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Phosphatidylcholine: Greasing the Cholesterol Transport Machinery. 磷脂酰胆碱:润滑胆固醇运输机制。
Pub Date : 2016-04-04 eCollection Date: 2015-01-01 DOI: 10.4137/LPI.S31746
Thomas A Lagace

Negative feedback regulation of cholesterol metabolism in mammalian cells ensures a proper balance of cholesterol with other membrane lipids, principal among these being the major phospholipid phosphatidylcholine (PC). Processes such as cholesterol biosynthesis and efflux, cholesteryl ester storage in lipid droplets, and uptake of plasma lipoproteins are tuned to the cholesterol/PC ratio. Cholesterol-loaded macrophages in atherosclerotic lesions display increased PC biosynthesis that buffers against elevated cholesterol levels and may also facilitate cholesterol trafficking to enhance cholesterol sensing and efflux. These same mechanisms could play a generic role in homeostatic responses to acute changes in membrane free cholesterol levels. Here, I discuss the established and emerging roles of PC metabolism in promoting intracellular cholesterol trafficking and membrane lipid homeostasis.

哺乳动物细胞中胆固醇代谢的负反馈调节确保了胆固醇与其他膜脂的适当平衡,其中主要是磷脂酰胆碱(PC)。胆固醇的生物合成和外排、脂滴中胆固醇酯的储存以及血浆脂蛋白的摄取等过程都与胆固醇/PC比值有关。动脉粥样硬化病变中装载胆固醇的巨噬细胞显示出增加的PC生物合成,缓冲胆固醇水平升高,也可能促进胆固醇运输,增强胆固醇感知和外溢。这些相同的机制可能在膜游离胆固醇水平急性变化的稳态反应中发挥一般作用。在这里,我讨论了PC代谢在促进细胞内胆固醇运输和膜脂稳态中的既定和新兴作用。
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引用次数: 36
Membrane Contact Sites: Complex Zones for Membrane Association and Lipid Exchange 膜接触部位:膜结合和脂质交换的复杂区域
Pub Date : 2016-02-29 DOI: 10.4137/LPI.S37190
Evan Quon, C. Beh
Lipid transport between membranes within cells involves vesicle and protein carriers, but as agents of nonvesicular lipid transfer, the role of membrane contact sites has received increasing attention. As zones for lipid metabolism and exchange, various membrane contact sites mediate direct associations between different organelles. In particular, membrane contact sites linking the plasma membrane (PM) and the endoplasmic reticulum (ER) represent important regulators of lipid and ion transfer. In yeast, cortical ER is stapled to the PM through membrane-tethering proteins, which establish a direct connection between the membranes. In this review, we consider passive and facilitated models for lipid transfer at PM–ER contact sites. Besides the tethering proteins, we examine the roles of an additional repertoire of lipid and protein regulators that prime and propagate PM–ER membrane association. We conclude that instead of being simple mediators of membrane association, regulatory components of membrane contact sites have complex and multilayered functions.
细胞内膜间脂质转运涉及到囊泡和蛋白质载体,但作为非囊泡性脂质转运的媒介,膜接触位点的作用越来越受到关注。作为脂质代谢和交换的区域,不同的膜接触位点介导不同细胞器之间的直接联系。特别是连接质膜(PM)和内质网(ER)的膜接触位点是脂质和离子转移的重要调节因子。在酵母中,皮质内质网通过膜系栓蛋白被钉在PM上,这在膜之间建立了直接连接。在这篇综述中,我们考虑了PM-ER接触部位的脂质转移的被动和促进模型。除了栓系蛋白外,我们还研究了一种额外的脂质和蛋白质调节因子的作用,这些调节因子启动和传播PM-ER膜结合。我们得出结论,膜接触位点的调节成分具有复杂和多层次的功能,而不是简单的膜结合介质。
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引用次数: 20
Role of Flippases in Protein Glycosylation in the Endoplasmic Reticulum 翻转酶在内质网蛋白糖基化中的作用
Pub Date : 2016-02-21 DOI: 10.4137/LPI.S31784
J. Rush
Glycosylation is essential to the synthesis, folding, and function of glycoproteins in eukaryotes. Proteins are co- and posttranslationally modified by a variety of glycans in the endoplasmic reticulum (ER); modifications include C- and O-mannosylation, N-glycosylation, and the addition of glycosylphosphatidylinositol membrane anchors. Protein glycosylation in the ER of eukaryotes involves enzymatic steps on both the cytosolic and lumenal surfaces of the ER membrane. The glycans are first assembled as precursor glycolipids, on the cytosolic surface of the ER, which are tethered to the membrane by attachment to a long-chain polyisoprenyl phosphate (dolichol) containing a reduced α-isoprene. The lipid-anchored building blocks then migrate transversely (flip) across the ER membrane to the lumenal surface, where final assembly of the glycan is completed. This strategy allows the cell to export high-energy biosynthetic intermediates as lipid-bound glycans, while constraining the glycosyl donors to the site of assembly on the membrane surface. This review focuses on the flippases that participate in protein glycosylation in the ER.
