摘要
目的：代谢紊乱及相关疾病已成为严重危害人类健康的主要疾病,其发病机制目前尚不清楚。流行病学提示代谢紊乱的发病率增加与人们精神应激增加和活动减少关系密切。本试验以束缚应激大鼠为模型,1、观察束缚应激对大鼠血脂、血糖的影响及肝脏、脂肪、肌肉和心肌等重要代谢和应激器官PPARs的变化,初步探讨PPARs在应激代谢中的作用；2、观察TZDs类降糖药吡格列酮对束缚应激大鼠代谢的干预作用及作用机制,为代谢紊乱的治疗提供试验依据。
方法：1、雄性Wister大鼠,分为正常对照组(C)、束缚1周组(R1)、束缚2周(R2)和束缚4周组(R4),测定各组大鼠血糖、TG、TC、HDL-C、LDL-C、FFA、血清皮质酮、胰岛素和去甲肾上腺素。以RT-PCR和western blot技术测定各组大鼠肝脏、肌肉、心肌和脂肪中PPARα、PPARβ／δ、PPARγ、GLUT-4、LPL和CPT-I(肝脏为L-CPT,肌肉、心肌和脂肪为M-CPT)mRNA和蛋白的表达。2、雄性Wister大鼠,分为正常对照组(C2)、束缚应激组(R)、束缚应激加小剂量吡格列酮治疗组(P10,10mg／kg·d)和束缚应激加大剂量吡格列酮治疗组(P20,20mg／kg·d)。应激大鼠给予4周束缚应激后测定各组大鼠血糖、TG、TC、HDL-C、LDL-C、FFA、血清皮质酮、胰岛素和去甲肾上腺素。以RT-PCR和western blot技术测定各组大鼠脂肪中PPARγ、GLUT-4和LPL mRNA和蛋白的表达。
结果：1、与C组大鼠相比, R1、R2、R4组大鼠血糖、TG、HDL-C、FFA、皮质酮、去甲肾上腺素和胰岛素明显升高(血糖R1、R2、R4组,HDL-C R2、R4组去甲肾上腺素R4组,胰岛素R1组P<0.05；其余P<0.01),胰岛素敏感指数降低(P<0.01),TC改变不明显(P>0.05),只有R1组LDL-C降低(P<0.05)。2、与R组大鼠相比,P20组大鼠血糖明显降低(P<0.05),两吡格列酮治疗组TG、FFA、胰岛素水平明显降低(P<0.01),胰岛素敏感性增加(P<0.01),TC、LDL-C、HDL-C、皮质酮、去甲肾上腺素变化不明显(P>0.05)。与C2组大鼠相比,P20组大鼠HDL-C明显升高(P<0.05),两吡格列酮治疗组HDL-C、皮质酮、去甲肾上腺素皮质酮、去甲肾上腺素升高(P<0.01),LDL-C降低(P10组P<0.05,P20组P<0.01),血糖、TG、TC、FFA、胰岛素、胰岛素敏感指数无明显差别(P>0.05)。3、与C1组大鼠相比,R1、R2、R4组大鼠肝脏中PPARα、L-CPTmRNA和蛋白表达明显升高(P<0.01),PPARβ／δ、PPARγ、GLUT-4 mRNA和蛋白表达明显降低(PPARβ／δ蛋白R1组P<0.05,其余P<0.01),LPL mRNA和蛋白表达变化不明显(P>0.05)；4、与C1组大鼠相比,R1、R2、R4组大鼠肌肉中PPARα、PPARβ/δ、PPARγ、GLUT-4、LPL和M-CPTmRNA和蛋白表达明显降低(M-CPTmRNA R1组、PPARβ／δ蛋白R1组P<0.05,其余P<0.01)；5、与C1组大鼠相比,R1、R2、R4组大鼠心肌中PPARα、LPL和M-CPTmRNA和蛋白表达明显升高(PPARamRNA R2组、M-CPT mRNA R2组、M-CPT蛋白R4组P<0.05,其余P<0.01)；PPARγ、GLUT-4mRNA和蛋白表达明显降低(P<0.01),PPARβ/δmRNA和蛋白表达变化不明显(P>0.05)；6、与C1组大鼠相比,R1、R2、R4组大鼠脂肪中PPARα、PPARβ/δ、PPARγ2、GLUT-4、LPL、M-CPTmRNA和蛋白表达明显降低(GLUT-4mRNA R1组、LPLmRNA R2和R4组、LPL蛋白R1和R4组P<0.05,其余P<0.01)；7、与R组大鼠相比,两吡格列酮治疗组大鼠脂肪中PPARγ、GLUT-4、LPLmRNA和蛋白表达明显升高(PPARγmRNA、GLUT-4mRNA均Plo组P<0.05,P20组P<0.01；其余P<0.01)。与C2大鼠相比,P10组大鼠脂肪中LPLmRNA、PPARγ、GLUT-4和LPL蛋白表达仍明显降低(P<0.05),Plo组大鼠脂肪中PPARγ和GLUT-4mRNA、P20组大鼠脂肪中PPARγy、GLUT-4、LPLmRNA和蛋白表达无明显差别(P>0.05)
结论：1、束缚应激大鼠存在代谢紊乱,以血糖和TG升高为主；2、束缚应激可影响大鼠肝脏、肌肉、心肌和脂肪PPARs及其调控基因mRNA和蛋白表达发生变化,这些变化可能与束缚应激导致的代谢紊乱有关；3、吡格列酮可通过增加脂肪中PPARγ及其调控基因表达和活性,改善束缚应激大鼠的代谢紊乱。
Objective:1.To investigate the changes of blood glucose and lipid of rats under restraint stress.2.To detct the expressions of PPARs in the liver、muscle、myocardium and fat in the rats under restraint stress.3、To explore the effects of pioglitazone on the metabolism of rats under restraint stress and its mechanism。
Methods:1.Male Wistar rats were divided into four groups:control and rats under 1 week (R1)、2 weeks (R2) or 4 weeks (R4) restraint stress. Blood glucose、TG、TC、HDL-C、LDL-C、FFA、corticosterone、noradrenaline and insulin were detected。The gene and protein expressions of PPARs、GLUT-4、LPL and CPT in the liver、muscle、myocardium and fat were evaluated by RT-PCR and western blot.2.Male Wistar rats were divided into four groups:control、rats under restraint stress、rats given both restraint stress and 10mg/kg-d pioglitazone (P10) and rats given both restraint stress and 20mg/kg-d pioglitazone (P20). Blood glucose、TG、TC、HDL-C、LDL-C、FFA、corticosterone、noradrenaline and insulin were detected. The gene and protein expressions of PPARγ、GLUT-4 and LPL in the fat were evaluated by RT-PCR and western blot. Probability values of 0.05 was considered as significant.
