Y., et al., Prolonged treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase [J] . J Biol Chem, 2007. 282(19): 14205-12.
[13] Zang, M., et al., AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells [J] . J Biol Chem, 2004. 279(46): 47898-905.
[14] Avramoglu, R.K., H. Basciano, and K. Adeli, Lipid and lipoprotein dysregulation in insulin resistant states [J] . Clin Chim Acta, 2006. 368(1-2): 1-19.
[15] Mokdad, A.H., et al., Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors [J] , 2001. JAMA, 2003. 289(1): 76-79.
[16] Ginsberg, H.N., Y.L. Zhang, and A. Hernandez-Ono, Regulation of plasma triglycerides in insulin resistance and diabetes [J] . Arch Med Res, 2005. 36(3): 232-40.
[17] Gertz, H.J. and M. Kiefer, Review about Ginkgo biloba special extract EGb 761 (Ginkgo) [J] . Curr Pharm Des, 2004. 10(3): 261-4.
[18] Sierpina, V.S., B. Wollschlaeger, and M. Blumenthal, Ginkgo biloba [J] .Am Fam Physician, 2003. 68(5): 923-6.
[19] Yoshikawa, T, Y. Naito, and M. Kondo, Ginkgo biloba leaf extract: review of biological actions and clinical applications [J] . Antioxid Redox Signal, 1999. 1(4): 469-80.
[20] Witte, S., I. Anadere, and E. Walitza, Improvement of hemorheology with ginkgo biloba extract. Decreasing a cardiovascular risk factor [J] . Fortschr Med, 1992. 110(13): 247-50.
[21] Choi, S.E., et al., Involvement of Ca2+, CaMK II and PKA in EGb 761-induced insulin secretion in INS-1 cells. [J] J Ethnopharmacol, 2007. 110(1): 49-55.
[22] Lippi, G., G. Targher, and G.C. Guidi, Ginkgo biloba, inflammation and lipoprotein(a) [J] . Atherosclerosis, 2007. 195(2): 417-418.
[23] Rodriguez, M., et al., Reduction of atherosclerotic nanoplaque formation and size by Ginkgo biloba (EGb 761) in cardiovascular high-risk patients [J] . Atherosclerosis, 2007. 192(2): 438-444.
[1]Neuschwander-Tetr,B.A.and S.H.Caldwell,Nonalcoholic steatohepatitis:summary of an AASLD Single Topic Conference[J].Hepatology,2003.37(5):1202-19.
[2]Angulo,P.,Nonalcoholic Fatty Liver Disease[J].N.Engl.J.Med.,2002.346(16):1221-1231.
[3]Rector,R.S.,et al.,Non-alcoholic fatty liver disease and the metabolic syndrome:an update[J].World J Gastroenterol,2008.14(2):185-92.
[4]Schinner,S.,et al.,Molecular mechanisms of insulin resistance[J].Diabetic Medicine,2005.22(6):674-682.
[5]Aller,R.,et al.,Influence of Insulin Resistance and Adipokines in the Grade of Steatosis of Nonalcoholic Fatty Liver Disease[J].Digestive Diseases and Sciences,2008.53(4):1088-1092.
[6]Taniguchi,C.M.,B.Emanuelli,and C.R.Kahn,Critical nodes in signalling pathways:insights into insulin action[J].Nat Rev Mol Cell Biol,2006.7(2):85-96.
[7]Eun Ju Bae,Y.M.Y.J.W.K.S.G.K,Identification of a novel class of dithiolethiones that prevent hepatic insulin resistance via the adenosine monophosphate-activated protein kinase-p70ribosomal S6 kinase-1 pathway[J].Hepatology,2007.46(3):730-739.
[8]Samuel,V.T.,et al.,Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease[J].J Clin Invest,2007.117(3):739-45.
[9]Qureshi,K.and G.A.Abrams,Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease[J].World J Gastroenterol,2007.13(26):3540-53.
[10]Day,C.P.,Non-alcoholic steatohepatitis(NASH):where are we now and where are we going?[J]Gut,2002.50(5):585-588.
[11]Donnelly,K.L.,et al.,Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease[J].J.Clin.Invest.,2005.115(5):1343-1351.
[12]Kim,S.P.,et al.,Primacy of Hepatic Insulin Resistance in the Development of the Metabolic Syndrome Induced by an Isocaloric Moderate-Fat Diet in the Dog[J].Diabetes,2003.52(10):2453-2460.
[13]Westerbacka,J.,et al.,Dietary Fat Content Modifies Liver Fat in Overweight Nondiabetic Subjects [J].J.Clin.Endocrinol.Metab.,2005.90(5):2804-2809.
[14]Hudgins,L.C.,et al.,Human Fatty Acid Synthesis Is Stimulated by a Eucaloric Low Fat,High Carbohydrate Diet[J].J.Clin.Invest.,1996.97(9):2081-2091.