在真核生物中,糖基化对糖蛋白的合成、折叠和功能至关重要。蛋白质在内质网(ER)中被多种聚糖共同修饰和翻译后修饰;修饰包括C-和o -甘露糖基化,n -糖基化,以及添加糖基磷脂酰肌醇膜锚点。真核生物内质网中的蛋白质糖基化涉及内质网膜细胞质和管腔表面的酶促步骤。聚糖首先作为前体糖脂在内质网的细胞质表面组装,通过附着于含有还原α-异戊二烯的长链聚异戊二烯磷酸(多醇)与膜相连。脂质锚定的构建块然后横向迁移(翻转)穿过内质网膜到管腔表面,在那里完成聚糖的最终组装。这种策略允许细胞输出高能生物合成中间体作为脂质结合聚糖,同时将糖基供体限制在膜表面的组装位点。本文就内质网中参与蛋白糖基化的翻转酶作一综述。
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引用次数: 8
Lipid Acyl Chain Remodeling in Yeast 酵母脂质酰基链重构
Pub Date : 2016-01-19 DOI: 10.4137/LPI.S31780
M. F. Renne, X. Bao, Cedric H. de Smet, A. D. de Kroon
Membrane lipid homeostasis is maintained by de novo synthesis, intracellular transport, remodeling, and degradation of lipid molecules. Glycerophospholipids, the most abundant structural component of eukaryotic membranes, are subject to acyl chain remodeling, which is defined as the post-synthetic process in which one or both acyl chains are exchanged. Here, we review studies addressing acyl chain remodeling of membrane glycerophospholipids in Saccharomyces cerevisiae, a model organism that has been successfully used to investigate lipid synthesis and its regulation. Experimental evidence for the occurrence of phospholipid acyl chain exchange in cardiolipin, phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine is summarized, including methods and tools that have been used for detecting remodeling. Progress in the identification of the enzymes involved is reported, and putative functions of acyl chain remodeling in yeast are discussed.
膜脂稳态是通过脂质分子的新生合成、细胞内转运、重塑和降解来维持的。甘油磷脂是真核生物膜中最丰富的结构成分,它受到酰基链重塑的影响,酰基链重塑被定义为一个或两个酰基链交换的合成后过程。本文综述了酿酒酵母(Saccharomyces cerevisiae)中膜甘油磷脂酰基链重构的研究。酿酒酵母是一种已成功用于研究脂质合成及其调控的模式生物。本文综述了磷脂酰链交换在心磷脂、磷脂酰胆碱、磷脂酰肌醇和磷脂酰乙醇胺中发生的实验证据,包括用于检测重塑的方法和工具。本文报道了相关酶的鉴定进展,并讨论了酵母菌中酰基链重塑的推测功能。
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引用次数: 28
Lipid Flippases for Bacterial Peptidoglycan Biosynthesis 细菌肽聚糖生物合成的脂质翻转酶
Pub Date : 2016-01-13 DOI: 10.4137/LPI.S31783
N. Ruiz
The biosynthesis of cellular polysaccharides and glycoconjugates often involves lipid-linked intermediates that need to be translocated across membranes. Essential pathways such as N-glycosylation in eukaryotes and biogenesis of the peptidoglycan (PG) cell wall in bacteria share a common strategy where nucleotide-sugars are used to build a membrane-bound oligosaccharide precursor that is linked to a phosphorylated isoprenoid lipid. Once made, these lipid-linked intermediates must be translocated across a membrane so that they can serve as substrates in a different cellular compartment. How translocation occurs is poorly understood, although it clearly requires a transporter or flippase. Identification of these transporters is notoriously difficult, and, in particular, the identity of the flippase of lipid II, an intermediate required for PG biogenesis, has been the subject of much debate. Here, I will review the body of work that has recently fueled this controversy, centered on proposed flippase candidates FtsW, MurJ, and AmJ.