Results:1.Compared with C1 group rats, blood glucose、TG、HDL-C、FFA、corticosterone、noradrenaline and insulin in the rats of R1、R2 and R4 group increased significantly, IAI decreased, LDL-C in R1 group also decreased, TC has no significant change.2.Compared with R group rats, blood glucose in the rats of P20 group decreased significantly, blood TG、FFA and insulin in the rats of P10 and P20 group decreased, IAI increased, blood TC、LDL-C、HDL-C、corticosterone and noradrenaline have no significant change.Compared with C2 group rats, blood HDL-C in the rats of P20 group increased significantly, blood HDL-C、corticosterone and noradrenaline in the rats of P10 and P20 group all increased, LDL-C decreased, blood glucose、TG、TC、FFA、 insulin and IAI have no significant change.3.The expressions of PPARα、L-CPT mRNA and protein in the liver of rats of R1、R2 and R4 group were all significantly higher than that of control group, PPARβ/δ、PPARγ、GLUT-4 mRNA and protein were all significantly lower, the expressions of LPL mRNA and protein have no signigfican change.4.The expressions of PPARα、PPARβ/δ、PPARγ、GLUT-4、LPL、M-CPT mRNA and protein in the muscle of rats of R1、R2 and R4 group were all significantly lowered than that of control group.5.The expressions of PPARα、LPL、M-CPT mRNA and protein in the myocardium of rats of R1、R2 and R4 group were significantly higher than that of control group, PPARγ、GLUT-4 mRNA and protein were significantly lower, the expressions of PPARβ/δmRNA and protein have no signigfican change.6.The expressions of PPARα、PPARβ/δ、PPARγ、GLUT-4、LPL、M-CPT mRNA and protein in the fat of rats of R1、R2 and R4 group were all significantly lower than that of control group.7.Compared with R group rats, the expressions of PPARγ、GLUT-4、LPL mRNA and protein in the fat of rats of P10 and P20 group decreased.Compared with C2 group rats, the expressions of LPL mRNA and PPARγ、GLUT-4、LPL protein in the fat of rats of P10 group still decreased, the expression of LPLmRNA、PPARγ、GLUT-4、LPL protein in P10 group and LPL mRNA、PPARγ、GLUT-4、LPL protein in P20 group have no signigfican change。
Conclusion:1.Rats under restraint stress have metabolic abnormality, with higer blood glucose and TG.2.The gene and protein expressions of PPARs in the liver、muscle、myocardium and fat were changed in the rats under restraint stress, which may have relationship with metabolic abnormality.3.Rats under restraint stress by pioglitazone treatment can inhibit metabolic abnormality by increasing the the expressions of PPARγ、GLUT-4、LPLmRNA and protein in the fat of rats.
引文
1. Chrousos GP, Gold PW. The concepts of stress system disorders:Overview of behavioral and physical homeostasis[J]. JAMA,1992,267(9):1244-1252
2. McEwen BS. Protective and damaging effects of stress mediators[J]. N Engl J Med, 1998,338(4):171-179.
3. Sjo"strand M, Eriksson JW. Neuroendocrine mechanisms in insulin resistance [J]. Mol Cell Endocrinol,2009,297(1-2):104-111.
4. Kyrou I, Chrousos GP, Tsigos C. Stress, visceral obesity and metabolic complications[J]. Ann NY Acad Sci,2006,1083:77-110.
5. Vale S. Psychosocial stress and cardiovascular diseases[J]. Postgrad Med J,2005, 81 (957):429-435.
6. Grippo AJ and Johnson AK. Stress, depression, and cardiovascular dysregulation:A review of neurobiological mechanisms and the integration of research from preclinical disease models[J]. Stress,2009, 12(1):1-21.
7. Abraham NG, Brunner EJ, Eriksson JW, et al.Metabolic syndrome:psychosocial, neuroendocrine and classical risk factors in type 2 diabetes[J]. Ann NY Acad Sci, 2007,1113:256-275.
8.Besedovsky HO, Del RA. Immune-neuro-endocrine interactions:facts and hypotheses[J]. Endocri Rev,1996,17(1):64-102
9.Besedovsky HO, Rey AD. Phyisiology of psychoneuimmunology:a perspective view[J]. Brain Behav Immun,2007,21(1):34-44.
10.Brunner EJ, Hemingway H, Walker BR, et al.Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome:nested case-control study[J]. Circulation,2002,106(21):2659-2665.
11.Elenko IJ, Chrousos GP. Stress hormones, proinflammatory and anti-inflammatory cytokines and autoimmunity[J]. Ann NY Acad Sci,2002,966:290-303.
12.Brydon L, Wright CE, O'Donnell K, et al. Stress-induced cytokine responses and central adiposity in young women[J]. Int.J Obes(Lond),2008,32(3):443-450.
13. Black PH. The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type Ⅱ diabetes and metabolic syndrome X[J]. Brain Behav Immun,2003,17(5):350-364.
14.Kyrou I, Tsigos C. Stress Mechanisms and Metabolic Complications[J]. Horm Metab Res,2007,39(6):430-438
15.Taegtmeyer H, Wilson C, Razeghu P, et al. Metabolic energetics and genetics in the heart[J]. Ann N Y Acad Sci,2005,1047:208-218
16.Brown JD, Plutzky J. Peroxisome Proliferator-Activated Receptors as transcriptional Nodal Points and Therapeutic Targets[J].Circulation,2007,15(4):518-533.
17.Feige JN, Gelman L, Michalik L, et al.From molecular action to physiological outputs:peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions[J]. Prog Lipid Res,2006,45(2):120-159.
18.Bocher V, Pineda-Torra I, Fruchart JC, et al. PPARs:transcription factors controlling lipid and lipoprotein metabolism[J]. Ann NY Acad Sc,2002,967:7-18
19.Lefebvre P, Chinetti G, Fruchart JC, et al.Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis[J].J Clin Invest,2006,116(3):571-580.
20.Furnsinn C, Willson TM, Brunmair B, et al. Peroxisome proliferator-activated receptor-delta, a regulator of oxidative capacity, fuel switching and cholesterol transport[J]. Diabetologia,2007,50(1):8-17.
21.Semple RK, Chatterjee VK, O'RahillyS. PPAR gamma and human metabolic disease[J]. J Clin Invest,2006,116(3):581-589.
22. Villacorta L, Schopfer FJ, Zhang J, et al. PPARγ and its ligands:therapeutic implications in cardiovascular disease[J]. Clin Sci(Lond),2009,116(3):205-218.
23.Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis[J]. Nature,2006,444(7121):847-853.
1. Abraham NG, Brunner EJ, Eriksson JW, et al. Metabolic syndrome:psychosocial, neuroendocrine and classical risk factors in type 2 diabetes[J].Ann NY Acad Sci, 2007,1113,256-275.
2. Agardh EE, Ahlbom A, Andersson T, et al. Work stress and low sense of coherence is associated with type 2 diabetes in middle-aged swedish women[J]. Diabetes Care, 2003,26(3):719-724.
3. Angela JG and Alan KJ. Stress, depression, and cardiovascular dysregulation:A review of neurobiological mechanisms and the integration of research from preclinical disease models[J]. Stress,2009,12(1):1-21.
4.钱令嘉.关于应激与军事应激医学研究的思考[J].解放军预防医学杂志,2001,19(4)：235-238.
5.钱令嘉.应激与应激医学[J].疾病控制杂志,.2003,7(5)：393-396.
6. Pham K, acher J, Hof PR, et al. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus[J]. Eur J Neurosci,2003,17(4):879-886.
7. Gregus A, W intink AJ, DavisA C, et al. Effectof repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats[J]. Behav Brain Res,2005,156(1):105-114.
8. Thorsell A, Michalkiewicz M and Dumont Y. Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression[J]. Proc Natl Acad Sci U S A,2000,97(23):12852-12857.
9. Rybkin Ⅱ, Zhou Y, Volaufova J, et al. Effect of restraint stress on food intake and body weight is determined by time of day[J]. Am J Physiol,1997,273(5 Pt 2): R1612-R1622.
10. Harris RB, Zhou J, Youngblood BD, et al. Effect of repeated stress on body weight and body composition of rats fed low-and high-fat diets[J]. Am J Physiol Regulatory Integrative Comp Physiol,1998,275(6 Pt 2):R1928-R1938.
11. Marti O, Marti J and Armario A. Effects of chronic stress on food intake in rats:influence of stressor intensity and duration of daily exposure[J]. Physiol.Behav, 1994,55(4):747-753.
