浆果儿全集 PPARγ盘考新进展

发布日期:2024-10-08 20:38    点击次数:76

浆果儿全集 PPARγ盘考新进展

过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor, PPAR)是退换方针基因抒发的核内受体转录因子超家眷成员[1], 1990 年Issemann 等[2]领先发现了这种能被一类脂肪酸样化合物过氧化物酶体增殖剂(peroxisome proliferators, PP) 激活, 而被定名为PP 激活受体( peroxisome proliferator activated receptor, PPAR)。凭据结构的不同,PPAR可分为α、β(或δ)和γ三种类型,其中PPARγ主要抒发于脂肪组织及免疫系统,与脂肪细胞分化、机体免疫及胰岛素违背关系密切,是胰岛素增敏剂噻唑烷二酮类药物(troglitazone, TZDs)作用的靶分子,成为连年来盘考热门。1. PPARγ的结构及特征PPARγ基因位于3号染色体短臂上[3],含有9个外显子。由于基因转录时所用的运转子和接拼样式的不同,PPARγ可以分为γ1、γ2和γ3三种亚型,其中γ3和γ1编码的卵白质计议[4,5]。PPARγ2编码的卵白质由505个氨基酸构成,比PPARγ1在氨基端多30个氨基酸。进一步盘考发现[6],PPARγ1mRNA是由8个外显子编码,而PPARγ2mRNA由7个外显子编码,编码的氨基酸数目虽有不同,但两者PPARγ的结构域、DNA联结域及配体联结域等澈底计议,作用基本计议。盘考发现浆果儿全集,不同种属间PPARγcDNA具有高度同源性浆果儿全集,如东谈主与小鼠的PPARγ1的一致性达91%[7]。在啮齿类动物中浆果儿全集,PPARγ主要在脂肪组织中抒发,而在东谈主体,除脂肪组织外,在巨噬细胞以过头他脂肪贮存细胞,如肝、肾、肺及直肠中均有抒发,而且东谈主肝组织比鼠肝抒发更为丰富,而肌肉组织基本不抒发。PPARγ1是PPARγ的主要方法,抒发界限相对泛泛,PPARγ2抒发界限较窄,主要在脂肪组织中抒发,PPARγ3仅抒发于巨噬细胞和大肠中[8,9]。2. PPARγ的配基和功能PPARγ的配基(又称快乐剂) 有两种,生感性配基和药感性配基。生感性配基有15-脱氧前线腺素J2 (15d-PGJ2)过头代谢家具和不足够脂肪酸等,药感性配基有胰岛素增敏剂噻唑烷酮类化合物(TZDs),它是PPARγ的高效配基。跟着盘考的不停真切,越来越多的配基不停被发现,Lehmann等报谈吲哚好意思辛等非甾体类抗炎药也能与PPARγ联结并使之活化[10],此外胰岛素可活化PPARγ,大鼠脂肪细胞经胰岛素惩处30min后,能使其磷酸化水平加多3倍,露馅PPARγ活性升高[11]。配基与PPARγ联结后,可激活PPARγ并退换方针基因的转录活性。PPARγ的N 端功能区含有一个能被有丝分袂原激活的卵白激酶磷酸化位点, 若该区域突变或在磷卵白磷酸酶共同作用下则不可产生磷酸化而使其活化[12]。配体与PPARγ联结并使之激活后, 与 视黄醛X受体α(retinoid X receptor α,RXRα)酿成异二聚体, 再联结于特异性DNA 序列而使靶基因活化, 此序列称为PPAR特异性响应元件(peroxisome proliferator responsive element,,PPRE)[13,14]。PPARγ还能影响NFκB、信号转录子、激活卵白-1介导的信号通路,通过扼制这些路线的激活达到扼制靶基因运转子激活和转录的方针。含有PPRE结构的基因包括已酰辅酶A合成酶、脂卵白脂肪酶(LPL)、胰岛素受体底物-2(IRS-2)、瘦素以及肿瘤坏死因子-α(TNF-α)等[15]。PPARγ通过退换联系基因的抒发,在脂肪酿成、糖脂代谢,以及在免疫系统中推崇遑急作用,并与多种疾病如糖尿病、肥壮、高血压、癌症等的发生、发展联系。尤其是PPARγ是脂肪细胞分化历程中的关键因子,连年来备受柔柔。3. PPARγ和成脂细胞的分化PPAR的三种亚型参与脂肪细胞分化作用的时相及进程各有不同,通过转染具有分化成脂肪细胞潜能的多种细胞系进行评价,PPARγ的成脂作用最强[16]。PPARγ具有脂肪组织特异性,能被脂肪酸及外源性过氧化物酶体增殖剂激活,而调控某些参与脂质代谢的酶的抒发。PPARγ在许多脂肪细胞基因转录激活前被教导,对细胞分化有遑急作用[17]。胰岛素、糖皮质激素以及胞内CAMP的教导剂可使前脂肪细胞分化成脂肪细胞,而表皮滋长因子(EGF)、转念滋长因子可扼制原代培养及前脂肪细胞系的分化同期有丝分袂原活化的卵白激酶可以使PPARγ磷酸化,扼制了配体的转录活化功能,指示PPARγ的转录活化作用可受到参与脂肪细胞分化历程中细胞因子的信号传导路线的退换[12]。在体外盘及第, 胚胎干细胞教导分化为脂肪细胞依赖于PPARγ的参与,通过对PPARγ阳性嵌合体小鼠和野生型小鼠盘考据明,PPARγ为皮脂腺细胞的分化所必需。在PPARγ的三种亚型中,PPARγ2与脂肪和皮脂腺细胞的分化尤其联系[18]。PPARγ2是脂肪细胞分化历程中遑急的退换因子,它可促使成纤维细胞或骨髓间充质干细胞向脂肪细胞分化[19]。Ren[20]等通过基因敲除的方法盘考标明是PPARγ2而非PPARγ1在脂肪分化的历程中起着至关遑急的作用。有盘考以为PPARγ1和PPARγ2均能有用刺激脂肪细胞的分化,但在低配体浓度的情况下,PPARγ2刺激脂肪组织酿成的智力判辨强于PPARγ1[21]。