脂肪细胞分化的调控通路研究

脂肪细胞分化是一个由多个转录因子共同调控的复杂过程.这些转录因子包括CCAAT增强子结合蛋白(C/EBP)、过氧化物酶体增殖物活化受体(PPAR)家族、Wnt通路、固醇调节元件结合蛋白(SREBP)等.因此,揭示脂肪细胞分化的细胞和分子机制,将为治疗肥胖和代谢综合征提供重要的理论基础.现综述脂肪细胞分化及参与其调控的各...     

固醇调节元件结合蛋白与脂代谢的基因调控

固醇调节元件结合蛋白(SREBPs)是脂肪合成基因重要的转录调节因子.SREBP-1a、-1c主要调节与脂肪酸代谢相关的酶,SREBP-2主要调控胆固醇代谢.SREBP-1c又称脂肪细胞定向和分化因子(ADD1),在脂肪细胞的分化中发挥重要作用.SREBPs还参与脂肪合成基因的营养调控,并受胰岛素/葡萄糖和瘦素调控,而且是代谢综合征中重要的基因调控连结点.对其调控作用进行全面深入的研究,将对糖尿病、肥胖等代谢综合征的发病机理和临床治疗有更新、更全面的认识.     

胰岛素对高脂诱导胰岛素抵抗L6细胞固醇调节元件结合蛋白-1c表达的影响

目的 探讨胰岛素对高脂诱导胰岛素抵抗的骨骼肌细胞脂代谢及相关基因、蛋白表达的影响和机制.方法 L6成肌细胞诱导分化后行棕榈酸干预建立胰岛素抵抗模型,胰岛素干预后,分别检测3组脂代谢相关基因和蛋白表达的变化.结果 与对照组比较,高脂组诱导胰岛素抵抗后,固醇调节元件结合蛋白(SREBP)-1c mRNA和蛋白水平明显升高,IRS-1 mRNA和蛋白水平明显降低.胰岛素干预后,SREBP-1c表达下降,IRS-1表达升高.3组中肿瘤坏死因子(TNF)-α、stat3 mRNA表达无明显变化.结论 高脂诱导骨骼肌胰岛素抵抗下,胰岛素干预可能通过影响脂质代谢通路中关键的转录因子改善胰岛素抵抗.     

固醇调节元件结合蛋白与脂代谢的基因调控

固醇调节元件结合蛋白(SREBPs)是脂肪合成基因重要的转录调节因子。SREBP-1a、-1c主要调节与脂肪酸代谢相关的酶，SREBP-2主要调控胆固醇代谢。SREBP-1c又称脂肪细胞定向和分化因子(ADD1)，在脂肪细胞的分化中发挥重要作用。SREBPs还参与脂肪合成基因的营养调控，并受胰岛素／葡萄糖和瘦素调控，而且是代谢综合征中重要的基因调控连结点。对其调控作用进行全面深入的研究，将对糖尿病、肥胖等代谢综合征的发病机理和临床治疗有更新、更全面的认识。     

固醇调节元件结合蛋白与脂质代谢的研究进展

固醇调节元件结合蛋白(SREBP)是重要的核转录因子之一,它能与脂质合酶基因的启动子/增强子的固醇调节元件结合,激活靶基因转录,特异性调控胆固醇和脂肪酸代谢.体内脂质代谢的稳定依赖于SREBP的调节.通过对SREBP作用和调控机制深入了解,将有助于提高对脂质代谢性疾病如糖尿病、高脂血症、脂肪肝、肥胖等的认识以及指导临床治疗.     

固醇调节元件结合蛋白研究进展

脊椎动物细胞的脂代谢平衡受到一类重要的膜结合转录因子家族-固醇调节元件结合蛋白（sterol regulatory elementbinding proteins，SREBPs）的调控。SREBPs直接激活胆固醇、脂肪酸、甘油三酯合成和摄取的相关基因达30个以上。     

Lipin:治疗胰岛素抵抗的新靶点

脂素基因(LPIN)是新近发现的双向调控身体脂肪的一个基因家族,至少包括LPIN1,LPIN2,LPIN3 3个成员.其蛋白产物称为脂素(lipin).该蛋白家族在不同组织发挥相似的功能,主要有两个作用:一是作为磷脂酸磷酸酶(PAP)1发挥甘油三酯、磷脂合成作用,二是作为转录协同刺激因子联系肝过氧化物酶体增殖物活化受体(PPAR)γ协同刺激因子1α(PGC1α)和PPARα,进而调节脂肪酸氧化基因的表达,因而在脂质合成和基因表达方面有双重作用,影响着糖脂代谢.该基因变异可能与胰岛素抵抗、肥胖、2型糖尿病及代谢综合征相关.Lipin可能为胰岛素抵抗、肥胖、糖尿病及其相关代谢异常提供新的治疗靶点.     

