转录调控脂肪形成——代谢性疾病的新一代治疗

2012年第72届美国糖尿病协会(ADA)年会上,Bruce Soiegelman教授获得Banting科学成就奖.会上Soiegelman作了题为“转录调控脂肪形成——代谢性疾病的新一代治疗”的演讲.他报道了一种新发现的糖代谢关键调节激素——虹神素(Irisin)和第三类型脂肪——米色脂肪组织的脂肪细胞.其研究工作包括:(1 )PR域包含蛋白16(PRDM16)是控制棕色脂肪组织与骨骼肌组织相互转换的开关.(2) PRDM16决定小鼠皮下白色脂肪组织的产热方式.(3)米色脂肪细胞是小鼠和人类一种独特的产热脂肪细胞.(4)米色脂肪组织可用于减肥.(5)过氧化物酶体增殖物活化受体(PPAR)-γ协同刺激因子(PGC)-1α依赖的白色脂肪棕色样改变及产热作用与Irisin有关.     

碳水化合物反应元件结合蛋白β对糖代谢稳态和脂肪组织产热功能的调控作用

目的:探讨碳水化合物反应元件结合蛋白-β（ChREBP-β）对白色脂肪棕色化的影响,并进一步明确其在糖代谢稳态中的作用。方法:利用Cre/loxP技术,将Rosa-LSL-ChREBP-β转基因小鼠与Adiponectin-Cre小鼠杂交,建立在脂肪组织中特异性过表达ChREBP-β的小鼠模型（AET-β）;以AET-...     

吡格列酮对肥胖小鼠原代棕色脂肪细胞分化和功能基因表达的影响

观察吡格列酮对肥胖小鼠原代棕色脂肪(brown adipose tissue,BAT)细胞分化和功能基因表达的影响,并为治疗肥胖相关疾病寻找新思路.结果显示吡格列酮通过增强特异基因表达、促进分化成脂、提高线粒体功能等方面增强BAT细胞功能(P＜0.05);这可能是吡格列酮改善机体代谢的重要原因.     

解偶联蛋白的产热机制及调控的研究进展

棕色脂肪组织（ＢＡＴ） 是哺乳动物体内非颤栗产热的主要来源。对于维持动物的体温和能量平衡起重要作用。位于ＢＡＴ 线粒体内膜的解偶联蛋白（ＵＣＰ） 是决定ＢＡＴ 功能的关键因素。线粒体内膜的ＵＣＰ 作为质子通道驱散氧化呼吸时形成的Ｈ＋ 梯度，从而增加呼吸，阻止ＡＴＰ 形成。去甲肾上腺素、胰岛素、甲状腺激素、视黄酸等因素调控着ＵＣＰ 的浓度和活性。     

脂肪分化相关蛋白基因与2型糖尿病相关

目的通过单核苷酸多态性(SNP)的检测及基因分型来研究脂肪分化相关蛋白基因(ADRP)与2型糖尿病的相关性。方法使用PCR测序方法,对ADRP基因的启动子、外显子以及临近的内含子,分别在正常人群、2型糖尿病人群进行测序,确定该基因是否与华东地区汉族2型糖尿病患者相关。结果所测ADRP基因片段总长度5003个碱基,有23个SNP,高频、低频分别是5个、18个。启动子的一个SNP(P/-407)在2型糖尿病人群与正常人群的等位基因型、基因型差异均有显著性(P<0.05);两个错义突变Ser251Pro、Thr396Ala分别在两个2型糖尿病家系中传递。结论ADRP可能与华东地区汉族人2型糖尿病相关。     