PPARγ在皮脂腺细胞分化历程中相似饰演极为遑急的变装[22,23]。在体外用雄激素教导皮脂腺分化很难达到预期扫尾,其原因可能在于短缺促分化因子, Rosenfield等[24]发现PPARγ激活剂和DHT能促使皮脂腺细胞分化,两者作用重叠,关联词单纯使用雄激素教导皮脂腺分化扫尾欠安,添加PPARγ快乐剂后,皮脂腺细胞出现判辨分化。进一步盘考发现PPARγ与RXR(retinoid X receptor)协同作用能促进皮脂腺细胞的发育和分化[25,26]。4. PPARγ与肿瘤过氧化物酶体增殖物激活受体PPAR是细胞核激素受体,它转录水平影响脂肪酸过头繁衍物的功能。通过以上的样式,PPAR可以退换细胞的分化、增殖和生计,从而在不同组织中端正癌症的发生。关联词每种PPAR亚型和癌发生有何关联呢?而且这些发现和东谈主体病理学及调整有何关联呢?PPARγ具有抗增殖及预调一火和促分化的功能[27],因而具有较全面的抗癌活性。PPARγ参与了前脂肪细胞分化成脂肪细胞以及单核细胞分化为巨噬细胞。当有PPARγ和RXR 配体存在时,骨髓细胞前分化为静息巨噬细胞,当两者捏续存在时,PPARγ可消退脂肪瘤细胞分化同期触发瘤细胞向脂肪细胞分化[28]。践诺发现PPARγ在渊博结肠细胞、高分化及低分化肠癌细胞中均高抒发[29]。PPARγ遴选性配体曲格列酮可扼制东谈主结肠癌细胞及乳腺癌细胞等肿瘤细胞的增殖、教导其分化,并可使裸鼠模子中肿瘤体积削弱50%,减少平均荷瘤数[30]。溃疡性结肠炎与结肠癌的发生密切联系,NSAIDS可看成PPARγ配体推崇作用PPARγ快乐剂可扼制COX-2的抒发,同期PPARγ快乐剂可扼制巨噬细胞的激活、炎性细胞因子的生成,可扼制炎症及致瘤损害的进展[31]。 当今曲格列酮已进行II期临床用于乳腺癌和前线腺癌的调整,临床盘考发现PPARγ快乐剂对胰腺癌有较强的扼制作用,已完成I期临床造就[32]。He等[33]盘考发现,体外渊博培养的大鼠角朊细胞不抒发PPARγ,关联词PPARγ的快乐剂TZD粗略通过扼制细胞的Cyclin D1的抒发,从而扼制其增殖并促其分化,作家以为,TZD可能看成一种有用的药物参与皮肤癌的调整。对于PPARγ抗肿瘤作用机制,当今以为PPARγ能镌汰凋一火扼制因子NF-κB的活性;减少凋一火扼制基因的c-myc的抒发;调控与细胞迁徙联系的因子的抒发:E-粘连卵白、桥粒芯糖卵白、p27、 β-连环卵白;退换促血管滋长因子VEGF的抒发。在翌日,PPARγ可能还有PPARβ/δ能成为肿瘤调整的诱东谈主的靶点。关联词在临床和科学方面的还需作进一步盘考。5. PPARγ和免疫PPARγ的配体15d-PGJ2 在许多免疫冒失中起退换作用,PPARγ存在的情况下,极低浓度的15d-PGJ2就可以扼制脂多糖教导的经由AP-1 (Active protein21) 、NF-κB、STAT1(signal transducer and activator of transcription 1) 介导的转录效应。PPARγ通过与NF-κB 间卵白-卵白相互作用,阻止NF-κB 与炎症因子基因运转子区的同源顺式元件联结[34]。Yang 等发现15d-PGJ2 与格列酮类均能通度日化的PPARγ而扼制PHA 教导的东谈主T细胞增殖及IL-2 基因抒发,扼制活化的T 细胞与IL-2 运转子中同源顺式元件相联结。PPARγ在退换诸如单核P巨噬细胞、T 细胞及NK细胞等免疫细胞的分化中有遑急意念念[35]。PPARγ 配体通过PPARγ依赖P非依赖路线扼制T 细胞及NK 细胞产生IFN2γ[36]。基因芯少顷期扫尾露馅PPARγ在2 型T 细胞中抒发要判辨强于1 型T 细胞(约莫5~8 倍) 。2型免疫细胞在培养条目下(加用IL-4 及IFN-γ抗体) 可教导东谈主NK细胞抒发PPARγ[37]。活化的PPARγ可介导扼制单核细胞炎症因子TNF-α, IL-1 , IL-2 和IL-6 的生成, 产生抗炎症作用。T 淋巴细胞活化的关键是端正淋巴细胞早期分化响应的IL-2 基因的抒发。PPARγ活化后可扼制IL-2 基因抒发从而扼制东谈主T 淋巴细胞的早期活化[38]。指示PPARγ配基可通过IL-2 基因抒发调整T 细胞介导的疾病,并具有临床后劲[39]。联系PPARγ的盘考报谈还是有许多,但仍有许多问题尚待真切盘考,如PPARγ在脂肪细胞增殖和分化中的着实作用,以及该受体奈何同赞助因子相互作用激活转录,奈何有遴选性地端正PPARγ介导的生物学效应等。当今东谈主们正尽力于探讨打扰PPARγ基因转录和影响PPARγ卵白功能的药物过头作用机制,若能全面地揭示PPARγ功能,则将对肥壮、糖尿病、肿瘤等疾病的调整大故意处。 参考文件1.  Zhu Y, Kan L, Qi C, et al . Isolation and characterization of peroxisome proliferator-activated receptor (PPAR) interacting protein (PRIP) as a coactivator for PPAR. J Biol Chem, 2000; 275(18):13510-13516.2.  Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 1990; 347(6294): 645-6503.  