12. Smagin GN, Howell LA, Redmann S, et al. Prevention of stress-induced weight loss by third ventricle CRF receptor antagonist[J].Am J Physiol Regulatory Integrative Comp Physiol,1998,276(5 Pt 2):R1461-R1468
13. Shimizu N, Oomura Y and Kai Y. Stress-induced anorexia in rats mediated by serotonergic mechanisms in the hypothalamus[J]. Physiol.Behav,1989,6(5): 835-841.
14. Krahn DD, Gosnell BA and Majchrzak MJ. The anorectic effects of CRH and restraint stress decrease with repeated exposures[J]. Biol Psychiatry,1990,27(10): 1094-1102.
15. Shimizu N, Take S, Hori T, et al. In vivo measurement of hypothalamic serotonin release by intracerebral microdialysis:significant enhancement by immobilization stress in rats[J].Brain Res Bull,1992,28(5):727-734.
16. Heilig M, Widerlov E. Neurobiology and clinical aspects of neuropeptide Y[J]. Crit Rev Neurobiol,1995,9(2-3):115-136
17. Marti O, Gavalda A, Jolin T, et al. Effect of regularity of exposure to chronic immobilization stress on the circadian pattern of pituitary adrenal hormones, growth hormone, and thyroid stimulating hormone in the adult male rat[J]. Psychoneuroendocrinology,1993,18(1):67-77.
18. Egawa M, Yoshimatsu H and Bray GA. Effect of corticotropin releasing hormone and neuropeptide Y on electrophysiological activity of sympathetic nerves to interscapular brown adipose tissue[J]. Neuroscience,1990,34(3):771-775.
19. Depke M, Fusch G, Domanska G, et al. Hypermetabolic Syndrome as a Consequence of Repeated Psychological Stress in Mice[J]. Endocrinology,2008, 149(6):2714-2723
20. Raikkonen K, Keltikangas-Jarvinen L, Adlercreutz H, et al. Restraint stress and the insulin resistance syndrome[J].Metabolism,1996,45(12):1533-1538.
21. Kyrou CT. Stress Mechanisms and Metabolic Complications[J]. Horm Metab Res, 2007,39(5):430-438
22. Villacorta L, Schopfer FJ, Zhang J, et al. PPARy and its ligands:therapeutic implications in cardiovascular disease [J]. Clin Sci(Lond),2009,116(3):205-218
23. Bjorntorp P, Holm G and Rosmond R. Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus[J]. Diabet Med,1999,16(5):373-383.
24. Frontoni S, Bracaglia D, Baroni A, et al. Early autonomic dysfunction in glucose-tolerant but insulin-resistant offspring of type 2 diabetic patients[J]. Hypertension,2003,41(6):1223-1227.
25. Huggett RJ, Hogarth AJ, Mackintosh AF, et al. Sympathetic nerve hyperactivity in non-diabetic offspring of patients with type 2 diabetes mellitus[J]. Diabetologia, 2006,49(11):2741-2744.
26. Qi D and Rodrigues B. Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism[J]. Am J Physiol Endocrinol Metab,2007,292(3): E654-E667
27. Lindmark S, Lonn L, Wiklund U,et al. Dysregulation of the autonomic nervous system can be a link between visceral adiposity and insulin resistance[J]. Obes Res, 2005,13(4):717-728.
28. Andrews RC, Herlihy O, Livingstone DEW, et al. Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance[J]. J Clin Endocrinol Metab,2002,87(12):5587-5593.
29. Bjorntorp P, Rosmond R. Neuroendocrine abnormalities in visceral obesity[J]. Int J Obes Relat Metab Disord,2000,24(Suppl.2):S80-S85.
30. Ward AM, Syddall HE, Wood PJ, et al.2004.Centra hypothalamic-pituitary-adrenal activity and the metabolic syndrome:studies using the corticotrophin-releasing hormone test[J].Metabolism,2004,53(6):720-726.
31. Navegantes LC, Sjostrand M, Gudbjornsdottir S, et al. Regulation and counter regulation of lipolysis in vivo:different roles of sympathetic activation and insulin[J]. J Clin Endocrinol Metab,2003,88(11):5515-5520.
32. Timothy JB and Song CK. Thematic review series:adipocyte biology. Sympathetic and sensory innervation of white adipose tissue[J]. J Lipid Res,2007,48(8):1655-1672.
33. Buckley S, Kudsk KA. Metabolic response to critical illness and injury[J]. AACN Clin Issues Crit Care Nurs,1994,5(4):443-449.
34. Battilana P, Seematter G, Schneiter P, et al. Effects of free fatty acids on insulin sensitivity and hemodynamics during mental stress[J]. J Clin Endocrinol Metab, 2001,86(1):124-128.
1. Kallwitz ER, McLachlan A, Cotler SJ. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease[J]. World J Gastroenterol,2008,14(1):22-28.
2.Musso G, Gambino R, Gassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease(NAFLD) [J]. Prog Lipid Res,2009,48(1):1-26.
3.Lemberger T, Saladin R, Vazquez M, et al. Expression of the gene is stimulated by stress and follows a diurnal rhythm[J]. J Biol Chem,1996,271(3):1764-1769.
4. Ha HY, Kim KS, Yeom YI, et al. Chronic restraint stress massively alters the expression of genes important for lipid metabolism and detoxification in liver[J]. Toxicol Lett,2003,146(1):49-63.
5.Grimaldi PA. Peroxisome proliferator-activated receptors as sensors of fatty acids and derivatives[J]. Cell Mol Life Sci,2007,64(19-20):2459-2464.
6.Forman BM, Chen J, Evans RM. Hypolipidemic drugs,polyunsaturated fatty acids,and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta[J].Proc Natl Acad Sci USA,1997,94(9):4312-4317.
7.Lemberger T, Staels B, Saladin R, et al. Regulation of the peroxisome proliferator-activated receptor alpha gene by glucocorticoids[J]. J Biol Chem,1994, 269(40):24527-24530.
8.Bernal-Mizrachi C, Weng S, Feng C, et al. Dexamethasone induction of hypertension and diabetes is PPAR-alpha dependent in LDL receptor-null mice[J]. Nat Med, 2003,9(8):1069-1075.
9.Steineger HH, Sorensen HN, Tugwood JD, et al. Dexamethasone and insulin demonstrate marked and opposite regulation of the steady-state mRNA level of the peroxisomal proliferator-activated receptor(PPAR) in hepatic cells. Hormonal modulation of fatty acid induced transcription[J]. Eur J Biochem,1994,225(3): 967-974.
10.Kersten S, Seydoux J, Peters JM, et al. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting[J]. J Clin Invest,1999,103(11): 1489-1498.
11.Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor(PPAR) in the cellular fasting response:the PPAR-null mouse as a model of fatty acid oxidation disorders[J]. Proc Natl Acad Sci USA, 1999,96(13):7473-7478.
12.Hashimoto T, Cook WS, QI C, et al. Defect in peroxisome proliferator-activated receptor a-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting[J]. J Biol Chem,2000,275(37):28918-28928.
13.Sugden MC, Bulmer K, Gibbons GF, et al. Peroxisome-proliferator-activated receptor-alpha(PPARalpha) deficiency leads to dysregulation of hepatic lipid and carbohydrate metabolism by fatty acids and insulin[J]. Biochem J,2002,364(Pt2): 361-368.
14.Mandard S, Muller M, Kersten S. Peroxisome proliferator-activated receptor alpha target genes[J]. Cell Mol Life Sci,2004,61(4):393-416
15.Sandelin A and Wasserman WW. Prediction of nuclear hormone receptor response elements[J].Mol Endocrinol,2005,19(3):595-606.