过氧化物酶体增殖物激活受体γ激动剂对肥胖小鼠非肾上腺素能原代棕色脂肪功能和分化的影响

目的探索过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂吡格列酮（PGZ）对肥胖小鼠非肾上腺素能条件下原代棕色脂肪分化和功能的影响,为2型糖尿病和肥胖的治疗提供新依据。方法高脂饮食诱导的4周龄雄性C57BL／6J肥胖小鼠20只,取肩胛间区棕色脂肪组织,分离并培养C57小鼠原代棕色脂肪细胞,等量分人10个培养皿中,等分为对照组和PGZ干预组,每组5皿,使用PGZ干预细胞,建立PGZ干预的细胞模型,使用和PGZ溶液等量的生理盐水处理对照组细胞。实时定量聚合酶链反应（RT-PCR）检测细胞模型的棕色脂肪基因：解偶联蛋白1（UCP-J）、超长链脂肪酸延长酶3（ELOVL3）、PPAR-γ共激活因子α和β（PGCI-α、PGCI-β）、PR包含域16区（PRDM16）、CCAAT增强子结合蛋白β（CEBP/β）、脂联素、脂肪细胞脂质结合蛋白2（AP2）、细胞色素C1氧化酶（CYC1）、线粒体转录因子A（TFAM）等表达水平;使用油红染色定量法检测细胞模型的棕色脂肪成脂功能;Western blotting法检测PGZ干预组UCP-1蛋白表达。2组间比较采用t检验,多组间比较采用方差分析和LSD检验。结果PGZ干预组细胞的棕色脂肪特异基因（UCP-1、ELOVL3、PGCI-α、PGCI-β）、成脂基因（AP2）、线粒体功能基因（CYCI、TFAM）和脂肪分化基因（PRDM16、CESP／β）表达量均显著高于对照组（相对表达量分别为：UCP-1：1100．0±612．0、2．0±0．4;ELOVL3：1461．0±617．0、2．0±1．2;PGCI-α：8．1±2．8、2．0±1．1;PGCI-β：8．3±2．8、2．0±1．3;脂联素：2．6±0．8、1．04±0．7;AP2：5．1±2．2、1．00±0．24;CYCI：3．1±0．8、1．0±0．4;TFAM：1．2±0．4、1．00±0．25;PRDM16：4．8±2．6、2．0±0．3;CEBP／β：6×10^8±5×10^8、2．0±0．6;t=2．45～5．22,均P〈0．05）;油红定量亦发现干预组成脂功能高于对照组（染色定量：1．2±0．2比1．0±0．1,t=2．45,P〈0．05）。Westernblotting检测PGZ干预组UCP-1表达高于对照组（灰度分析相对定量分别为1．24±0．25和1．00±0．14,t=2．63,P〈0．05）。结论PGZ可能通过增强棕色脂肪特异基因表达、促进细胞分化成脂、提高线粒体功能等方面增强棕色脂肪细胞功能,这可能是其改善机体代谢的原因之一。     

脂肪因子网膜素生物学特性的研究进展

网膜素（omentin）是由美国马里兰大学Yang等于2003年首先发现的特异性表达于网膜脂肪组织的细胞因子,近年来发现它与脂肪组织分泌的其他细胞因子如瘦素、脂联素和内脂素等共同参与了糖代谢及血管内皮功能调节。同时网膜素与肥胖、2型糖尿病、动脉粥样硬化及炎症密切相关,在这些疾病发病机制中的作用也备受关注。笔者就网膜素生物学特性的研究进展作一简介。     

线粒体功能调控动脉粥样硬化的研究进展

血管内皮细胞损伤、巨噬细胞吞噬脂质泡沫化以及平滑肌细胞的增殖和迁移是动脉粥样硬化的主要病理特征。线粒体是细胞的“ATP工厂”,高脂应激造成线粒体氧化磷酸化效率降低,ATP合成受阻,活性氧生成增加,脂质蓄积形成脂质核心。重要事件包括过氧化物酶体增殖物激活受体α和过氧化物酶体增殖物激活受体γ协同激活因子-1α表达降低,线粒体DNA生物合成减少,线粒体膜电位降低,ATP含量下降,活性氧累积。现探讨动脉粥样硬化病理发生过程中的线粒体功能与临床干预治疗,为动脉粥样硬化的靶向干预治疗提供思路。     

血管紧张素Ⅱ1型受体拮抗剂抗动脉粥样硬化机制研究进展

血管紧张素Ⅱ1型受体拮抗荆从多方面阻滞血管紧张素Ⅱ的功能，来抑制动脉粥样硬化的形成和发展：降低核因子κB活性而抑制趋化因子及粘附分子的释放，对抗炎症反应；降低细胞内总氧化能力，减少自由基生成，减弱低密度脂蛋白氧化，抑制巨噬细胞吞噬氧化型低密度脂蛋白的能力，从而减少泡沫细胞形成；增加内皮源性血管舒张因子水平，保护血管内皮；抑制血管平滑肌细胞迁移和增殖；降低血小板黏附、聚集活性，抑制血栓形成；减少动脉斑块内胆固醇酯含量，减少巨噬细胞浸润、抑制基质金属蛋白酶1的表达，增加斑块稳定性。     