[15]Samuel,V.T.,et al.,Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease [J].J.Biol.Chem.,2004.279(31):32345-32353.
[16]Memon,R.A.,et al.,Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines[J].Am J Physiol Endocrinol Metab,1998.274(2):E210-217.
[17]Shimomura,I.,et al.,Nuclear Sterol Regulatory Element-binding Proteins Activate Genes Responsible for the Entire Program of Unsaturated Fatty Acid Biosynthesis in Transgenic Mouse Liver[J].J.Biol.Chem.,1998.273(52):35299-35306.
[18]Araya,J.,et al.,Increase in long-chain polyunsaturated fatty acid n-6/n-3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease[J].Clin.Sci.,2004.106(6):635-643.
[19]Postic,C.and J.Girard,Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance:lessons from genetically engineered mice[J].J Clin Invest,2008.118(3):829-38.
[20]Bradbury,M.W.and P.D.Berk,Lipid metabolism in hepatic steatosis[J].Clin Liver Dis,2004.8(3):639-71,ⅹⅰ.
[21]Cuchel,M.,et al.,Inhibition of Microsomal Triglyceride Transfer Protein in Familial Hypercholesterolemia [J] . N Engl J Med, 2007. 356(2): 148-156.
[22] Letteron, P., et al., Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice [J] . Hepatology, 2003. 38(1): 133-40.
[23] Reddy, J.K., Nonalcoholic Steatosis and Steatohepatitis: III. Peroxisomal beta -oxidation, PPARalpha , and steatohepatitis [J] . Am J Physiol Gastrointest Liver Physiol, 2001. 281(6): G1333-1339.
[24] McGarry, J.D., G.P. Mannaerts, and D.W. Foster, A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis [J] . J Clin Invest, 1977. 60(1): 265-70.
[25] McGarry, J.D., Banting Lecture 2001: Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes [J] . Diabetes, 2002. 51(1): 7-18.
[26] Anstee, Q.M. and R.D. Goldin, Mouse models in non-alcoholic fatty liver disease and steatohepatitis research [J] . International Journal of Experimental Pathology, 2006. 87(1): 1-16.
[27] Gavrilova, O., et al., Liver Peroxisome Proliferator-activated Receptor {gamma} Contributes to Hepatic Steatosis, Triglyceride Clearance, and Regulation of Body Fat Mass [J] . J. Biol. Chem., 2003. 278(36): 34268-34276.
[28] Vidal-Puig, A., et al., Regulation of PPAR gamma gene expression by nutrition and obesity in rodents [J] . J Clin Invest, 1996. 97(11): 2553-61.
[29] Marchesini, G., et al., Nonalcoholic Fatty Liver Disease: A Feature of the Metabolic Syndrome [J] . Diabetes, 2001. 50(8): 1844-1850.
[30] Lam, T.K.T., et al., Mechanisms of the free fatty acid-induced increase in hepatic glucose production [J] . Am J Physiol Endocrinol Metab, 2003. 284(5): E863-873.
[31] Shimano, H., et al., Isoform 1c of Sterol Regulatory Element Binding Protein Is Less Active Than Isoform 1a in Livers of Transgenic Mice and in Cultured Cells [J] . J. Clin. Invest., 1997. 99(5): 846-854.
[32] Tamura, S. and I. Shimomura, Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease [J] . J. Clin. Invest., 2005. 115(5): 1139-1142.
[33] Yahagi, N., et al., Absence of Sterol Regulatory Element-binding Protein-1 (SREBP-1) Ameliorates Fatty Livers but Not Obesity or Insulin Resistance in Lepob/Lepob Mice [J]. J. Biol. Chem., 2002. 277(22): 19353-19357.
[34] Wolfrum, C, et al., Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes [J] . Nature, 2004. 432(7020): 1027-32.
[35] Rajala, M.W. and P.E. Scherer, Minireview: The Adipocyte-At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis [J] . Endocrinology, 2003. 144(9): 3765-3773.
[36] Westerbacka, J., et al., Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk[J].Diabetologia,2004.47(8):1360-9.
[37]Targher,G.,et al.,Decreased plasma adiponectin concentrations are closely associated with nonalcoholic hepatic steatosis in obese individuals[J].Clin Endocrinol(Oxf),2004.61(6):700-3.
[38]Hui,J.M.,et al.,Beyond insulin resistance in NASH:TNF-alpha or adiponectin?[J]Hepatology,2004.40(1):46-54.
[39]Masaki,T.,et al.,Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice[J].Hepatology,2004.40(1):177-84.
[40]Xu,A.,et al.,The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice[J].J.Clin.Invest.,2003.112(1):91-100.
[41]Kamada,Y.,et al.,Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin [J].Gastroenterology,2003.125(6):1796-807.
[42]Hotamisligil,G.S.,et al.,IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-alpha-and Obesity-Induced Insulin Resistance[J].Science,1996.271(5249):665-670.