Fajas L, Auboeuf D, Raspe E, et al. The organization, promoter analysis, and expression of the human PPAR gamma gene .J Biol Chem,1997; 272: 18779-18789.4.  Zhu Y, Alvares K, Huang Q, et al. Cloning of a member of the peroxisome proliferator activated receptor gene family from mouse liver. J Bio Chem, 1993; 268:26817-268205.  Saladin R, Fajas L, Dana S, et al. Differential regulation of peroxisome proliferator activated receptor gamma 1(PPAR gamma 1) and PPAR gamma 2 messenger RNA expression in the early stages of adipogenesis. Cell Growth Differ, 1999; 10: 43-48.6.  Weman A, Hollenberg A, Solanes G, et al. Ligand independent activation domain in the N terminal of peroxisome proliferator activated receptorγ(PPARγ), Differential activity of PPARgamma1 and -2 isoforms and influence of insulin. J Biol Chem, 1997;272(32): 20230-202357.  Elbrecht A, Chen Y, Cullinan CA, et al. Molecular cloning, rxpression and characterization of human peroxisome proliferator activated receptor γ1 and γ2. Biochem Biophys Res Commun, 1996;224:31-388.  Kliewer SA, Forman BM, Ong ES, et al. Differential expression and activate of a family of murine peroxisome proliferator activated receptors. Proc Natl Acad Sci USA, 1994; 91:7355-73599.  Kubota T , Koshizuka K,Williamson EA , et al . Ligand for peroxisome proliferator activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res ,1998 ,58(15) :3344-335210.  Lehmann MJ, Lenhard JM, Oliver BB, et al. Peroxisome proliferator activated receptor α and γ are activated by indomethacin and other non- steroidal anti-inflammatory durgs. J Biol Chem, 1997;272:3406-341011.  Shalev A, Siegrist CA, Yen PM, et al. The Peroxisome proliferator activated receptor α and γ are the phosphoprotein: regulation by insulin. Endocrinology, 1996;137 (10):4499-450212.  Adams M, Reginato MJ, Shao D, et al. Transcriptional activation by peroxisome proliferator activated receptorγ is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site.J Bio l Chem, 1997; 272: 5128-513213.  Juge Aubry CE, Gorla Bajszczak A, Pernin A, et al. Peroxisome proliferator activated receptor mediates cross-talk with thyroid receptor by competition for retinoid X receptor. J Bio l Chem, 1995; 270(30):18117-1812214.  Gottlicher M, Widmark E, Li Q, et al. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci U SA , 1992; 89(10): 4653-465715.  