非酒精性脂肪性肝病分子机制研究进展

非酒精性脂肪性肝病(NAFLD)是一种以肝细胞脂肪变性和脂质沉积为特征,但无过量饮酒史的临床综合征。NAFLD疾病谱包括非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎(NASH)、NASH相关肝纤维化和肝硬化。NAFLD的发病机制较为复杂,至今尚未完全阐明。本文就近年NAFLD分子机制研究的新进展,包括胰岛素抵抗(IR)、肝脂肪变性、氧化应激等方面作一综述。     

Recent Advances in Understanding the Molecular Mechanisms of the Long QT Syndrome

Long QT Syndrome. Competing theories to explain the congenital long QT syndrome have included an imbalance in sympathetic innervation of the heart or a defect in repolarizing ion currents. Recent studies have identified at least four chromosomal loci at which mutations cause the congenital long QT syndrome in different families. The specific genes mutated in affected individuals have been identified at two of these loci, and both encode cardiac ion channels. The affected genes are SCN5A, the cardiac sodium channel gene, and HERG, whose protein product likely underlies I_Kr, the rapidly activating delayed rectifier. Thus, currently available evidence indicates that the congenital long QT syndrome is a primary disease of cardiac ion channels. Abnormalities in either inward or outward currents can cause the disease. Ongoing studies are evaluating the function of the mutant ion channels and the relationship between individual mutations and the clinical manifestations of the syndrome.     

The Mechanisms Responsible for Lack of Reproducible Induction of Atrioventricular Nodal Reentrant Tachycardia

Lack of AVNRT Induction. Introduction : AV nodal reentrant tachycardia (AVNRT) is not always reproducibly inducible. The purpose of this study was to determine the mechanisms responsible for the lack of reproducible induction of AVNRT.
Methods and Results : The induction of AVNRT was assessed with atrial burst pacing, and with atrial and ventricular programmed stimulation, each with one and two extrastimuli, in 103 patients with AVNRT. The stimulation protocol was repeated 10 times in the baseline state, during isoproterenol infusion, and after atropine administration, or until AVNRT was induced in 7 of 10 attempts. The mechanisms responsible for < 7 of 10 inductions were classified as: (1) the inability to achieve critical AH prolongation; (2) fast pathway block; and (3) slow pathway block. The induction endpoint was achieved in 90 patients: 55 in the baseline state, 34 during isoproterenol infusion, and 1 after atropine. Tbe mechanism of noninducibility in the baseline state (n = 48) was the inability to achieve a critical AH interval in 20%, fast pathway block in 49%, and slow pathway block in 31% (P = 0.02). During isoproterenol administration (n = 14) and after atropine administration (n = 13), the three mechanisms were equally responsible for nonreproducible induction of AVNRT.
Conclusions : The induction of AVNRT is poorly reproducible in approximately 10% of patients. In the baseline state, the most common reason for the inability to reproducibly induce AVNRT is fast pathway block. In the presence of isoproterenol or atropine, each of the three mechanisms was equally responsible for noninducibility of AVNRT.     

经体循环脐血细胞移植治疗脑梗死机制及其疗效影响因素

本综述重点总结、回顾经体循环移植脐血细胞治疗脑梗死实验与临床研究结果,探讨其疗效机制。并就经体循环移植脐血细胞治疗脑梗死的优势、缺陷及影响其疗效的因素进行讨论。     

Mechanisms of Stone Formation

We have reviewed the general mechanisms involved in kidney stone formation, with reference to those composed of calcium oxalate or phosphate, uric acid, and cystine. These processes include nucleation of individual crystals, aggregation or secondary nucleation to produce small intrarenal multicrystalline aggregates, fixation within the kidney, and further aggregation and secondary nucleation to produce the clinical stone. The factors regulating these processes have been discussed as well as the effects of tubular fluid or urine pH and promoters or inhibitors, including urate or uric acid in the case of calcium oxalate stones, citrate, pyrophosphate, phytate, and urinary proteins. We also discuss the potential for macromolecular inhibitors to actually promote stone formation when they are fixed to some intrarenal structure or if they themselves become aggregated into protein?Cprotein complexes.     