[43]Tilg,H.and A.M.Diehl,Cytokines in Alcoholic and Nonalcoholic Steatohepatitis[J].N.Engl.J.Med.,2000.343(20):1467-1476.
[44]Li,Z.,et al.,Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease[J].Hepatology,2003.37(2):343-50.
[45]Gainsford,T.,et al.,Leptin can induce proliferation,differentiation,and functional activation of hemopoietic cells[J].PNAS,1996.93(25):14564-14568.
[46]Leclercq,I.A.,et al.,Leptin is essential for the hepatic fibrogenic response to chronic liver injury[J].J Hepatol,2002.37(2):206-13.
[47]Jarrar,M.H.,et al.,Adipokines and cytokines in non-alcoholic fatty liver disease[J].Alimentary Pharmacology & Therapeutics,2008.27(5):412-421.
[48]Petersen,K.F.,et al.,Reversal of Nonalcoholic Hepatic Steatosis,Hepatic Insulin Resistance,and Hyperglycemia by Moderate Weight Reduction in Patients With Type 2 Diabetes[J].Diabetes,2005.54(3):603-608.
[49]Luyckx,F.H.,et al.,Liver abnormalities in severely obese subjects:effect of drastic weight loss after gastroplasty[J].Int J Obes Relat Metab Disord,1998.22(3):222-6.
[50]Hundal,R.S and S.E.Inzucchi,Metformin:new understandings,new uses[J].Drugs,2003.63(18):1879-94.
[51]Lin,H.Z.,et al.,Metformin reverses fatty liver disease in obese,leptin-deficient mice[J].Nat Med,2000.6(9):998-1003.
[52]Zhou,G,,et al.,Role of AMP-activated protein kinase in mechanism of metformin action[J].J.Clin.Invest.,2001.108(8):1167-1174.
[53]Marchesini,G.,et al.,Metformin in non-alcoholic steatohepatitis[J].Lancet,2001.358(9285): 893-4.
[54]Bugianesi,E,et al.,A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease[J].Am J Gastroenterol,2005.100(5):1082-90.
[55]Tiikkainen,M.,et al.,Effects of Rosiglitazone and Metformin on Liver Fat Content,Hepatic Insulin Resistance,Insulin Clearance,and Gene Expression in Adipose Tissue in Patients With Type 2Diabetes[J].Diabetes,2004.53(8):2169-2176.
[56]Miyazaki,Y.,et al.,Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type Ⅱ diabetic patients[J].Diabetologia,2001.44(12):2210-9.
[57]Miyazaki,Y.,et al.,Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Type 2 Diabetic Patients[J].J.Clin.Endocrinol.Metab.,2002.87(6):2784-2791.
[58]Virtanen,K.A.,et al.,Differential Effects of Rosiglitazone and Metformin on Adipose Tissue Distribution and Glucose Uptake in Type 2 Diabetic Subjects[J].Diabetes,2003.52(2):283-290.
[59]Mayerson,A.B.,et al.,The Effects of Rosiglitazone on Insulin Sensitivity,Lipolysis,and Hepatic and Skeletal Muscle Triglyceride Content in Patients With Type 2 Diabetes[J].Diabetes,2002.51(3):797-802.
[60]Gomez-Perez,F.J.,et al.,Further insight on the hypoglycemic and nonhypoglycemic effects of troglitazone 400 or 600 mg/d:effects on the very-low-density and high-density lipoprotein particle distribution[J].Metabolism,2002.51(1):44-51.
[61]Yu,J.G.,et al.,The Effect of Thiazolidinediones on Plasma Adiponectin Levels in Normal,Obese,and Type 2 Diabetic Subjects[J].Diabetes,2002.51(10):2968-2974.
[62]Ahuja,H.S.,et al.,Differential Effects of Rexinoids and Thiazolidinediones on Metabolic Gene Expression in Diabetic Rodents[J].Mol.Pharmacol.,2001.59(4):765-773.
[2]Neuschwander-Tetr,B.A.and S.H.Caldwell,Nonalcoholic steatohepatitis:summary of an AASLD Single Topic Conference[J].Hepatology,2003,37(5):1202-19.
[3]Day,C.and S.Saksena,Non-alcoholic steatohepatitis:Definitions and pathogenesis[J].J Gastroenterol Hepatol,2002,17 Suppl 3:S377-S384.
[4]Rector,R.S.,et al.,Non-alcoholic fatty liver disease and the metabolic syndrome:an update[J].World J Gastroenterol,2008,14(2):185-92.
[5]Farrell,G.C.and C.Z.Larter,Nonalcoholic fatty liver disease:from steatosis to cirrhosis[J].Hepatology,2006,43(2 Suppl 1):S99-S112.
[6]Rinella,M.E.and R.M.Green,The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance[J].J Hepatol,2004,40(1):47-51.
[7]Evans,R.M.,2003 Keio Medical Science Prize commemorative lecture.PPARs and the complex journey to obesity[J].Keio J Med,2004,53(2):53-8.