16. Cavalieri D, Calura E, Romualdi E, et al. Filling gaps in PPAR-alpha signaling through comparative nutrigenomics analysis[J]. BMC Genomics,2009,10:596
17.Aoyama T, Peters JM, Iritani N, et al. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator activated receptor alpha(PPARa) [J]. J.Biol Chem,1998,273(10):5678-5684
18.Rodriguez JC, Gil-Gomez G, Hegardt FG, et al. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids[J]. J Biol Chem,1994,269(29):18767-18772.
19.Ringseis R, Eder K. Influence of pharmacological PPARa activators on carnitine homeostasis in proliferating and non-proliferating species[J]. Pharmacol Res,2009, 60(3):179-184.
20.Kersten S,Mandard S,Escher P,et al.The peroxisome proliferator-activated receptor alpha regulates amino acid metabolism[J].FASEB J,2001,15(11):1971-1978.
21. Reddy JK and Rao SM. Lipid Metabolism and Liver Inflammation. Ⅱ. Fatty liver disease and fatty acid oxidation[J]. Am J Physiol Gastrointest Liver Physiol,2006, 290(5):G852-G858.
22.Higashiyama H, Billin AN, Okamoto Y,et al. Expression profiling of peroxisome proliferator-activated receptor-delta(PPAR-delta) in mouse tissues using tissue microarray[J]. Histochem Cell Biol,2007,127(5):485-494.
23.Akiyama TE, Lambert G, Nicol CJ, et al. Peroxisome proliferator-activated receptor beta/delta regulates very low density lipoprotein production and catabolism in mice on a Western diet[J]. J Biol Chem,2004,279(20):20874-20881.
24.PetersJM, Lee SS, Li W, et al. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delter) [J]. Mol Cell Biol,2000,20(14):5119-5128.
25.Lee CH, Olson P, Hevener A, et al. PPARdelta regulates glucose metabolism and insulin sensitivity[J]. Proc Natl Acad Sci U S A,2006,103(9):3444-3449.
26.Kamei Y, Ohizumi H, Fujitani Y, et al. PPARgamma coactivator lbetta/ERR ligand 1 is an ERR protein ligand, whose expression induces a hign-energy expenditure and antagonized obesity[J]. Proc Natl Acad Sci USA,2003,100(21):12378-12383.
27.Masternak MM, Al-Regaiey KA, Del Rosario Lim MM, et al. Effects of caloric restriction and growth hormone resistance on the expression level of peroxisome proliferator-activated receptors superfamily in liver of normal and long-lived growth hormone receptor/binding protein knockout mice[J]. J Gerontol Bio Sci Med Sci, 2005,60(11):1394-1398.
28. Momon RA, Tecott LH, Nogogaki K, et al. Up-Regulation of Peroxisome Proliferator-Activated Receptorsa(PPAR-a) and PPARy-Messenger Ribonucleic Acid Expression in the Liver in Murine Obesity:Troglitazone Induces Expression of PPARγ-Responsive Adipose Tissue-Specific Genes in the Liver of Obese Diabetic Mice[J]. Endocrinology,2000,141(11):4021-4031.
29. Yu S, Matsusue K, Kashireddy P, et al. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1(PPARy 1) overexpression[J]. J Biol Chem,2003,278(1):498-505.
30.Matsusue K, Haluzik M, Lambert G, et al. Liver-specific disruption of PPARy in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes[J]. J Clin Invest.2003,111(5):737-747.
31. Vidal-Puig AJ, Considine RV, Jimenez-Linan M, et al. Peroxisome proliferator-activated receptor gene expression in human tissues:effects of obesity, weight loss, and regulation by insulin and glucocorticoids[J]. J Clin Invest,1997,99(10):2416-2422.
32.Picard F and Auwerx J. PPAR(gamma) and glucose homeostasis[J]. Annu Rev Nutr, 2002,22:167-197.
33.Al-Khalili L, Forsgren M, Kannisto K, et al. Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1[J]. Diabetologia,2005,48(6):1173-1179.
34. Mora S, Pessin JE. The MEF2A isoform is required for striated muscle-specific expression of the insulin-responsive GLUT4 glucose transporter[J]. J Biol Chem, 2000,275(21):16323-16328.
35.Goldberg IJ. Lipoprotein lipase and lipolysis:central roles in lipoprotein metabolism and atherogenesis[J]. J Lipid Res,1996,37(4):693-707.
36.Zechner R.The tissue-specific expression of lipoprotein lipase:implications for energy and lipoprotein metabolism[J].Curr Opin Lipidol,1997,8(2):77-88.
37.Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, et al. PPARa and PPARy activators direct a tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene[J]. EMBO J,1996,15(19):5336-5348
38.Louet JF, May CL, Pegorier JP, et al. Regulation of liver carnitine palmitoyltransferase I gene expression by hormones and fatty acids[J]. Biochem Soc Trans,2001,29(Pt2):310-316.
1. Gilde AJ and Van Bilsen M. Peroxisome proliferator-activated receptors(PPARS): regulators of gene expression in heart and skeletal muscle[J].Acta Physiol Scand, 2003,178(4):425-434.
2. Minnich A, Tian N, Byan L,et al. A potent PPARalpha agonist stimulates mitochondrial fatty acid beta-oxidation in liver and skeletal muscle[J]. Am J Physiol Endocrinol Metab,2001,280(2):E270-E279.
3. Muoio DM, Way JM, Tanner CJ, et al. Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells[J]. Diabetes,2002,51(4):901-909.
4. Muoio DM, MacLean PS, Lang DB, et al. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor(PPAR)alpha knock-out mice. Evidence for compensatory regulation by PPAR delta[J]. J Biol Chem,2002,277(29):26089-26097.
5. Horowitz JF, Leone TC, Feng W, et al. Effect of endurance training on lipid metabolism in women:a potential role for PPAR in the metabolic response to training[J]. Am J Physiol Endocrinol Metab,2000,279(2):E348-E355.
6. Manetta J, Brun JF, Perez-Martin A, et al. Fuel oxidation during exercise in middle-aged men:role of training and glucose disposal[J]. Med Sci Sports Exerc, 2002,34(3):423-429.
7. Braissant O, Foufelle F, Scotto C, et al. Differential expression of peroxisome proliferator-activated receptors(PPARs):tissue distribution of PPAR-alpha,-beta and-gamma in the adult rat[J].Endocrinology,1996,137(1):354-366.
8. Holst D, Luquet S, Nogueira V, et al. Nutritional regulation and role of peroxisome proliferator-activated receptor delta in fatty acid catabolism in skeletal muscle[J]. Biochim Biophys Acta,2003,1633(1):43-50
9. Tanaka T, Yamamoto J, Iwasaki S, et al. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome[J]. Proc Natl Acad Sci U.S.A,2003,100(26): 15924-15929.
10. Kramer DK, Al-Khalili L, Perrini S, et al. Direct activation of glucose transport in primary human myotubes after activation of peroxisome proliferator-activated receptor delta[J]. Diabetes,2005,54(4):1157-1163.
11. Wang YX, Zhang CL, Yu RT,et al. Regulation of muscle fiber type and running endurance by PPARdelter[J]. PLoS Biol,2004,2(10):1532-1539.
12. Luquet S, Lopez-Soriano J, Holst D, et al.Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability[J].FASEB J, 2003,17(15):2299-2301.
13.Verma NK, Singh J, Dey CS. PPARy expression modulation insulin sensitivity in C2C12 skeletal muscle cells[J]. Br J Pharmacol,2004,143(8):1006-1013.