细胞多糖和糖缀合物的生物合成通常涉及需要跨膜转运的脂质连接中间体。真核生物中的n -糖基化和细菌中肽聚糖(PG)细胞壁的生物发生等基本途径都有一个共同的策略,即核苷酸糖被用来构建与磷酸化的类异戊二烯脂相连接的膜结合寡糖前体。一旦合成,这些脂质连接的中间体必须跨膜转运,这样它们才能在不同的细胞室中作为底物。易位是如何发生的尚不清楚,尽管它显然需要转运体或翻转酶。众所周知,这些转运体的鉴定是非常困难的,特别是脂质II翻转酶的鉴定,这是PG生物发生所需的中间产物,一直是许多争论的主题。在这里,我将回顾最近引发这一争议的工作主体,重点是提出的翻转酶候选物FtsW, MurJ和AmJ。
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引用次数: 83
Trafficking and Functions of Bioactive Sphingolipids: Lessons from Cells and Model Membranes 生物活性鞘脂的运输和功能:来自细胞和模型膜的教训
Pub Date : 2015-12-08 DOI: 10.4137/LPI.S31615
Kecheng Zhou, T. Blom
Ceramide and sphingosine and their phosphorylated counterparts are recognized as “bioactive sphingolipids” and modulate membrane integrity, the activity of enzymes, or act as ligands of G protein-coupled receptors. The subcellular distribution of the bioactive sphingolipids is central to their function as the same lipid can mediate diametrically opposite effects depending on its location. To ensure that these lipids are present in the right amount and in the appropriate organelles, cells employ selective lipid transport and compartmentalize sphingolipid-metabolizing enzymes to characteristic subcellular sites. Our knowledge of key mechanisms involved in sphingolipid signaling and trafficking has increased substantially in the past decades—thanks to advances in biochemical and cell biological methods. In this review, we focus on the bioactive sphingolipids and discuss how the combination of studies in cells and in model membranes have contributed to our understanding of how they behave and function in living organisms.
神经酰胺和鞘苷及其磷酸化对应物被认为是“生物活性鞘脂”,可调节膜完整性、酶活性或作为G蛋白偶联受体的配体。生物活性鞘脂的亚细胞分布是其功能的核心,因为相同的脂质可以根据其位置介导截然相反的作用。为了确保这些脂质以适当的数量存在于适当的细胞器中,细胞使用选择性脂质转运并将鞘脂代谢酶区隔到特征的亚细胞位点。在过去的几十年里,由于生物化学和细胞生物学方法的进步,我们对神经鞘脂信号传导和运输的关键机制的了解大大增加了。在这篇综述中,我们重点介绍了生物活性鞘脂,并讨论了如何结合细胞和模型膜的研究来帮助我们了解它们在生物体中的行为和功能。
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引用次数: 25
OSBP-Related Protein Family in Lipid Transport Over Membrane Contact Sites 膜接触部位脂质转运的osbp相关蛋白家族
Pub Date : 2015-11-12 DOI: 10.4137/LPI.S31726
V. Olkkonen
Increasing evidence suggests that oxysterol-binding protein-related proteins (ORPs) localize at membrane contact sites, which are high-capacity platforms for inter-organelle exchange of small molecules and information. ORPs can simultaneously associate with the two apposed membranes and transfer lipids across the interbilayer gap. Oxysterol-binding protein moves cholesterol from the endoplasmic reticulum to trans-Golgi, driven by the retrograde transport of phosphatidylinositol-4-phosphate (PI4P). Analogously, yeast Osh6p mediates the transport of phosphatidylserine from the endoplasmic reticulum to the plasma membrane in exchange for PI4P, and ORP5 and -8 are suggested to execute similar functions in mammalian cells. ORPs may share the capacity to bind PI4P within their ligand-binding domain, prompting the hypothesis that bidirectional transport of a phosphoinositide and another lipid may be a common theme among the protein family. This model, however, needs more experimental support and does not exclude a function of ORPs in lipid signaling.