[8]Forcheron,F.,et al.,Mechanisms of the triglyceride-and cholesterol-lowering effect of fenofibrate in hyperlipidemic type 2 diabetic patients[J].Diabetes,2002,51(12):3486-91.
[9]Yki-Jarvinen,H.,Thiazolidinediones[J].N Engl J Med,2004,351(11):1106-18.
[10]Harrity,T.,et al.,Muraglitazar,a Novel Dual({alpha}/{gamma}) Peroxisome Proliferator-Activated Receptor Activator,Improves Diabetes and Other Metabolic Abnormalities and Preserves{beta}-Cell Function in db/db Mice[J].Diabetes,2006,55(1):240-248.
[11]Ye,F.,et al.,Utilization of fluorescence tracer in hyperinsulinemic-euglycemic clamp test in mice[J].J Biochem Biophys Methods,2008,70(6):978-84.
[12]de Oliveira,C.P.,et al.,Hepatic gene expression profile associated with non-alcoholic steatohepatitis protection by S-nitroso-N-acetylcysteine in ob/ob mice[J].J Hepatol,2006,45(5):725-33.
[13]Day,C.P.,Non-alcoholic steatohepatitis(NASH):where are we now and where are we going?[J]Gut,2002,50(5):585-588.
[14]James,O.F.and C.P.Day,Non-alcoholic steatohepatitis(NASH):a disease of emerging identity and importance[J].J Hepatol,1998,29(3):495-501.
[15]Browning,J.D.and J.D.Horton,Molecular mediators of hepatic steatosis and liver injury[J].J Clin Invest,2004,114(2):147-52.
[16]Bradbury,M.W.and P.D.Berk,Lipid metabolism in hepatic steatosis[J].Clin Liver Dis,2004,8(3):639-71,ⅹⅰ.
[17]Schinner,S.,et al.,Molecular mechanisms of insulin resistance[J].Diabetic Medicine,2005,22(6):674-682.
[18]Postic,C.and J.Girard,Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance:lessons from genetically engineered mice[J].J Clin Invest,2008,118(3):829-38.
[19]Utzschneider,K.M.and S.E.Kahn,Review:The role of insulin resistance in nonalcoholic fatty liver disease[J].J Clin Endocrinol Metab,2006,91(12):4753-61.
[20]Marchesini,G.,et al.,Nonalcoholic Fatty Liver Disease:A Feature of the Metabolic Syndrome[J].Diabetes,2001,50(8):1844-1850.
[21]Choi,C.S.,et al.,Suppression of diacylglycerol acyltransferase-2(DGAT2),but not DGAT1,with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance[J].J Biol Chem,2007,282(31):22678-88.
[22]Tilg,H.and A.M.Diehl,Cytokines in Alcoholic and Nonalcoholic Steatohepatitis[J].N.Engl.J.Med.,2000,343(20):1467-1476.
[23]Savage,D.B.,K.F.Petersen,and G.I.Shulman,Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance[J].Physiol.Rev.,2007,87(2):507-520.
[24]Angulo,P.and K.D.Lindor,Treatment of non-alcoholic steatohepatitis[J].Best Pract Res Clin Gastroenterol,2002.16(5):797-810.
[25]Haque,M.and A.J.Sanyal,The metabolic abnormalities associated with non-alcoholic fatty liver disease[J].Best Pract Res Clin Gastroenterol,2002.16(5):709-31.
[26]Anstee,Q.M.and R.D.Goldin,Mouse models in non-alcoholic fatty liver disease and steatohepatitis research[J].International Journal of Experimental Pathology,2006.87(1):1-16.
[27]Nanji,A.A.,Animal models of nonalcoholic fatty liver disease and steatohepatitis[J].Clin Liver Dis,2004.8(3):559-74,ⅸ.
[28]Zou,Y.,et al.,High-fat emulsion-induced rat model of nonalcoholic steatohepatitis[J].Life Sci,2006.79(11):1100-7.
[29]Koteish,A.and A.M.Diehl,Animal models of steatosis[J].Semin Liver Dis,2001.21(1):89-104.
[30]Yu,S.,et al.,Adipocyte-specific Gene Expression and Adipogenic Steatosis in the Mouse Liver Due to Peroxisome Proliferator-activated Receptor gamma 1(PPARgamma 1) Overexpression[J].J.Biol.Chem.,2003.278(1):498-505.
[31]Araya,J.,et al.,Increase in long-chain polyunsaturated fatty acid n-6/n-3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease[J].Clin.Sci.,2004.106(6):635-643.
[32]Shimomura,I.,et al.,Nuclear Sterol Regulatory Element-binding Proteins Activate Genes Responsible for the Entire Program of Unsaturated Fatty Acid Biosynthesis in Transgenic Mouse Liver[J].J.Biol.Chem.,1998.273(52):35299-35306.
[33]Towle,H.C.,E.N.Kaytor,and H.M.Shih,Regulation of the expression of lipogenic enzyme genes by carbohydrate[J].Annu Rev Nutr,1997.17:405-33.