Lapsys NM, Kriketos AD , Linr Fraser M, et al . Expression of genes involved in lipid mestabolism correlate with peroxisome roliferators activated receptor gamma expression in human skeletal muscle. J Clin Endocrinol Metab ,2000 ;85 (11): 4293-4297.16.  Rosen ED ,Sarraf P , Troy AE , et al. PPARγ is required for the differentiation of adipose tissue in vivo and in vitro .Mol Cell ,1999 ;4 :611-61817.  Karen LH, Bridget MC, Pamela JS. Peroxisome proliferator-activated receptor gamma(PPARγ) and its ligands: A review. Domest anim endocrin. 2002; 22:1-2318.  Singh R, Artaza JN, Taylor WE, et al. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology, 2003; 144(11): 5081-508819.  Tontonoz P, Hu E, Spiegelman BM, et al. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell, 1994;79 (7):1147-115620.  Ren D, Collingwood TN, Rebar EJ, et al. PPARγ knockdown by engineered transcription fators: exogenous PPARγ2 but not PPARγ1 reactivates adipogenesis. Genes Dev, 2002,98:5306-531121.  Muller E, Drori S, Aiyer A, et al. Genetic analysis of adipogenesis through peroxisome proliferator activated receptor γ isoforms. J Biol Biochem, 2002,277: 41925-4193022.  Chen WC, Yang CC, Sheu HM, et al. Expression of Peroxisome Proliferator Activated Receptor and CCAAT/Enhancer Binding Protein Transcription Factors in Cultured Human Sebocytes. J Invest Dermatol; 2003;121(3):441-44723.  Di-Poi N, Michalik L, Desvergen B, et al. Functions of peroxisome proliferator activated receptors (PPAR) in skin homeostasis. Lipids. 2004;39(11):1093-109924.  Rosenfield R, Deplewski D, Kentsis A, et al. Mechanisms of androgen induction of sebocyte differentiation. Dermatology, 1998,196(1):43-46.25.  Kim MJ, Deplewski D, Ciletti N, et al. Limited cooperation between peroxisome proliferator-activated receptors and retinoid X receptor agonists in sebocyte growth and development. Mol Genet Metab, 2001, 74: 362–369.26.  Downie MM, Sanders D, Maier L, et al. Peroxisome proliferator-activated receptor and farnesoid X receptor ligands differentially regulate sebaceous differentiation in human sebaceous gland organ cultures in vitro. Br J Dermatol, 2004,151(4):766-775.27.  Bishop-Baily D, Warner TD. PPAR gamma ligands induce prostaglandin production in vascular smooth muscle cells: indomethacin acts as a peroxisome proliferator-activated receptor-gamma antagonist. FASEB J, 2003; 17(13): 1925-1927 28.  Demetri GD, Fletcher CD, Mueller E, et al. Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor gamma ligand troglitazone in patients with liposarcoma. Proc Natl Acad Sci U S A, 1999, 96: 3951-3956.29.  Girnun GD, Smith WM, Drori S, ET AL. APC-dependent suppression of colon carcinogenesis by PPARgamma. Proc Natl Acad Sci USA;2002.99:1377130.  Suh N , Wang Y, Williams CR , et al . A new ligand for the peroxisome proliferator-activated receptor gamma ( PPAR gamma ) , GW7845 ,inhibits rat mammary carcinogenesis . Cancer Res , 1999; 59 (22)∶5671-567331.  Ricote M,Li AC ,Willson TM, et al . The peroxisome proliferators-activated receptorγis a negative regulator of macrophage activation. Nature ,1998 ,391 (6662) :79-82.32.  Motomura W, Okumura T , Takahashi N , et al . Activation of peroxisome proliferator-activated receptor gamma by troglitazone inhibits cell growth through the increase of p27KiP1 in human Pancreatic carcinoma cells . Cancer Res , 2000 ; 60 (19)∶5558-556433.  He G,Thuillier P, Fischer SM, et al. Troglitazone inhibits cyclin D1 expression and cell cycling independently of PPARγ in normal mouse skin keratinocytes. J Invest Dermatol, 2004;123:1110-111934.  Nencioni A ,Wesselborg S ,Brossart P, et al. Role of peroxisome proliferator-activated receptor gamma and its ligands in the control of immune responses. Crit Rev Immunol ,2003, 23(122) :1213-121935.  Knethen A, Brune B. PPARγ2 an important regulator of monocyte macrophage function. Arch Immunol Ther Exp (Warsz) , 2003 ,51 (4) :219-226.36.  Marx N, Kehrle B, Kohlhammer K, et al . PPAR activators as antiinflammatory mediators in human T lymphocytes :implications for atherosclerosis and transplantation associated arteriosclerosis . Circ Res , 2002 , 90 :703-710.37.  Cuzzocrea S ,Pisano B ,Dugo L ,et al . Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor gamma, reduces acute inflammation. Eur J Pharmacol, 2004 ,483 (1) :79-93.38.  Jiang C, Ting A T, Seed B, et al. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature,1998,391:82-86.39.  Wang N,Verna L,Chen N G,et al. Constitutive activation of peroxisome proliferator- activated receptor-γ suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells.J Biol Chem, 2002, 277: 34176-3418106年写的综述,一直也莫得投稿,拿出来和大家交流一下,宽容月旦指正,呵呵可以啊,相等感谢相等感谢,我正巧也在搞这方面盘考,顶!国内偷拍摄视频在线观看





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