越来越多的证据表明,氧甾醇结合蛋白相关蛋白(orp)定位于膜接触位点,这是小分子和信息在细胞器间交换的高容量平台。orp可以同时与两个相对的膜结合,并通过双层间隙传递脂质。在磷脂酰肌醇-4-磷酸(PI4P)逆行转运的驱动下,氧甾醇结合蛋白将胆固醇从内质网转移到反式高尔基体。类似地,酵母Osh6p介导磷脂酰丝氨酸从内质网转运到质膜,以换取PI4P, ORP5和-8被认为在哺乳动物细胞中执行类似的功能。orp可能在其配体结合区域内具有结合PI4P的能力,这促使人们提出了这样的假设:磷酸肌苷和另一种脂质的双向运输可能是蛋白质家族的共同主题。然而,该模型需要更多的实验支持,并不能排除orp在脂质信号传导中的作用。
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引用次数: 61
The effects of serum from prostate cancer patients with elevated body mass index on prostate cancer cells in vitro. 体质指数增高前列腺癌患者血清对体外前列腺癌细胞的影响。
Pub Date : 2015-04-19 eCollection Date: 2015-01-01 DOI: 10.4137/LPI.S23135
Benjamin C Mora, Neil E Fleshner, Laurence H Klotz, Vasundara Venkateswaran

We examined whether serum from obese, compared to non-obese, PCa (prostate cancer) patients creates a growth-enhancing tumor micro-environment in vitro. Serum from 80 subjects was divided into four groups: normal weight men with and without PCa and overweight/obese men with and without PCa. Cell proliferation, migration, and invasion were measured in LNCaP, and PC3 cells treated with patient serum were obtained from the above groups. The results reveal that proliferation of LNCaP cells was significantly (P = 0.05) greater with serum from non-obese (mean = 1.26 ± 0.20) compared to that from obese patients (mean = 1.16 ± 0.19). Serum from obese PCa patients compared to non-obese PCa patients induced significantly greater amounts of cell migration (P < 0.01) in PC3 cells. Serum from obese patients induced significantly (P < 0.01) lower amounts of cell invasion (mean = 8.2 ± 4.5) compared to non-obese patients (mean = 18.1 ± 5.0) when treated on PC3 cells. Serum TNF-α (tumor necrosis factor alpha) levels correlated with LNCaP cell proliferation in vitro in non-obese PCa (P < 0.01) and non-obese control groups (P = 0.05). All statistical calculations controlled for age, since the PCa patient groups were significantly older than the control groups (P < 0.01). In conclusion, serum from obese PCa patients induced greater PCa cell migration and lower cell proliferation and invasion in vitro.

我们研究了肥胖前列腺癌患者的血清与非肥胖前列腺癌患者的血清是否在体外创造了促进肿瘤生长的微环境。80名受试者的血清被分为四组:有和没有前列腺癌的正常体重男性和有和没有前列腺癌的超重/肥胖男性。LNCaP检测细胞增殖、迁移和侵袭,并从上述各组中获得经患者血清处理的PC3细胞。结果显示,非肥胖患者血清LNCaP细胞增殖(平均1.26±0.20)明显高于肥胖患者血清LNCaP细胞增殖(平均1.16±0.19)(P = 0.05)。与非肥胖PCa患者相比,肥胖PCa患者血清中PC3细胞的迁移量显著增加(P < 0.01)。肥胖患者血清中PC3细胞的侵袭量(平均= 8.2±4.5)明显低于非肥胖患者(平均= 18.1±5.0)(P < 0.01)。非肥胖PCa组和非肥胖对照组血清TNF-α水平与LNCaP细胞体外增殖相关(P < 0.01)。所有统计计算均控制年龄,因为PCa患者组明显大于对照组(P < 0.01)。综上所述,肥胖前列腺癌患者血清在体外诱导前列腺癌细胞迁移,降低细胞增殖和侵袭。
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引用次数: 0
Free-radical Destruction of Sphingolipids Resulting in 2-hexadecenal Formation. 自由基破坏鞘脂导致2-十六烯醛的形成。
Pub Date : 2015-03-25 eCollection Date: 2015-01-01 DOI: 10.4137/LPI.S24081
Oleg Shadyro, Alexandra Lisovskaya, Galina Semenkova, Irina Edimecheva, Nadezda Amaegberi

The action of hypochlorous acid (HOCl) and γ-radiation on aqueous lysosphingolipid dispersions was found to produce 2-hexadecenal (Hex). This process includes the stages of formation of nitrogen-centered radicals from the starting molecules and the subsequent fragmentation of these radicals via the rupture of C-C and O-H bonds. These findings prove the existence of a nonenzymatic pathway of sphingolipid destruction leading to the formation of Hex, which possesses a wide spectrum of biological activity. Analysis of the effect of HOCl on transplantable rat glioma C6 cells and human embryonic kidney 293 cells points to the formation of Hex. This suggests that the described mechanism of free-radical destruction of sphingolipids may be replicated on cell culture under the stress of active chlorine forms.