[34]Fukuda,H.,et al.,Transcriptional regulation of fatty acid synthase gene by insulin/glucose,polyunsaturated fatty acid and leptin in hepatocytes and adipocytes in normal and genetically obese rats [J].Eur J Biochem,1999.260(2):505-11.
[35]Xu,J.,et al.,Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids.A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats[J].J Biol Chem,1999.274(33):23577-83.
[36]Rahimian,R.,et al.,Hepatic over-expression of peroxisome proliferator activated receptor gamma2 in the ob/ob mouse model of non-insulin dependent diabetes mellitus[J].Mol Cell Biochem,2001.224(1-2):29-37.
[37]Reddy,J.K,Nonalcoholic Steatosis and Steatohepatitis:Ⅲ.Peroxisomal beta-oxidation,PPARalpha,and steatohepatitis[J].Am J Physiol Gastrointest Liver Physiol,2001.281(6):G1333-1339.
[38]den Boer,M.,et al.,Hepatic Steatosis:A Mediator of the Metabolic Syndrome.Lessons From Animal Models[J].Arterioscler.Thromb.Vasc.Biol.,2004.24(4):644-649.
[39]Nagasawa,T.,et al.,Effects of bezafibrate,PPAR pan-agonist,and GW501516,PPARdelta agonist,on development of steatohepatitis in mice fed a methionine-and choline-deficient diet[J].Eur J Pharmacol,2006.536(1-2):182-91.
[40]Ntambi,J.M.and M.Miyazaki,Regulation of stearoyl-CoA desaturases and role in metabolism[J].Prog Lipid Res,2004.43(2):91-104.
[41]Cao,J.,et al.,Molecular identification of microsomal acyl-CoA:glycerol-3-phosphate acyltransferase,a key enzyme in de novo triacylglycerol synthesis[J].Proc Natl Acad Sci U S A,2006.103(52):19695-700.
[42]Gibbons,G.F.,et al.,Synthesis and function of hepatic very-low-density lipoprotein[J].Biochem Soc Trans,2004.32(Pt 1):59-64.
[43]Wetterau,J.R.,et al.,Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia[J].Science,1992.258(5084):999-1001.
[44]Letteron,P.,et al.,Inhibition of microsomal triglyceride transfer protein:another mechanism for drug-induced steatosis in mice[J].Hepatology,2003.38(1):133-40.
[45]Bugianesi,E.,et al.,Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease:sites and mechanisms[J].Diabetologia,2005.48(4):634-42.
[46]Seppala-Lindroos,A.,et al.,Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men[J].J Clin Endocrinol Metab,2002.87(7):3023-8.
[47]Marchesini,G.,et al.,Association of nonalcoholic fatty liver disease with insulin resistance[J].Am J Med,1999.107(5):450-5.
[48]Abdul-Ghani,M.A.,D.Tripathy,and R.A.DeFronzo,Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose[J].Diabetes Care,2006.29(5):1130-9.
[49]Dong,X.,et al.,Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth [J].J Clin Invest,2006.116(1):101-14.
[50]Tonks,N.K.,Protein tyrosine phosphatases:from genes,to function,to disease[J].Nat Rev Mol Cell Biol,2006.7(11):833-46.
[51]Klaman,L.D.,et al.,Increased Energy Expenditure,Decreased Adiposity,and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice[J].Mol.Cell.Biol.,2000.20(15):5479-5489.
[1]Rader,D.J.,Effect of Insulin Resistance,Dyslipidemia,and Intra-abdominal Adiposity on the Development of Cardiovascular Disease and Diabetes Mellitus[J].The American Journal of Medicine,2007.120(3,Supplement 1):S12-S18.
[2]Smith,J.V.and Y.Luo,Studies on molecular mechanisms of Ginkgo biloba extract[J].Appl Microbiol Biotechnol,2004.64(4):465-72.
[3]Coskun,O.,et al.,Protection of endotoxin-induced oxidative renal tissue damage of rats by vitamin E or/and EGb 761 treatment[J].J Appl Toxicol,2005.25(1):8-12.
[4] Kudolo, G.B., D. Delaney, and J. Blodgett, Short-term oral ingestion of Ginkgo biloba extract (EGb 761) reduces malondialdehyde levels in washed platelets of type 2 diabetic subjects [J] . Diabetes Research and Clinical Practice, 2005. 68(1): 29-38.
[5] Abdel-Salam, O.M., et al., Evaluation of the anti-inflammatory, anti-nociceptive and gastric effects of Ginkgo biloba in the rat [J] . Pharmacol Res, 2004. 49(2): 133-42.
[6] Yao, Z.X., et al., Ginkgo biloba extract (Egb 761) inhibits beta-amyloid production by lowering free cholesterol levels [J] . J Nutr Biochem, 2004. 15(12): 749-56.
[7] Van Gaal, L.F., I.L Mertens, and C.E. De Block, Mechanisms linking obesity with cardiovascular disease [J] . Nature, 2006. 444(7121): 875-80.