分子性心肌成形术的进展

分子性心肌成形术是治疗心肌异常性疾病的新方法。现分别从心肌干细胞的增殖、心肌中非肌性细胞向肌性细胞转化、减少心肌细胞凋亡等方面综述了分子性心肌成形术的基础及临床研究进展,并介绍了目前存在的问题。     

心力衰竭分子机制的研究进展

心力衰竭是许多心血管疾病的最终归宿.近年的研究在适应性和不良适应性心肌肥厚以及对应激信号反应分子机制的认识有了更进一步的认识,并显示有多个细胞因子和信号途径与此有关.对心力衰竭分子机制的进一步认识利于研究新的治疗方法.     

Molecular Mechanisms Involved in Atherosclerosis

Background: Research in atherosclerosis is a good example how helpful different disciplines such as clinicians, epidemiologists and basic science can collaborate. In recent years our knowledge on cellular and subcellular mechanisms involved in initiation and progress of atherosclerosis has expanded due to the shared knowledge of different disciplines and thanks to new technologies in molecular biology. Pathophysiology of LDL and HDL Metabolism: The understanding of the molecular basis of inborn errors of LDL metabolism - such as familial hypercholesterolemia due to a defect of the LDL receptor - provided us new insights in physiology and pathophysiology of LDL metabolism. Most recently we have learned much about the vasoprotective HDL cholesterol. HDL is the major player in reverse cholesterol transport and some of its receptors such as ABCA1 and SR-BI were identified. This knowledge gives us a deeper understanding of the complex system which performs reverse cholesterol transport from peripheral tissue and the vessel wall back to the liver. Plaque Formation: Furthermore the process of formation and progression of the atherosclerotic plaque has been the focus of recent research. The stability or instability of plaques is depending on the complex interaction of adhesion molecules, monocytes, macrophages, endothelial cells, cytokines, transmitters and proteinases. Since we are unable to prevent plaque formation completely, the stabilization of plaques is a major goal for the coming years. Despite some success (such as the use of statines and ACE inhibitors) there is still a long way to go. Hintergrund: Durch die Nutzung neuer molekularbiologischer Techniken hat sich in den letztenJahren unser Wissen über molekulare und zelluläre Mechanismen der Pathogenese der Atherosklerose deutlich erweitert. Der Kampf gegen den Herzinfarkt ist ein beeindruckendes Beispiel, wie sehr Kliniker, Epidemiologen und Grundlagenforscher voneinander bei ihrer Arbeit profitieren können. Waren es ursprünglich rein klinische und epidemiologische Beobachtungen, die uns die Bedeutung erhöhter Cholesterinwerte für die Atherosklerose nahe legten, so kennen wir heute eine Vielzahl (wenngleich auch noch lange nicht alle) der hierfür verantwortlichen molekularen Mechanismen. Pathophysiologie des LDL- und HDL-Metabolismus: So wissen wir, dass bei der familiären Hypercholesterinämie der primäre Defekti bei einem mutierten LDL-Rezeptor zu suchen ist, der zu einer Erhöhung der atherogenen Lipoproteine, dem LDL-Cholesterin, führt. Die vasoprotektiven Lipoproteine, das HDL-Cholesterin, werden derzeit mit Hochdruck erforscht. Dabei gelang erst vor kurzem die Beschreibung einiger wesentlicher Rezeptoren wie ABCA1 und SR-BI, die uns helfen, das komplexe System des Cholesterinrücktransports vom peripheren Gewebe und der Gefäßwand zurück zur "Entgiftungszentrale" der Leber zu verstehen. Plaqueformation: Wir sehen mittlerweile den atheromatösen Plaque als ein dynamisches, überaus vulnerables Gebilde. Die Stabilität oder Instabilität eines solchen Plaques entscheidet über Leben oder Tod der Betroffenen und ist das Ergebnis aus dem Wechselspiel einer Vielzahl von Einzelspielern: Adhäsionsmolekülen, Monozyten, Makrophagen, Endothelzellen, Zytokinen, zellulären Transmittern und Proteinasen. Solange wird nicht in der Lage sind, die Plaqueentstehung gänzlich zu verhindern, werden wir versuchen müssen, die Stabilität der Plaques zu erhöhen. Mit einigen therapeutischen Ansätzen ist uns dies bereits gelungen (CSE-Hemmer-Therapie, ACE-Hemmer-Therapie), wenngleich noch ein langer Weg vor uns liegt.