过氧化物酶体增殖物活化受体δ及其在代谢综合征中的作用

摘要/Abstract

摘要： 肥胖与胰岛素抵抗、脂代谢紊乱、高血压及糖耐量降低是代谢综合征的主要特点。过氧化物酶体增殖物活化受体(PPAR) δ是新近发现的PPAR 家族的新成员, 存在多种配体。激活PPARδ可增强脂肪及肌肉组织中的脂肪酸氧化和能量偶联, 抑制巨噬细胞内的炎症反应, 同时具有改善血脂和胰岛素抵抗的作用。这些功能提示PPARδ可用于控制体重、增加胰岛素敏感性, 缓减冠心病症状, 可能是极具潜力的代谢综合征治疗的新靶点。

关键词: 过氧化物酶体增殖物活化受体δ, 代谢综合征, 胰岛素抵抗

Abstract: Obesity, insulin resistance, dyslipidemia, hypertension and glucose intolerance are some major characteristics of metabolic syndrome. PPARδ is a novel discovered isoform of PPARs family with abundant ligands. Activation of PPARδ can enhance fatty acid oxidation and energy uncoupling in adipose tissue and muscle, suppress macrophage-derived inflammation, and improve both hypertriglyceridemia and insulin resistance. These physiological functions of PPARδ imply that it may be a therapeutic target for the treatment of metabolic syndrome via controlling body weight, improving insulin sensitivity, and ameliorating the symptom of atherosclerosis.

Key words: PPARδ, metabolic syndrome, insulin resistance

中图分类号:

R589

杨敏, 刘昭前. 过氧化物酶体增殖物活化受体δ及其在代谢综合征中的作用[J]. 中国临床药理学与治疗学, 2007, 12(11): 1205-1210.

YANG Ming, LIU Zhao-qian. PPAR δ and its role in the metabolic syndrome[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2007, 12(11): 1205-1210.