[8] Long, Y.C. and J.R. Zierath, AMP-activated protein kinase signaling in metabolic regulation [J] . J Clin Invest, 2006. 116(7): 1776-83.
[9] Abdul-Ghani, M.A., D. Tripathy, and R.A. DeFronzo, Contributions of {beta}-Cell Dysfunction and Insulin Resistance to the Pathogenesis of Impaired Glucose Tolerance and Impaired Fasting Glucose [J] . Diabetes Care, 2006. 29(5): 1130-1139.
[10] Taniguchi, C.M., B. Emanuelli, and C.R. Kahn, Critical nodes in signalling pathways: insights into insulin action [J] . Nat Rev Mol Cell Biol, 2006. 7(2): 85-96.
[11] Qiu, W, et al., Hepatic PTP-1B expression regulates the assembly and secretion of apolipoprotein B-containing lipoproteins: evidence from protein tyrosine phosphatase-1B overexpression, knockout, and RNAi studies [J] . Diabetes, 2004. 53(12): 3057-66.
[12] Liu, H.Y., et al., Prolonged treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase [J] . J Biol Chem, 2007. 282(19): 14205-12.
[13] Zang, M., et al., AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells [J] . J Biol Chem, 2004. 279(46): 47898-905.
[14] Avramoglu, R.K., H. Basciano, and K. Adeli, Lipid and lipoprotein dysregulation in insulin resistant states [J] . Clin Chim Acta, 2006. 368(1-2): 1-19.
[15] Mokdad, A.H., et al., Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors [J] , 2001. JAMA, 2003. 289(1): 76-79.
[16] Ginsberg, H.N., Y.L. Zhang, and A. Hernandez-Ono, Regulation of plasma triglycerides in insulin resistance and diabetes [J] . Arch Med Res, 2005. 36(3): 232-40.
[17] Gertz, H.J. and M. Kiefer, Review about Ginkgo biloba special extract EGb 761 (Ginkgo) [J] . Curr Pharm Des, 2004. 10(3): 261-4.
[18] Sierpina, V.S., B. Wollschlaeger, and M. Blumenthal, Ginkgo biloba [J] .Am Fam Physician, 2003. 68(5): 923-6.
[19] Yoshikawa, T, Y. Naito, and M. Kondo, Ginkgo biloba leaf extract: review of biological actions and clinical applications [J] . Antioxid Redox Signal, 1999. 1(4): 469-80.
[20] Witte, S., I. Anadere, and E. Walitza, Improvement of hemorheology with ginkgo biloba extract. Decreasing a cardiovascular risk factor [J] . Fortschr Med, 1992. 110(13): 247-50.
[21] Choi, S.E., et al., Involvement of Ca2+, CaMK II and PKA in EGb 761-induced insulin secretion in INS-1 cells. [J] J Ethnopharmacol, 2007. 110(1): 49-55.
[22] Lippi, G., G. Targher, and G.C. Guidi, Ginkgo biloba, inflammation and lipoprotein(a) [J] . Atherosclerosis, 2007. 195(2): 417-418.
[23] Rodriguez, M., et al., Reduction of atherosclerotic nanoplaque formation and size by Ginkgo biloba (EGb 761) in cardiovascular high-risk patients [J] . Atherosclerosis, 2007. 192(2): 438-444.
[1]Neuschwander-Tetr,B.A.and S.H.Caldwell,Nonalcoholic steatohepatitis:summary of an AASLD Single Topic Conference[J].Hepatology,2003.37(5):1202-19.
[2]Angulo,P.,Nonalcoholic Fatty Liver Disease[J].N.Engl.J.Med.,2002.346(16):1221-1231.
[3]Rector,R.S.,et al.,Non-alcoholic fatty liver disease and the metabolic syndrome:an update[J].World J Gastroenterol,2008.14(2):185-92.
[4]Schinner,S.,et al.,Molecular mechanisms of insulin resistance[J].Diabetic Medicine,2005.22(6):674-682.
[5]Aller,R.,et al.,Influence of Insulin Resistance and Adipokines in the Grade of Steatosis of Nonalcoholic Fatty Liver Disease[J].Digestive Diseases and Sciences,2008.53(4):1088-1092.
[6]Taniguchi,C.M.,B.Emanuelli,and C.R.Kahn,Critical nodes in signalling pathways:insights into insulin action[J].Nat Rev Mol Cell Biol,2006.7(2):85-96.
[7]Eun Ju Bae,Y.M.Y.J.W.K.S.G.K,Identification of a novel class of dithiolethiones that prevent hepatic insulin resistance via the adenosine monophosphate-activated protein kinase-p70ribosomal S6 kinase-1 pathway[J].Hepatology,2007.46(3):730-739.
[8]Samuel,V.T.,et al.,Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease[J].J Clin Invest,2007.117(3):739-45.