14.Ye P, Zhang XJ, Wang ZJ. Effect of aging on the expression of peroxisome proliferator-activated receptor gamma and the possible relation to insulin resistance[J]. Gerontology,2006,52(2):69-75.
15. Singh J, Verma NK, Kansagra SM, et al Altered PPARy expression inhibits myogenic differentiation in C2C12 skeletal muscle cells[J]. Mol Cell Biochem, 2007,294(1-2):163-171.
16.Solanes G, Pedraza N, Iglesias R, et al.Functional relationship between MyoD and peroxisome proliferator receptor-activated receptor dependent regulatory pathways
in the control of the human uncoupling protein-3 gene transcription[J].Mol Endocrinol,2003,17(10):1944-1958.
17.Christiana K, Jan Kru"tzfeldt, Anja Witke, et al. Effects of Troglitazone on Cellular Differentiation,Insulin Signaling, and Glucose Metabolism in Cultured Human Skeletal Muscle Cells[J]. Biochem Biophys Res Commun,2001,280(3):664-674.
18.Norris AW, Chen L, Fisher SJ, et al. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones[J]. J Clin Invest,2003,112(4):608-618.
19.Hevener AL, He W, Barak Y, et al. Muscle-specific PPARy deletion causes insulin resistance[J]. Nat Med,2003,9(12):1491-1497.
20.Wu Z, Xie Y, Morrison RF,et al. PPARgamma induces the insulin-dependent glucose transporter GLUT4 in the absence of C/EBPalpha during the conversion of 3T3 fibroblasts into adipocytes[J].J Clin Invest,1998,101(1):22-32.
21.Verma NK, Singh J, Dey CS. PPARy expression modulation insulin sensitivity in C2C12 skeletal muscle cells[J].Br J Pharmacol,2004,143(8):1006-1013.
22.Dressel U, Allen TL, Pippal JB, et al.The peroxisome proliferator-activated receptor beta/delta agonist, GW501516,regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells[J]. Mol Endocrinol, 2003,17(12):2477-2493.
23.Merkel M, Eckel RH, and Goldberg IJ. Lipoprotein lipase:genetics,lipid uptake and regulation[J]. J Lipid Res,2002,43(12):1997-2006.
24.Zechner R. The tissue-specific expression of lipoprotein lipase:implications for energy and lipoprotein metabolism[J]. Curr Opin Lipidol,1997,8(2):77-88.
25.Mascaro C, Acosta E, Ortiz JA, et al. Control of human muscle-type carnitine palmitoyltrans-ferase I gene transcription by peroxisome proliferator-activated receptor[J]. J Bio Chem,1998,273(15):8560-8563.
1. Frayn KN, Fielding BA and Karpe F. Adipose tissue fatty acid metabolism and cardiovascular disease[J]. Curr Opin Lipidol,2005,16(4):409-415.
2. Constantinos C, Antonio VP. PPARs and adipocyte function[J]. Mol Cell Endocrinol, 2009,28(2):243-248
3. Guzman M, Lo Verme J, Fu J, et al. Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptora(PPAR-a) [J]. J Biol Chem,2004,279(27):27849-27854.
4. Fu J, Oveisi F, Gaetani S, Lin E, et al.Oleoylethanolamide, an endogenous PPAR-alpha agonist lowers body weight and hyperlipidemia in obese rats[J]. Neuropharmacology,2005,48(8):1147-1153.
5. Cabrero A, Alegret M, Sanchez RM, et al. Bezafibrate reduces mRNA levels of adipocyte markers and increases fatty acid oxidation in primary culture of adipocytes[J]. Diabetes,2001,50(8):1883-1890.
6. Vazquez M, Roglans N, Cabrero A, et al. Bezafibrate induces acyl-CoA oxidase mRNA levels and fatty acid peroxisomal beta-oxidation in rat white adipose tissue[J]. Mol Cell Biochem,2001,216(1-2):71-78.
7. Okamoto Y, Higashiyama H, Inoue H, et al. Quantitative image analysis in adipose tissue using an automated image analysis system:differential effects of peroxisome proliferator-activated receptor-and-agonist on white and brown adipose tissue morphology in AKR obese and db/db diabetic mice[J]. Pathol Int,2007,57(6): 369-377.
8. Hill MR, Young MD, McCurdy CM, et al. Decreased expression of murine PPARy in adipose tissue during endoxemia[J]. Endocrinology,1997,138(7):3073-3076.
9. Bogacka I, Xie H, Bray GA, et al. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo[J]. Diabetes,2005,54(5):1392-1399.
10.Jeong S,Yoon M.Troglitazone lowers serum triglycerides with sexual dimorphism in C57BL/6J mice[J]. J Exp Biomed Sci,2006,12:65-72.
11.Bastie C, Luquet S, Holst D, et al. Alterations of peroxisome proliferator-activated receptor delta activity affect fatty acid-controlled adipose differentiation[J]. J Biol Chem,2008,275(49):38768-38773.
12.Higashiyama H, Billin AN, Okamoto Y, et al. Expression profiling of peroxisome proliferator-activated receptor-delta(PPAR-delta) in mouse tissues using tissue microarray[J]. Histochem Cell Biol,2007(5),127:485-494.
13.Wang YX, Lee CH, Tiep S, et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity[J]. Cell,2003,113(2):159-170.
14.Escher P, Braissant O, Basu-Modak S, et al. Rat PPARs:quantitative analysis in adult rat tissues and regulation in fasting and refeeding[J]. Endocrinology,2001, 142(10):4195-4202.
15.Medina-Gomez G, Virtue S, Lelliott C, et al. The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-gamma2 isoform[J].Diabetes,2005,54(6):1706-1716.
16.Rosen ED, Spiegelman BM. Molecular regulation of adipogenesis[J]. Annu Rev Cell Dev Biol,2000,16:145-171.
17.Grimaldi PA. The roles of PPARs in adipocyte differentiation[J]. Prog Lipid Res, 2001,40(4),269-281.
18.Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transactivation factor[J]. Cell,1994,79(7): 1147-1156.
19.Medina-Gomez G, Gray SL, Yetukuri L, et al. PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism[J]. PLoS Genet,2007, (4):e64.0634-0647.
20.Koh YJ, Park BH, Park JH, et al. Activation of PPARγ induces profound multilocularization of adipocytes in adult mouse white adipose tissues[J]. Exp Mol Med,2009,41(12):880-895.
21.Brasaemle DL.Thematic review series:adipocyte biology.The perilipin family of structural lipid droplet proteins:stabilization of lipid droplets and control of lipolysis[J].J Lipid Res,2007,48(12),2547-2559.
22.Dalen KT, Schoonjans K, Ulven SM, et al. Adipose tissue expression of the lipid droplet-associating proteins S3-12 and perilipin is controlled by peroxisome proliferator-activated receptor-gamma[J]. Diabetes,2004,53(5),1243-1252.
23.Matsusue K, Peters JM and Gonzalez FJ. PPARbeta/delta potentiates PPARgamma-stimulated adipocyte differentiation[J]. FASEB J,2004,18(12): 1477-1479.
24.Vidal-Puig A, Jimenez-Linan M, Lowell BB, et al. Regulation of PPAR gamma gene expression by nutrition and obesity in rodents[J]. J Clin Invest,1996,97(11):2553-2561.
25. Vidal-Puig AJ, Considine RV, Jimenez-Linan M, et al. Peroxisome Proliferator-activated Receptor Gene Expression in Human Tissues[J]. J Clin Invest,1997, 99(10):2416-2422.