参考文献

1 Hihi AK, Michal.ik L, Wahli W. PPARs: transcriptional. effectors of fatty acids and their derivatives[J]. CMLS, 2002;59: 790-798.
2 Guan Y, Zhang Y, Breyer MD. The role of PPARs in the transcriptional. control of cellular processes[J]. Drug News Perspect, 2002; 15:147-154.
3 Fredenrich A, Grimaldi PA.PPAR delta:an uncompletely known nuclear receptor[J]. Diabetes Metab, 2005; 31:23-27.
4 Wahli W. Peroxisome proliferator-activated receptors(PPARs): from metabolic control to epidermal. wound healing[J]. Swiss Med Wkly, 2002;132: 83-91.
5 Peters JM, Lee ST, Li W, et al.Growth, adipose, brain and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptorβ/δ[J]. Mol Cell Biol, 2000;20:5119-5128.
6 Gupta RA, Wang D, Katkuri S, et al.Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-δ accelerates intestinal.adenoma growth[J]. Nat Med, 2004;10: 245-247.
7 Haman FS, Nicol CJ, Marin HE, et al.Peroxisome proliferator-activated receptor-δattenuates colon carcinogenesis[J]. Nat Med, 2004;10: 481-483.
8 Holst D, Maldi PA.New factors in the regulation of adipose differentiation and metabolism[J]. Curr Opin Lipidol, 2002; 13:241-245.
9 Shaw N, Elholm M, Noy N.Retinoic acid is a high affinity selective ligand for peroxisome proliferator-activated receptorβ/δ[J]. J Biol Chem, 2003;278: 41589-41592.
10 Ren XD, Lu YQ, Ye KH, et al.The anti-tumor molecular mechanisms of non-steroid anti-inflammatory drugs[J]. Chin Pharmacol Bull, 2005;21:527-531.
11 Welch JS, Ricote M, Akiymna TE, et al.PPARγand PPARδ negatively regulate specific subsets of lipopolysaccharide and IFN-α target genes in macmphages[J]. Proc Natl Acad Sci USA, 2003;100:6712-6717.
12 Akiyama TE, Lambert G, Nicol CJ, et al.Proliferator-activated receptorβ/δ regulates very low density lipoprotein production and catabolism in mice on a western diet[J]. J Biol Chem, 2004; 279:20874-20881.
13 Oliver WR, Shenk JL, Snaith MR, et al.A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport[J]. Proc Natl Acad Sci USA, 2001; 98: 5306-5311.
14 Leibowitz MD, Fievet C, Hennuyer N, et al.Activation of PPARdelta a1ters lipid metabolism in db/db mice[J]. FEBS Lett, 2000; 473:333-336.
15 van der Veen JN, Kruit JK, Havinga R, et al.Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestina1 expression of NPC1L1[J]. J Lipid Res, 2005; 46:526-534.
16 Wang XY, Lee CH, Tiep S, et al.Peroxisome proliferator-activated receptor delta activates fat metabolism to prevent obesity[J]. Cell, 2003;113:159-170.
17 Tanaka T, Yamamoto J, Iwasaki S, et al.Activation of peroxisome proliferator-activated receptor delta induces fatty acid betaoxidation in skeleta1 muscle and attenuates metabolic syndrome[J]. Proc Natl Acad Sci USA, 2003; 100: 15924-15929.
18 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; 137:354-366.
19 Wang YX, Zhang CL, Yu RT, et al.Regulation of muscle fiber type and running endurance by PPARdelta[J]. PLoS Biol, 2004; 2:e294.
20 Grima1di PA.Roles of ppar delta in the control of muscle development and metabolism[J]. Biochem Soc Trans, 2003;31: 1130-1132.
21 Luquet S, Lopez-Soriano J, Holst D, et al.Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability[J]. FASEB J, 2003;17:2299-2301.
22 Watt MJ, Southgate RJ, Holmes AG, et al.Suppression of plasma free fatty acids upregulates peroxisome proliferator-activated receptor (PPAR) a1pha and delta and PPAR coactivator 1 a1.pha in human skeleta1 muscle, but not lipid regulatory genes[J]. J Mol Endocrinol, 2004;33:533-544.
23 Mahoney DJ, Parise G, Melov S, et al.Ana1ysis of globa1 mRNA expression in human skeleta1 muscle during recovery from endurance exercise[J]. FASEB J, 2005;9:1498-1500.
24 Holst D, Luquet S, Nogueira V, et al.Nutritiona1 regulation of peroxisome proliferator-activated receptor delta in fatty acid catabolism in skeleta1 muscle Biochim[J]. Biophys Acta, 2003; 1633:43-50.
25 Cheng L, Ding G, Qin Q, et al.Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardia1 fatty acid oxidation and leads to cardiomyopathy[J]. NatMed, 2004;10:1245-1250.
26 Cheng L, Ding G, Qin Q, et al.Peroxisome proliferator-activated receptor delta activates fatty acid oxidation in cultured neonata1 and adult cardiomyocytes[J]. Biophys Res Commun, 2004;313:277-286.
27 Planavila A, Rodríguez-Ca1vo R, Jovéet M, et al.Peroxisome proliferators-activated receptor beta/delta activation inhibits hypertrophy in neonata1 rat cardiomyocytes[J]. Cardiovasc Res, 2005;65: 832-841.
28 Vosper H, Patel L, Graham TL, et al.The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages[J]. J Biol Chem, 2001; 276:44258-44265.
29 Li AC, Binder CJ, Gutierrez A, et al.Differentia1 inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ[J]. J Clin Invest, 2004; 114: 1564-1576.
30 Lee CH, Chawla A, Urbiztondo N, et al.Transcription a1 repression of atherogenic inflammation:modulation by PPARdelta[J]. Science, 2004; 302:453-457.
31 Kharroubi I, Lee CH, Hekerman P, et al.BCL-6:a possible missing link for anti-inflammatory PPAR-delta signa1ling in pancreatic beta cells[J]. Diabetologia, 2006;4: 2350-2358.
32 Graham TL, Mookherjee C, Suckling KE, et al.The PPARdelta agonist GW0742X reduces atherosclerosis in LDLR(-/-) mice[J]. Atherosclerosis, 2005;181: 29-37.
33 Choi KC, Lee SY, Yoo HJ, et al.Effect of PPAR-δagonist on the expression of visfatin, adiponectin, and resistin in rat adipose tissue and 3T3-L1 adipocytes[J]. Biochem Biophys Res Commun, 2007; 357:62-67.
34 Spiegelman BM, Flier JS.Obesity and the regulation of energy bal1ance[J]. Cell, 2001;104:531-543.
35 Grarup N, Albrechtsen A, Ek J, et al.Variation in the peroxisome proliferator-activated receptor delta gene in relation to common metabolic traits in 7, 495 middle-aged white people[J]. Diabetologia, 2007; 50: 1201-1208.
36 VanttinenM, Nuutifa P, Kuulasmaa T, et al.Single nucleotide polymorphisms in the peroxisome proliferator-activated receptor δgene are associated with skeleta1muscle glucose uptake[J]. Diabetes, 2005; 54:3587-3591.
37 Gouni-Berthold I, Giannakidou E, FaustM, et al.The peroxisome proliferator-activated receptor delta +294T/C polymorphism in relation to lipoprotein metabolism in patients with diabetes mellitus type 2 and in non-diabetic controls[J]. Atherosclerosi, 2005;183:336-341.
38 Aberle J, Hopfer I, Beil FU, et al.Association of the T+294C polymorphism in PPAR δ with low HDL cholesterol andcoronary heart disease risk in women[J]. Int J Med Sci, 2006;3:108-111.
39 Chen S, Tsybouleva N, Ballantyne CM, et al.Effects of PPARα, γandδhaplotypes on plasma levels of lipids and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study[J]. Pharmacogenet, 2004;14:61-71.
40 Hu C, Jia W, Fang Q, et al.Peroxisome proliferator-activated receptor (PPAR) delta genetic polymorphism and its association with insulin resistance index and fasting plasma glucose concentrations in Chinese subjects[J]. Diabet Med, 2006; 23: 1307-1312.

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