[9]Qureshi,K.and G.A.Abrams,Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease[J].World J Gastroenterol,2007.13(26):3540-53.
[10]Day,C.P.,Non-alcoholic steatohepatitis(NASH):where are we now and where are we going?[J]Gut,2002.50(5):585-588.
[11]Donnelly,K.L.,et al.,Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease[J].J.Clin.Invest.,2005.115(5):1343-1351.
[12]Kim,S.P.,et al.,Primacy of Hepatic Insulin Resistance in the Development of the Metabolic Syndrome Induced by an Isocaloric Moderate-Fat Diet in the Dog[J].Diabetes,2003.52(10):2453-2460.
[13]Westerbacka,J.,et al.,Dietary Fat Content Modifies Liver Fat in Overweight Nondiabetic Subjects [J].J.Clin.Endocrinol.Metab.,2005.90(5):2804-2809.
[14]Hudgins,L.C.,et al.,Human Fatty Acid Synthesis Is Stimulated by a Eucaloric Low Fat,High Carbohydrate Diet[J].J.Clin.Invest.,1996.97(9):2081-2091.
[15]Samuel,V.T.,et al.,Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease [J].J.Biol.Chem.,2004.279(31):32345-32353.
[16]Memon,R.A.,et al.,Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines[J].Am J Physiol Endocrinol Metab,1998.274(2):E210-217.
[17]Shimomura,I.,et al.,Nuclear Sterol Regulatory Element-binding Proteins Activate Genes Responsible for the Entire Program of Unsaturated Fatty Acid Biosynthesis in Transgenic Mouse Liver[J].J.Biol.Chem.,1998.273(52):35299-35306.
[18]Araya,J.,et al.,Increase in long-chain polyunsaturated fatty acid n-6/n-3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease[J].Clin.Sci.,2004.106(6):635-643.
[19]Postic,C.and J.Girard,Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance:lessons from genetically engineered mice[J].J Clin Invest,2008.118(3):829-38.
[20]Bradbury,M.W.and P.D.Berk,Lipid metabolism in hepatic steatosis[J].Clin Liver Dis,2004.8(3):639-71,ⅹⅰ.
[21]Cuchel,M.,et al.,Inhibition of Microsomal Triglyceride Transfer Protein in Familial Hypercholesterolemia [J] . N Engl J Med, 2007. 356(2): 148-156.
[22] Letteron, P., et al., Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice [J] . Hepatology, 2003. 38(1): 133-40.
[23] Reddy, J.K., Nonalcoholic Steatosis and Steatohepatitis: III. Peroxisomal beta -oxidation, PPARalpha , and steatohepatitis [J] . Am J Physiol Gastrointest Liver Physiol, 2001. 281(6): G1333-1339.
[24] McGarry, J.D., G.P. Mannaerts, and D.W. Foster, A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis [J] . J Clin Invest, 1977. 60(1): 265-70.
[25] McGarry, J.D., Banting Lecture 2001: Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes [J] . Diabetes, 2002. 51(1): 7-18.
[26] Anstee, Q.M. and R.D. Goldin, Mouse models in non-alcoholic fatty liver disease and steatohepatitis research [J] . International Journal of Experimental Pathology, 2006. 87(1): 1-16.
[27] Gavrilova, O., et al., Liver Peroxisome Proliferator-activated Receptor {gamma} Contributes to Hepatic Steatosis, Triglyceride Clearance, and Regulation of Body Fat Mass [J] . J. Biol. Chem., 2003. 278(36): 34268-34276.
[28] Vidal-Puig, A., et al., Regulation of PPAR gamma gene expression by nutrition and obesity in rodents [J] . J Clin Invest, 1996. 97(11): 2553-61.
[29] Marchesini, G., et al., Nonalcoholic Fatty Liver Disease: A Feature of the Metabolic Syndrome [J] . Diabetes, 2001. 50(8): 1844-1850.
[30] Lam, T.K.T., et al., Mechanisms of the free fatty acid-induced increase in hepatic glucose production [J] . Am J Physiol Endocrinol Metab, 2003. 284(5): E863-873.
[31] Shimano, H., et al., Isoform 1c of Sterol Regulatory Element Binding Protein Is Less Active Than Isoform 1a in Livers of Transgenic Mice and in Cultured Cells [J] . J. Clin. Invest., 1997. 99(5): 846-854.
[32] Tamura, S. and I. Shimomura, Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease [J] . J. Clin. Invest., 2005. 115(5): 1139-1142.
[33] Yahagi, N., et al., Absence of Sterol Regulatory Element-binding Protein-1 (SREBP-1) Ameliorates Fatty Livers but Not Obesity or Insulin Resistance in Lepob/Lepob Mice [J]. J. Biol. Chem., 2002. 277(22): 19353-19357.
[34] Wolfrum, C, et al., Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes [J] . Nature, 2004. 432(7020): 1027-32.
[35] Rajala, M.W. and P.E. Scherer, Minireview: The Adipocyte-At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis [J] . Endocrinology, 2003. 144(9): 3765-3773.
