病毒介导的海洋球石藻(Coccolithophores)鞘脂类代谢调控

海洋球石藻(Coccolithophores)是一种全球广泛分布且具有重要生态功能的真核浮游植物,有些种类是大洋和近岸常见的赤潮种。自然海域中,病毒感染是导致球石藻死亡和赤潮消亡的一个关键因素。基于一株海洋球石藻Emiliania huxleyi及其特异性裂解病毒全基因组测序注释的结果,研究者们发现病毒可能通过基因横向转移从宿主基因组中获取了一系列与鞘脂类代谢相关的关键酶基因,进而在一定程度上掌控了宿主鞘脂类代谢,大量合成、积累病毒性鞘脂类物质,并最终诱导宿主细胞以凋亡的形式死亡。因此,病毒介导的宿主鞘脂类代谢在调节病毒与宿主间相互作用中具有重要意义。本文着重综述海洋球石藻病毒与宿主间的基因横向转移、病毒介导的宿主鞘脂类代谢特点及其生态学意义,以期深入了解海洋球石藻病毒与宿主间复杂的相互作用关系。     

甘油二酯激活蛋白激酶C

钙依赖性蛋白激酶分为两类:一类与调钙素结合就激活,如肌球蛋白轻链激酶;另一类为蛋白激酶C,它分布很广,由磷脂酰丝氨酸及其他脂类激活。在细胞外信号刺激一定的受体后,膜的含肌醇的脂质短时分解产生甘油二酯(DG),它能在未激动的细胞内钙浓度下激活蛋白激酶C。DG 还能提高蛋白激酶C 对Ca~(2 )的敏感性。在有DG 时,当游离钙在10~(-7)mol 上下时,蛋白激酶C 就被激活。没有DG,即使有磷脂     

蛋白激酶A与脂类代谢

蛋白激酶A(protein kinase A,PKA)为重要细胞信号传导因子,在机体脂类代谢调控中发挥关键作用。PKA激活关键性脂肪水解酶,如激素敏感脂肪酶(hormone sensitive lipase,HSL)与脂肪甘油三酯脂肪酶(adipose triglyceride lipase,ATGL),以促进脂肪动员。PKA上调解偶联蛋白-1(uncoupling protein 1,UCP-1)表达,促进棕色脂肪细胞线粒体热量生成,上调机体产热量。PKA密切参与肝脏细胞脂类合成代谢调控过程。值得关注的是,PKA信号传导异常,是脂质代谢异常相关疾病,如肥胖、心脑血管疾病、2型糖尿病等疾病的重要发病机制之一。药理学研究亦显示,PKA与主要调血脂药的药理作用密切相关。本文综述五年来有关PKA参与脂类代谢调控的研究进展,以期深入了解PKA在脂类代谢中发挥的作用,并为相关疾病的诊疗提供新思路。     

鞘氨醇-1磷酸盐的生理功能研究进展

鞘氨醇－1磷酸盐（SPP）是神经鞘磷脂代谢产生的一种有生物活性的脂类,在细胞的多种生物学过程中起着重要的作用。包括细胞的增殖、存活、细胞骨架改变、迁移、血管发生、创伤愈合和胚胎发育等。本文综述了SPP在细胞生物功能调节和信号转导中的作用。     

脂类代谢异常在恶性肿瘤中的研究进展

过度增殖是恶性肿瘤细胞的生物学特性,为满足不断增殖及生存的需要,肿瘤细胞需重新编码代谢通路。近年来的研究认为,脂类代谢异常是肿瘤细胞的重要特征之一,肿瘤细胞中异常的脂类代谢不仅与代谢酶有关,还与代谢通路以及其他相关信号传导有关。本文通过回顾既往研究报道的肿瘤细胞脂类代谢的变化,探讨脂类代谢的异常调节与肿瘤发生的可能机制,为肿瘤的预防及治疗提供新思路。     

综述: 线粒体自噬在低氧适应中的作用

低氧是一种典型的应激环境,细胞在低氧条件下能量和氧化代谢发生改变,其中线粒体产生的大量活性氧严重威胁细胞的存活．线粒体自噬是近年来被发现的细胞适应低氧的一种适应性代谢反应．细胞在低氧条件下能通过上调低氧诱导因 子1(HIF-1),激活BNIP3/BNIP3L及Beclin-1介导的通路诱导线粒体自噬,最终减少ROS的产生,促进细胞的存活,使机体产生低氧适应．综述了线粒体自噬在低氧适应中的作用及其机制．     