26.Gurnell M, Savage DB, Chatterjee VK, et al. The metabolic syndrome:peroxisome proliferator-activated receptor and its therapeutic modulation[J].J Clin Endocrinol Metab,2003,88(6):2412-2421.
27.Way JM, Harrington WW, Brown KK, et al. Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues[J].Endocrinology,2001,142(3):1269-1277.
28.Takazawa T, Yamauchi T, Tsuchida A, et al. Peroxisome proliferator-activated receptor gamma agonist rosiglitazone increases expression of very low density lipoprotein receptor gene in adipocytes[J]. J Biol Chem,2009,284(44): 30049-30057.
29.Mukherjee R, Hoener PA, Jow L, et al. A selective peroxisome proliferator activated receptor-y(PPARy) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes[J]. Mol Endocrinol,2000,14(9):1425-1433.
30.Picard F and Auwerx J. PPAR(gamma) and glucose homeostasis[J]. Annu Rev Nutr, 2002,22:167-197.
31. Al-Khalili L, Forsgren M, Kannisto K, et al. Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1 [J]. Diabetologia,2005; 48(6):1173-1179.
32.Preiss-Landl K, Zimmermann R, Hammerle G, et al. Lipoprotein lipase:the regulation of tissue specific expression and its role in lipid and energy metabolism[J]. Curr Opin Liplidol.2002,13(5):471-481.
33.Farese RV Jr, Yost TJ and Eckel RH. Tissue-specific regulation of lipoprotein lipase activity by insulin/glucose in normal-weight humans[J]. Metabolism,1991,40(2): 214-216.
34.Samra JS. Sir David Cuthbertson Medal. Lecture.Regulation of lipid metabolism in adipose tissue[J]. Proc Nutr Soc,2000,59(3):441-446.
35.Feingold KR, Marshall M, Gulli R, et al. Effect of endoxin and cytokines on lipoprotein activity in mice[J]. Arterioscler Thromb,1994,14(11):1866-1872.
36.Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, et al. PPARa and PPARy activators direct a tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene[J]. EMBO J,1996,15(19):5336-5348.
37.张芳林,罗敏.肉碱棕榈酰转移酶-Ⅰ的研究进展[J].国外医学内分泌分册,2002,22(3)：166-169.
1. Taegtmeyer H, Wilson C, Razeghu P, et al. Metabolic energetics and genetics in the heart[J]. Ann N Y Acad Sci,2005,1047:208-218.
2. Zhao Y, Wang W and Qian L.Hsp70 may protect cardiomyocytes from stress-induced injury by inhibiting Fas-mediated apoptosis[J].Cell Stress Chaperones,2007,12(1):83-95.
3. Yang Q and Li Y. Roles of PPARs on regulating myocardial energy and lipid homeostasis[J]. J Mol Med,2007,85(1):697-706.
4. Finck BN and Kelly DP. Peroxisome proliferator-activated receptora (PPARa) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart [J]. J Mol Cell Cardiol,2002,34(10):1249-1257.
5. Horowitz JF, Leone TC, Feng W, et al. Effect of endurance training on lipid metabolism in women:a potential role for PPAR in the metabolic response to training[J]. Am J Physiol Endocrinol Metab,2000,279(2):E348-E355.
6. Watanabe K, Fujii H, Takahashi T, et al. Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity[J]. J Biol Chem,2000,275(29): 22293-22299.
7. Luptak I, Balschi JA, Xing Y, et al. Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization[J].Circulation,2005,112(15): 2339-2346.
8. Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus[J].J Clin Invest, 2002,109(1):121-130.
9. Park SY, Cho YR, Finck BN, et al. Cardiac-specific overexpression of peroxisome proliferator-activated receptor-alpha causes insulin resistance in heart and liver[J]. Diabetes,2005,54(9):2514-2524.
10. Panania M, Gibbons GF, Radda GK, et al. PPAR-alpha activation required for decreased glucose uptake and increased susceptibility to injury during ischemia[J]. Am J Physiol Heart Circ Physiol,2005,288(6):H2677-H2683.
11. Sambandam N, Morabito D, Wagg C, et al. Chronic activation of PPARalpha is detrimental to cardiac recovery after ischemia[J]. Am J Physiol Heart Circ Physiol, 2006,290(1):H87-H95.
12. Durgan DJ, Moore MW, Ha NP, et al.Circadian rhythms in myocardial metabolism and contractile function:influence of workload and oleate[J].Am J Physiol Heart Circ Physiol,2007,293(4):H2385-93.
13.Huang B, Wu P, Bowker-Kinley MM, et al. Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, lucocorticoids, and insulin[J]. Diabetes,2002,51(2):276-283.
14. Cheng L, Ding G, Qin Q, et al. Peroxisome proliferator-activated receptor delta activates fatty acid oxidation in cultured neonatal and adult cardiomyocytes[J]. Biochem Biophys Res Commun,2004,313(2):277-286.
15.Cheng L, Ding G, Qin Q, et al. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy[J]. Nat Med,2004,10(11):1245-1250.
16. Burkart EM, Sambandam N, Han X, et al. Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart[J]. J Clin Invest,2007,117(12):3930-3939.
17. Son NH, Park TS, Yamashita H, et al. Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice[J].J Clin Invest,2007,117(10):2791-2801.
18. Duan SZ, Ivashchenko CY, Russell MW, et al. Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice[J]. Circ Res,2005,97(4):372-379.
19. Ding G, Fu M, Qin Q, et al. Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage[J].Cardiovasc Res,2007,76(2):269-279.
20. Eileen MB, Nandakumar S, Xianlin H,et al. Nuclear receptors PPARβ/δ and PPARα direct distinct metabolic regulatory programs in the mouse heart[J]. J Clin Invest, 2007,117(12):3930-3939.
21. Tian,R.,and Abel ED. Responses of GLUT4-deficient hearts to ischemia underscore the importance of glycolysis[J]. Circulation,2001,103 (24):2961-2966.
22. Yagyu H, Chen G,Yokoyama M, et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy[J]. J Clin Invest,2003,111(3):419-426.
23. Augustus A,Yagyu H, Haemmerle G, et al. Cardiac-specific knock-out of lipoprotein lipase alters plasma lipoprotein triglyceride metabolism and cardiac gene expression[J].J Biol Chem,2004,279(24):25050-25057.
24. Yokoyama M., Yagyu H, Hu Y, et al. Apolipoprotein B production reduces lipotoxic cardiomyopathy:studies in heart-specific lipoprotein lipase transgenic mouse[J]. J Biol Chem,2004,279(6):4204-4211.
25. Pulinikunnil T and Rodrigues B. Cardiac lipoprotein lipase:Metabolic basis for diabetic heart disease[J]. Cardiovascular Research,2006,69(2):329-340.
26. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, et al. PPARa and PPARy activators direct a tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene[J].EMBO J,1996,15(19):5336-5348.
27.张芳林,罗敏.肉碱棕榈酰转移酶-Ⅰ的研究进展[J].国外医学内分泌分册,2002,22(3)：166-169.
28. Brandt JM, Djouadi F and Kelly DP. Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha[J]. J Bio Chem,1998,273(37):23786-23792.
29. Cheng L, Ding G, Qin Q, et al. Peroxisome proliferator-activated receptorδ activates fatty acid oxidation in cultured neonatal and adult cardiomyocytes[J]. Biochem Biophys Res Commun,2004,913(2):277-286.
30. Lionetti V, Linke A, Chandler MP, et al. Carnitine palmitoyl transferase-Ⅰ inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure[J]. Cardiovasc Res,2005,66(3):454-461.