[36] Westerbacka, J., et al., Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk[J].Diabetologia,2004.47(8):1360-9.
[37]Targher,G.,et al.,Decreased plasma adiponectin concentrations are closely associated with nonalcoholic hepatic steatosis in obese individuals[J].Clin Endocrinol(Oxf),2004.61(6):700-3.
[38]Hui,J.M.,et al.,Beyond insulin resistance in NASH:TNF-alpha or adiponectin?[J]Hepatology,2004.40(1):46-54.
[39]Masaki,T.,et al.,Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice[J].Hepatology,2004.40(1):177-84.
[40]Xu,A.,et al.,The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice[J].J.Clin.Invest.,2003.112(1):91-100.
[41]Kamada,Y.,et al.,Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin [J].Gastroenterology,2003.125(6):1796-807.
[42]Hotamisligil,G.S.,et al.,IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-alpha-and Obesity-Induced Insulin Resistance[J].Science,1996.271(5249):665-670.
[43]Tilg,H.and A.M.Diehl,Cytokines in Alcoholic and Nonalcoholic Steatohepatitis[J].N.Engl.J.Med.,2000.343(20):1467-1476.
[44]Li,Z.,et al.,Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease[J].Hepatology,2003.37(2):343-50.
[45]Gainsford,T.,et al.,Leptin can induce proliferation,differentiation,and functional activation of hemopoietic cells[J].PNAS,1996.93(25):14564-14568.
[46]Leclercq,I.A.,et al.,Leptin is essential for the hepatic fibrogenic response to chronic liver injury[J].J Hepatol,2002.37(2):206-13.
[47]Jarrar,M.H.,et al.,Adipokines and cytokines in non-alcoholic fatty liver disease[J].Alimentary Pharmacology & Therapeutics,2008.27(5):412-421.
[48]Petersen,K.F.,et al.,Reversal of Nonalcoholic Hepatic Steatosis,Hepatic Insulin Resistance,and Hyperglycemia by Moderate Weight Reduction in Patients With Type 2 Diabetes[J].Diabetes,2005.54(3):603-608.
[49]Luyckx,F.H.,et al.,Liver abnormalities in severely obese subjects:effect of drastic weight loss after gastroplasty[J].Int J Obes Relat Metab Disord,1998.22(3):222-6.
[50]Hundal,R.S and S.E.Inzucchi,Metformin:new understandings,new uses[J].Drugs,2003.63(18):1879-94.
[51]Lin,H.Z.,et al.,Metformin reverses fatty liver disease in obese,leptin-deficient mice[J].Nat Med,2000.6(9):998-1003.
[52]Zhou,G,,et al.,Role of AMP-activated protein kinase in mechanism of metformin action[J].J.Clin.Invest.,2001.108(8):1167-1174.
[53]Marchesini,G.,et al.,Metformin in non-alcoholic steatohepatitis[J].Lancet,2001.358(9285): 893-4.
[54]Bugianesi,E,et al.,A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease[J].Am J Gastroenterol,2005.100(5):1082-90.
[55]Tiikkainen,M.,et al.,Effects of Rosiglitazone and Metformin on Liver Fat Content,Hepatic Insulin Resistance,Insulin Clearance,and Gene Expression in Adipose Tissue in Patients With Type 2Diabetes[J].Diabetes,2004.53(8):2169-2176.
[56]Miyazaki,Y.,et al.,Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type Ⅱ diabetic patients[J].Diabetologia,2001.44(12):2210-9.
[57]Miyazaki,Y.,et al.,Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Type 2 Diabetic Patients[J].J.Clin.Endocrinol.Metab.,2002.87(6):2784-2791.
[58]Virtanen,K.A.,et al.,Differential Effects of Rosiglitazone and Metformin on Adipose Tissue Distribution and Glucose Uptake in Type 2 Diabetic Subjects[J].Diabetes,2003.52(2):283-290.
[59]Mayerson,A.B.,et al.,The Effects of Rosiglitazone on Insulin Sensitivity,Lipolysis,and Hepatic and Skeletal Muscle Triglyceride Content in Patients With Type 2 Diabetes[J].Diabetes,2002.51(3):797-802.
[60]Gomez-Perez,F.J.,et al.,Further insight on the hypoglycemic and nonhypoglycemic effects of troglitazone 400 or 600 mg/d:effects on the very-low-density and high-density lipoprotein particle distribution[J].Metabolism,2002.51(1):44-51.
[61]Yu,J.G.,et al.,The Effect of Thiazolidinediones on Plasma Adiponectin Levels in Normal,Obese,and Type 2 Diabetic Subjects[J].Diabetes,2002.51(10):2968-2974.
[62]Ahuja,H.S.,et al.,Differential Effects of Rexinoids and Thiazolidinediones on Metabolic Gene Expression in Diabetic Rodents[J].Mol.Pharmacol.,2001.59(4):765-773.