德氮吡格影响人肝癌细胞株QGY-7701亚细胞的蛋白质组学研究

目的 观察德氮吡格(TNBG)对人肝癌细胞QGY-7701亚细胞蛋白表达的影响,探讨其影响脂代谢的分子机制. 方法 分别提取TNBG处理前后人肝癌细胞QGY-7701的细胞质、细胞膜和细胞核蛋白进行双向电泳,PDQuest 7.4.0软件分析比对图像,采用基质辅助激光解吸电离飞行时间质谱技术(MALDI-TOF-MS)鉴定差异蛋白质点. 结果 TNBG作用于人肝癌细胞QGY-770172h后,细胞质的差异表达蛋白质点有56个,细胞膜的差异表达蛋白质点有65个,细胞核的差异表达蛋白质点有34个,共计155个.利用MALDI-TOF-MS技术鉴定出其中33个差异表达蛋白质点,其中包括与脂质合成有关的10个蛋白质点和与脂质降解、转运有关的7个蛋白质点,如3-羟基-3甲基戊二酸单酰辅酶A还原酶、角鲨烯合成酶、低密度脂蛋白受体、三磷酸腺柠檬酸裂解酶、甘油醛-3-磷酸脱氢酶、甘油-3-磷酸酰基转移酶、长链酯 辅酶A脱氢酶等,这些都是固醇调节元件结合蛋白调控的靶基因.结论 TNBG可能通过固醇调节元件结合蛋白途径增加胆固醇和甘油三酯合成,导致肿瘤细胞内脂滴大量聚积.     

高脂饮食诱导的胰岛素抵抗大鼠肝脏固醇调节元件结合蛋白-1c mRNA的表达

胰岛素抵抗是2型糖尿病发病的主要病理生理基础之一,近年来,人们发现一些重要的转录因子也参与了胰岛素抵抗的发生,如过氧化物酶体增殖物激活受体(PPAR)、肝X受体、固醇调节元件结合蛋白-1c(sterol-regulatory element binding protein-1c, SREBP-1c)等.SREBP-1c是核转录因子SREBPs的一个亚型,是脂肪代谢中重要的转录调节因子,在维持脂质代谢平衡中发挥着非常重要的作用.     

他汀类药物与血脑屏障

他汀类药物通过抑制羟甲基戊二酰辅酶A(HMG-CoA)还原酶,上调脑组织内皮型一氧化氮合酶(eNOS)的表达和活化,升高血清过氧化氢酶和血浆NO浓度,增强抗氧化能力,降低氧自由基含量,改善紧密连接的闭锁小带和跨膜蛋白以及星形胶质细胞的胶质纤维酸性蛋白的免疫反应性。他汀类药物还可能发挥与抑制HMG-CoA还原酶完全无关的效应,即与白细胞功能抗原-1的L位点结合,抑制其与细胞间黏附分子-1之间的相互作用,起到抗炎和免疫调节作用。以上机制均有助于保持病理情况下血脑屏障的完整性和星形胶质细胞的功能。     

Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins

Two classes of sterols, cholesterol and oxysterols, block export of sterol regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum (ER) to the Golgi by preventing the binding of COPII-coated proteins to a hexapeptide sorting signal (MELADL) in Scap, the SREBP-escort protein. Here, we show that anti-MELADL blocks COPII binding in vitro, and microinjection of Fab anti-MELADL blocks Scap.SREBP movement in cells. Cholesterol and oxysterols block COPII binding to MELADL by binding to different intracellular receptors, cholesterol to Scap and oxysterols to Insig. Cysteine labeling shows that both binding events produce a conformational change near the MELADL sequence, abrogating COPII binding but not anti-MELADL binding. Mutagenesis experiments raise the possibility that the distance of MELADL from the ER membrane is crucial for COPII binding, and we speculate that sterols and Insig block SREBP transport by altering the location of MELADL with respect to the membrane, rendering it inaccessible to COPII proteins.     

Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins

This paper describes insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. The sequences of human insig-1 and -2 are 59% identical. Both proteins are predicted to contain six transmembrane helices. The proteins differ functionally in two respects: (i) production of insig-1, but not insig-2, in cultured mammalian cells requires nuclear SREBPs; and (ii) at high levels of expression, insig-1, but not insig-2, can block SCAP movement in the absence of exogenous sterols. The combined actions of insig-1 and -2 permit feedback regulation of cholesterol synthesis over a wide range of sterol concentrations.     

Specificity in cholesterol regulation of gene expression by coevolution of sterol regulatory DNA element and its binding protein

When demand for cholesterol rises in mammalian cells, the sterol regulatory element (SRE) binding proteins (SREBPs) are released from their membrane anchor through proteolysis. Then, the N-terminal region enters the nucleus and activates genes of cholesterol uptake and biosynthesis. Basic helix–loop–helix (bHLH) proteins such as SREBPs bind to a palindromic DNA sequence called the E-box (5′-CANNTG-3′). However, SREBPs are special because they also bind direct repeat elements called SREs. Importantly, sterol regulation of all promoters studied thus far is mediated by SREBP binding only to SREs. To study the reason for this we converted the direct repeat SRE from the sterol-regulated low-density lipoprotein receptor promoter into an E-box. In this report we show that SREBPs are still able to bind and activate this promoter however, sterol regulation is lost. The results are consistent with the mutant promoter being a target for promiscuous activation by constitutively expressed E-box binding bHLH proteins that are not regulated by cholesterol. Kim and coworkers [Kim, J. B., Spotts, G. D., Halvorsen, Y.-D., Shih, H.-M., Ellenberger, T., Towle, H. C. & Spiegelman, B. M. (1995) Mol. Cell. Biol. 15, 2582–2588] demonstrated that the dual DNA binding specificity of SREBPs is caused by a specific tyrosine in the conserved basic region of the DNA binding domain that corresponds to an arginine in all other bHLH proteins that recognize only E-boxes. Taken together the data suggest an evolutionary mechanism where a DNA binding protein along with its recognition site have coevolved to ensure maximal specificity and sensitivity in a crucial nutritional regulatory response.