发现次氯酸(HOCl)和γ辐射对溶解鞘脂分散体的作用产生2-十六烯醛(Hex)。这个过程包括从开始的分子形成氮中心自由基的阶段,以及随后通过C-C和O-H键的断裂使这些自由基断裂的阶段。这些发现证明鞘脂破坏的非酶途径的存在导致Hex的形成,其具有广泛的生物活性。分析HOCl对可移植大鼠胶质瘤C6细胞和人胚胎肾293细胞的影响,提示Hex的形成。这表明上述自由基破坏鞘脂的机制可能在活性氯形式胁迫下的细胞培养中复制。
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引用次数: 10
Lack of Association between Polymorphisms of Hepatic Lipase with Lipid Profile in Young Jordanian Adults. 缺乏肝脏脂肪酶多态性与年轻约旦成年人血脂之间的联系。
Pub Date : 2014-04-21 eCollection Date: 2014-01-01 DOI: 10.4137/LPI.S14798
Omar F Khabour, Mahmoud A Alomari, Karem H Alzoubi, Mohammad Y Gharaibeh, Farah H Alhashimi

The human hepatic lipase (LIPC) gene encodes hepatic lipase, an enzyme involved in lipoprotein metabolism and regulation. Therefore, variants in LIPC gene may influence plasma lipoprotein levels. In this study, the association of LIPC C-514T and G-250A polymorphisms with plasma lipid profiles in 348 young Jordanians was investigated. Genotyping of C-514T and G-250A was performed by polymerase chain reaction and subsequent digestion with DraI and NiaIII restriction enzymes, respectively, while Roche analyzer was used to determine plasma total cholesterol, triglycerides, low-and high-density lipoprotein. The G-250 and C-514 alleles were most abundant in Jordanians with 79 and 80% frequencies, respectively. Additionally, no difference was found in the lipid-lipoprotein profile between the different genotype groups of C-514T or G-250A polymorphisms, even when males and females were examined separately (P > 0.05). In young Jordanian adults, the examined LIPC polymorphisms seem to play a limited role in determining the lipid profile.

人肝脂肪酶(LIPC)基因编码肝脂肪酶,一种参与脂蛋白代谢和调节的酶。因此,LIPC基因的变异可能影响血浆脂蛋白水平。在这项研究中,研究了348名约旦年轻人的LIPC C-514T和G-250A多态性与血浆脂质谱的关系。C-514T和G-250A分别采用聚合酶链反应和DraI和NiaIII酶切进行基因分型,同时采用罗氏分析仪测定血浆总胆固醇、甘油三酯、低脂蛋白和高密度脂蛋白。G-250和C-514等位基因在约旦人中最为丰富,频率分别为79%和80%。此外,C-514T或G-250A多态性的不同基因型组之间的脂质-脂蛋白谱没有差异,即使将男性和女性分开检测(P > 0.05)。在年轻的约旦成年人中,检查的LIPC多态性似乎在决定脂质谱方面发挥有限的作用。
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引用次数: 1
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Lipid insights
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