1. Kersten S, Desvergne B and Wahli W. Roles of PPARS in health and disease[J]. Nature,2000,405(6785):421-424.
2. Desvergne B and Wahli W. Peroxisome proliferator-activated receptors:nuclear control of metabolism[J]. Endocr Rev,1999,20(5),649-688.
3. Adiels M, Olofsson SO, Taskinen MR, et al. Diabetic dyslipidaemia[J]. Curr Opin Lipidol,2006,17(2):238-246.
4. Fisher EA, Ginsberg HN. Complexity in the secretory pathway:the assembly and secretion of apolipoprotein B-containing lipoproteins[J]. J Biol Chem,2002, 277(20):17377-17380.
5. Ameen C, Edvardsson U, LjungbergL, et al. Activation of peroxisome proliferator-activated receptor alpha increases the expression and activity of microsomal triglyceride transfer protein in the liver[J]. J Biol Chem,2005,280 (2):1224-1229.
6. Linden D, Lindberg K, Oscarsson J, et al. Influence of peroxisome proliferator-activated receptor alpha agonists on the intracellular turnover and secretion of apolipoprotein(Apo)B-100 and ApoB-48[J]. J Biol. Chem,2002,277(25):23044-23053.
7. Hashimoto T, Cook WS, Qi C, et al. Defect in peroxisome proliferator-activated receptora-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting[J]. J Bio Chem,2000,275 (37):28918-28928.
8. Stienstra R, Mandard S, Patsouris D, et al. Peroxisome proliferator-activated receptora protects against obesity-induced hepatic inflammation[J].Endocrinology, 2007,148(6):2753-2763.
9. Harano Y,Yasui K, Toyama T, et al. Fenofibrate, a peroxisome proliferator-activated receptoraagonist,reduces hepatic steatosis and lipid peroxidation in fatty liver Shionogimice with hereditary fatty liver[J]. Liver Int,2006,26(5):613-620.
10. Martin PG, Guillou H, Lasserre F, et al. Novel aspects of PPARalphar-mediated regulation of lipid and xenobiotic metabolism revealed through a nutrigenomic study[J].Hepatology,2007,45 (3):767-777.
11. Waterman IJ,. Zammit VA. Differential effects of fenofibrate or simvastatin treatment of rats on hepatic microsomal overt and latent diacylglycerol acyltransferase activities [J]. Diabetes,2002,51(6):1708-1713.
12. Targett-Adams P,. McElwee MJ, Ehrenborg E, et al. A PPAR response element regulates transcription of the gene for human adipose differentiation-related protein[J]. Biochim Biophys Acta,2005,1728(1-2):95-104.
13. Linden D, Lindberg K, Oscarsson J, et al. Influence of peroxisome proliferator-activated receptoraagonists on the intracellular turnover and secretion of apolipoprotein(Apo)B-100 and ApoB-48[J]. J Biol Chem,2002,277(25): 23044-23053.
14. Linden D, Alsterholm M, Wennbo H, et al. PPARa deficiency increases secretion and serum levels of apolipoprotein B-containing lipoproteins[J]. J Lipid Res,2001, 42(11):1831-1840.
15. Santos RD, Ventura LI, Sposito AC, et al. The effects of gemfibrozil upon the metabolism of chylomicron-like emulsions in patients with endogenous hypertriglyceridemia[J]. Cardiovasc Res,2001,49 (2):456-465.
16. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, et al. PPARa and PPARy activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene[J]. EMBO J,1996,15(19):5336-5348.
17. Raspe E, Duez H, Mansen A, et al. Identification of Reverba as a physiological repressor of apoC-III gene transcription[J]. J Lipid Res,2002,43(12):2172-2179.
18. Schultze AE, Alborn WE, Newton RK, et al. Administration of a PPARaagonist increases serum apolipoprotein A-V levels and the apolipoprotein A-V/ apolipoprotein C-III ratio[J]. J Lipid Res,2005,46 (8):1591-1595.
19. Qu S, Su D, Altomonte J, et al. PPAR-{alpha}Mediates the Hypolipidemic action of Fibrates by Antagonizing FoxO1[J]. Am J Physiol Endocrinol Metab,2007,292(2): E421-E434.
20. Mandard S, Zandbergen F, van Straten E, et al. The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity[J]. J Biol Chem,2006,281(2):934-944.
21. Mandard S, Zandbergen F, Tan NS, et al.The direct peroxisome proliferator-activated receptor target fasting-induced adipose factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a truncated protein that is increased by fenofibrate treatment[J]. J Biol Chem,2004,279(33):34411-34420.
22. Ferreira AV, Parreira GG, Green A, et al. Effects of fenofibrate on lipid metabolism in adipose tissue of rats[J]. Metabolism,2006,55(6):731-735.
23. Gbaguidi FG, Chinetti G, Milosavljevic D, et al. Peroxisome proliferator-activated receptor(PPAR) agonists decrease lipoprotein lipase secretion and glycated LDL uptake by human macrophages[J]. FEBS Lett,2002,512(1-3):85-90.
24. Birjmohun RS, Hutten BA, Kastelein JP,et al. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds:a meta-analysis of randomized controlled trials[J]. J Am Coll Cardiol,2005,45(2):185-197.
25. Brunham LR, Singaraja RR, and.Hayden MR. Variations on a gene:rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis[J]. Annu Rev Nutr,2006,26(1):105-129.
26. McNeish J,Aiello RJ, Guyot D,et al. High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1[J]. Proc Natl Acad Sci U S A,2000,97(8):4245-4250.
27. Knight BL, Patel DD, Humphreys SM, et al. Inhibition of cholesterol absorption associated with a PPARa-dependent increase in ABC binding cassette transporter Al in mice[J]. J Lipid Res,2003,44(11):2049-2058.
28. Chinetti G, Lestavel S, Bocher V, et al. PPAR-a and PPAR-y activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway[J]. Nat Med,2001,7(1):53-58.
29. Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma[J]. J Clin Invest,2004,114(11):1564-1576.
30. Chinetti G, Lestavel S, Fruchart JC, et al. Peroxisome proliferator-activated receptor alpha reduces cholesterol esterification in macrophages[J]. Circ Res,2003, 92(2):212-217.
31. Bouly M, Masson D, Gross B, et al. Induction of the phospholipid transfer protein gene accounts for the high density lipoprotein enlargement in mice treated with fenofibrate[J]. J Biol Chem,2001,276(28):25841-25847.
32. van der Hoogt CC, de Haan W, Westerterp M, et al. Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression[J]. J Lipid Res,2007,48(8):1763-1771.
33. Mardones P, Pilon A, Bouly M, et al. Fibrates down-regulate hepatic scavenger receptor class B type Ⅰ protein expression in mice[J]. J Biol Chem,2003,278(10): 7884-7890.
34. Fang HL, Strom SC, Cai H, et al. Regulation of human hepatic hydroxysteroid sulfotransferase gene expression by the peroxisome proliferator-activated receptor alpha transcription factor[J]. Mol Pharmacol,2005,67(4):1257-1267.
35. Post SM, Duez H, Gervois PP, et al. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression[J]. Arterioscler Thromb Vasc Biol,2001,21(11):1840-1845.
36. Hunt MC, Yang YZ, Eggertsen G, et al. The peroxisome proliferator-activated receptor alpha(PPARalpha) regulates bile acid biosynthesis[J]. J Biol Chem,2000, 275(37):28947-28953.
37. Jung D, Fried M, Kullak-Ublick GA. Human apical sodium-dependent bile salt transporter gene(SLC10A2) is regulated by the peroxisome proliferator-activated receptor alpha[J].J Biol Chem,2002,277(34):30559-30566.
38 Akiyama TE, Lambert G, Nicol CJ, et al. Peroxisome proliferator-activated receptor beta/delta regulates very low density lipoprotein production and catabolism in mice on a Western diet[J]. J Biol Chem,2004,279(20):20874-20881.
39. Leibowitz MD, Fievet C, Hennuyer N, et al. Activation of PPARdelta alters lipid metabolism in db/db mice[J]. FEBS Lett,2000,473(3):333-336.
40. Oliver WR Jr, Shenk JL, Snaith MR, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport[J]. Proc Natl Acad Sci U S A,2001,98(9):5306-53011.
41. Sprecher DL, Massien C, Pearce G et al.Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor 8 agonist[J]. Arterioscler Thromb Vasc Biol,2007,27(2): 359-365.
42 Wallace JM, Schwarz M, Coward P, et al. Effects of peroxisome proliferator-activated receptor alpha/delta agonists on HDL-cholesterol in vervet monkeys[J]. J Lipid Res,2005,46(5):1009-16.
43 van der Veen JN, Kruit JK, Havinga R. Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1[J]. J Lipid Res,2005,46(3):526-534
44. Jones JR, Barrick C, Kim K-A, et al. Deletion of PPARy in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance[J]. Proc Natl Acad Sci U S A,2005,102(17):6207-6212.
45. Kobayashi J, Nagashima I, Hikita M, et al. Effect of troglitazone on plasma lipid metabolism and lipoprotein lipase[J]. Br J Clin Pharmacol,1999,47(4):433-439.
46. Tan GD, Fielding BA, Currie JM, et al. The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes[J]. Diabetologia,2005,48(1):83-95.
47. Nagashima K, Lopez C, Donovan D, et al. Effects of the PPARy agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus[J]. J Clin Invest,2005,115(5):1323-1332.
48 Tan GD, Fielding BA, Currie.MJ, et al. The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes[J]. Diabetologia,2005,48(1):83-95.
49. Laplante M, Festuccia WT, Soucy, et al. Mechanisms of the depot specificity of peroxisome proliferator-activated receptor gamma action on adipose tissue metabolism[J]. Diabetes,2006,55(10):2771-2778.
50 Xu A, Lam MC, Chan KW, et al. Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice[J]. Proc Natl Acad Sci U S A,2005,102(17):6086-6091.
51 Gauthier A, Vassiliou G, Benoist F, et al.Adipocyte low density lipoprotein receptor-related protein gene expression and function is regulated by peroxisome proliferator-activated receptory[J]. J Bio Chem,2003,278(14):11945-11953.
52. Goldberg RB,. Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia[J]. Diabetes Care,2005,28(7):1547-1554.
53. Kahn SE, Haner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy[J]. N Engl J Med,2006,355(23): 2427-2443.
54. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macro Vascular Events):a randomized controlled trial[J]. Lancet,2005,366(9493):1279-1289.
55. Chiquette E, Ramirez G and DeFronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors[J].Arch Intern Med,2004,164(19): 2097-2104.
56. Chawla A, Boisvert WA, Lee CH,et al. A PPARgamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis[J]. Mol Cell,2001, 7(1):161-171.
1.Sheng L, Ye P, Liu YX. Atorvastatin upregulates the expression of PPAR alpha/gamma and inhibits the hypertrophy of cardiac myocytes in vitro[J]. Zhonghua Xin Xue Guan Bing Za Zhi,2005,33(12):1080-1084.
2.van Bilsen M, Smeets PJ, Gilde AJ, et al.Metabolic remodelling of the failing heart: the cardiac burn-out syndrome[J]? Cardiovasc Res,2004,61(2):218-226.
3.Leone TC, Weinheimer CJ, Kelly DP.A critical role for the peroxisome proliferator-activated receptor alpha(PPARalpha) in the cellular fasting response:the PPARalpha-null mouse as a model of fatty acid oxidation disorders[J].Proc Natl Acad Sci U S A,1999,96(13):7473-7478.
4.Watanabe K, Fujii H, Takahashi T, et al.Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity[J].J Biol Chem,2000,275(29):22293-22299.
5.Luptak I, Balschi JA, Xing Y, et al.Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization[J].Circulation,2005,112(15): 2339-2346.
6.Campbell FM, Kozak R, Wagner A, et al.A role for peroxisome proliferator-activated receptor alpha(PPARalpha) in the control of cardiac malonyl-CoA levels:reduced fatty acid oxidation rates and increased glucose oxidation rates in the hearts of mice lacking PPARalpha are associated with higher concentrations of malonyl-CoA and reduced expression of malonyl-CoA decarboxylase[J]. J Biol Chem,2002,277(6): 4098-4103.
7.Sambandam N, Morabito D, Wagg C, et al.Chronic activation of PPARalpha is detrimental to cardiac recovery after ischemia[J].Am J Physiol Heart Circ Physiol, 2006,290(1):H87-95.
8.Panagia M, Gibbons GF, Radda GK, et al.PPAR-alpha activation required for decreased glucose uptake and increased susceptibility to injury during ischemia[J].Am J Physiol Heart Circ Physiol,2005,288(6):H2677-2683.
9.Finck BN, Lehman JJ, Leone TC, et al.The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus[J].J Clin Invest,2002, 109(1):121-130.
lO.Finck BN, Han X, Courtois M, et al. A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy:modulation by dietary fat content[J].Proc Natl Acad Sci USA,2003,100(3):1226-1231.
11.Yang J, Sambandam N, Han X, et al.CD36 deficiency rescues lipotoxic cardiomyopathy[J]. Circ Res,2007,100(8):1208-1217.
12.Park SY, Cho YR, Finck BN, et al.Cardiac-specific overexpression of peroxisome proliferator-activated receptor-alpha causes insulin resistance in heart and liver[J].Diabetes,2005,54(9):2514-2524.
13.Sambandam N, Morabito D, Wagg C, et al.Chronic activation of PPARalpha is detrimental to cardiac recovery after ischemia[J].Am J Physiol Heart Circ Physiol, 2006,290(1):H87-95.
14.Sheng L, Ye P, Liu YX, et al.Peroxisome proliferator-activated receptor beta/delta activation improves angiotensin Ⅱ-induced cardiac hypertrophy in vitro[J].Clin Exp Hypertens,2008,30(2):109-119.
15.Gilde AJ, van der Lee KA, Willemsen PH, et al.Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism[J].Circ Res,2003,92(5): 518-524.
16.Cheng L, Ding G, Qin Q, et al.Peroxisome proliferator-activated receptor delta activates fatty acid oxidation in cultured neonatal and adult cardiomyocytes[J].Biochem Biophys Res Commun,2004,313(2):277-286.
17.Cheng L, Ding G, Qin Q, et al.Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy[J].Nat Med,2004,10(11):1245-1250.
18.Burkart EM, Sambandam N, Han X, et al.Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart[J].J Clin Invest,2007,117(12):3930-3939.
19.Cao Z, Ye P, Long C, et al. Effect of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on ischemia-reperfusion injury in rats[J]. Pharmacology,2007,79 (3):184-192.
20.Nissen SE, Wolski K.Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes[J].N Engl J Med,2007,356(24):2457-2471.
21.Duan SZ, Ivashchenko CY, Russell MW, et al. Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice[J].Circ Res,2005,97(4):372-379.
22.Ding G, Fu M, Qin Q, et al.Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage[J].Cardiovasc Res,2007,76(2):269-279.
23.Son NH, Park TS, Yamashita H, et al.Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice[J].J Clin Invest,2007,117(10):2791-2801.