人脂素基因LIPIN1在酵母中的异源表达及细胞功能分析

脂类代谢调控是维持生物体能量平衡的重要环节,脂类代谢调控的紊乱与肥胖症、糖尿病和高血压等疾病密切相关。脂素基因三LIPIN1是诱导脂肪细胞分化、调控脂类合成的关键基因．其编码的磷脂磷酸酶（phosphatidate phosphatase,PAP）在人体三酰甘油合成中起关键作用,是维持人体脂类平衡的重要保障。此外,该基因还作为重要的转录辅激活因子参与多种生长及营养代谢调控。多种生物中均有类似功能的基因被发现,暗示了其功能的多样性及物种间的保守性。该文利用酿酒酵母在脂类代谢研究中性状易于表征、同源基因剧刖功能明确的优势,通过同源重组技术构建脂素缺陷型酵母,探索脂素基因在维持酵母正常生长及脂类合成中的重要作用,并通过功能互补及生物信息学技术对比分析了人源LIPIN1基因与酵母PdH1基因编码蛋白在结构和功能上的保守性,为脂素基因LIPIN1的细胞功能研究提供基础数据。     

哺乳动物DGAT基因及其生物学功能研究进展

二酰基甘油酰基转移酶(DGAT, EC2.3.1.20)是一种微粒体酶, 与脂肪代谢、脂类在组织中的沉积有很大关系, 它的主要作用机制是使二酰甘油加上脂肪酸酰基形成三酰甘油。DGAT在细胞甘油代谢中起根本性的作用, 并在高等真核生物甘油三酯代谢途径如肠脂肪吸收、脂蛋白集合、脂肪形成和泌乳中发挥着重要的功能, 提示DGAT不仅是调控甘油三酯与脂肪酸之间的关键因子, 而且可能在动物脂肪沉积中起着关键的调控作用。     

内质网应激与脂类代谢

内质网应激激活的未折叠蛋白反应(unfolded protein response,UPR)是维持机体代谢平衡的重要信号通路。同时,内质网与脂类合成、转运和分解密切相关。近来研究发现UPR对脂类代谢具有调节作用。主要讨论内质网应激激活的UPR对脂类合成、转运和分解的影响及其机制。     

脂滴:与肿瘤发展密切相关的特殊细胞器

脂滴(Lipid droplet,LD)存在于从酵母菌到人类的大多数细胞中,是储存中性脂的主要场所。近年来提出脂滴是一种高度活跃的细胞脂类代谢细胞器,是脂质代谢、转运以及信号传递的主要调控因子。脂滴作为脂质中心,可以参与细胞内的脂质合成与代谢,其代谢与肿瘤密切联系在一起,并在各种肿瘤细胞中大量积累。本文从脂滴的生物发生、结构和功能等方面进行了详细的描述,进一步探讨了脂滴在不同类型肿瘤发展过程中的作用,以期为肿瘤的临床诊疗提供参考依据。     

Diacylglycerol Kinase Inhibition and Vascular Function

Diacylglycerol kinases (DGKs), a family of lipid kinases, convert diacylglycerol (DG) to phosphatidic acid (PA). Acting as a second messenger, DG activates protein kinase C (PKC). PA, a signaling lipid, regulates diverse functions involved in physiological responses. Since DGK modulates two lipid second messengers, DG and PA, regulation of DGK could induce related cellular responses. Currently, there are 10 mammalian isoforms of DGK that are categorized into five groups based on their structural features. These diverse isoforms of DGK are considered to activate distinct cellular functions according to extracellular stimuli. Each DGK isoform is thought to play various roles inside the cell, depending on its subcellular localization (nuclear, ER, Golgi complex or cytoplasm). In vascular smooth muscle, vasoconstrictors such as angiotensin II, endothelin-1 and norepinephrine stimulate contraction by increasing inositol trisphosphate (IP(3)), calcium, DG and PKC activity. Inhibition of DGK could increase DG availability and decrease PA levels, as well as alter intracellular responses, including calcium-mediated and PKC-mediated vascular contraction. The purpose of this review is to demonstrate a role of DGK in vascular function. Selective inhibition of DGK isoforms may represent a novel therapeutic approach in vascular dysfunction.     

Nuclear expression of diacylglycerol kinases: possible involvement in DNA replication

The existence of intranuclear lipid-dependent signal transduction systems has been demonstrated by several independent groups. Remarkably, intranuclear lipid-dependent signal transduction pathways are regulated independently from their membrane/cytosolic counterparts. A sizable body of evidence suggests that nuclear lipid signaling controls critical biological functions such as cell proliferation, differentiation, and apoptosis. Diacylglycerol (DG) is a fundamental lipid second messenger which is produced in the nucleus. Since the levels of nuclear DG fluctuate during the cell cycle progression, it has been suggested that this lipid second messenger has important regulatory roles. Most likely, nuclear DG serves as a chemoattractant for some isoforms of protein kinase C that migrate to the nucleus in response to a variety of agonists. The nucleus also contains diacylglycerol kinases (DGKs), i.e. the enzymes that, by converting DG into phosphatidic acid (PA), terminate DG-dependent events. This review aims at highlighting the different isozymes of DGKs present within the nucleus as well as at discussing their potential functions with particular emphasis placed on DNA replication.     

Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells

How cellular metabolic activities regulate autophagy and determine the susceptibility to oxidative stress and ultimately cell death in neuronal cells is not well understood. An important example of oxidative stress is 4-hydroxynonenal (HNE), which is a lipid peroxidation product that is formed during oxidative stress, and accumulates in neurodegenerative diseases causing damage. The accumulation of toxic oxidation products such as HNE, is a prevalent feature of neurodegenerative diseases, and can promote organelle and protein damage leading to induction of autophagy. In this study, we used differentiated SH-SY5Y neuroblastoma cells to investigate the mechanisms and regulation of cellular susceptibility to HNE toxicity and the relationship to cellular metabolism. We found that autophagy is immediately stimulated by HNE at a sublethal concentration. Within the same time frame, HNE induces concentration dependent CASP3/caspase 3 activation and cell death. Interestingly, both basal and HNE-activated autophagy, were regulated by glucose metabolism. Inhibition of glucose metabolism by 2-deoxyglucose (2DG), at a concentration that inhibited autophagic flux, further exacerbated CASP3 activation and cell death in response to HNE. Cell death was attenuated by the pan-caspase inhibitor Z-VAD-FMK. Specific inhibition of glycolysis using koningic acid, a GAPDH inhibitor, inhibited autophagic flux and exacerbated HNE-induced cell death similarly to 2DG. The effects of 2DG on autophagy and HNE-induced cell death could not be reversed by addition of mannose, suggesting an ER stress-independent mechanism. 2DG decreased LAMP1 and increased BCL2 levels suggesting that its effects on autophagy may be mediated by more than one mechanism. Furthermore, 2DG decreased cellular ATP, and 2DG and HNE combined treatment decreased mitochondrial membrane potential. We conclude that glucose-dependent autophagy serves as a protective mechanism in response to HNE.     

Unraveling uncultivable pesticide degraders via stable isotope probing (SIP)

Uncultivable microorganisms account for over 99% of all species on earth, playing essential roles in ecological processes such as carbon/nitrogen cycle and chemical mineralization. Their functions remain unclear in ecosystems and natural habitats, requiring cutting-edge biotechnologies for a deeper understanding. Stable isotope probing (SIP) incorporates isotope-labeled elements, e.g. ^13?C, ^18?O or ^15?N, into the cellular components of active microorganisms, serving as a powerful tool to link phylogenetic identities to their ecological functions in situ. Pesticides raise increasing attention for their persistence in the environment, leading to severe damage and risks to the ecosystem and human health. Cultivation and metagenomics help to identify either cultivable pesticide degraders or potential pesticide metabolisms within microbial communities, from various environmental media including the soil, groundwater, activated sludge, plant rhizosphere, etc. However, the application of SIP in characterizing pesticide degraders is limited, leaving considerable space in understanding the natural pesticide mineralization process. In this review, we try to comprehensively summarize the fundamental principles, successful cases and technical protocols of SIP in unraveling functional-yet-uncultivable pesticide degraders, by raising its shining lights and shadows. Particularly, this study provides deeper insights into various feasible isotope-labeled substrates in SIP studies, including pesticides, pesticide metabolites, and similar compounds. Coupled with other techniques, such as next-generation sequencing, nanoscale secondary ion mass spectrometry (NanoSIMS), single cell genomics, magnetic-nanoparticle-mediated isolation (MMI) and compound-specific isotope analysis (CSIA), SIP will significantly broaden our understanding of pesticide biodegradation process in situ.     

Lipidomic Profiling of Di- and Tri-Acylglycerol Species in Weight-Controlled Mice

Weight control by dietary calorie restriction (DCR) or exercise has been shown to prevent cancer in various models. However, the mechanisms as to how weight control is beneficial are not well understood. While previous reports have investigated the effects of weight control on total lipid levels or lipid composition within cellular membranes, there has been little work surrounding changes to individual lipids following weight control interventions. In this study, using a model of skin carcinogenesis centered on the tumor promotion stage, CD-1 mice were randomly assigned into 4 groups: ad libitum and sedentary (control), ad libitum with exercise (AL+Exe), exercise with pair feeding of a diet isocaloric with control (PF+Exe), and sedentary with 20% DCR compared to control. After ten weeks, body weight and body fat percentages significantly decreased in the PF+Exe and DCR groups but not AL+Exe when compared with sedentary controls. Murine skin and plasma samples were obtained for analysis. Lipidomics using electrospray ionization MS/MS was employed to profile triacylglycerol (TG) and diacylglycerol (DG) species. Both plasma and tissue TG species containing fatty acid chains with length 18:1 were significantly decreased following DCR when compared to sedentary control animals. In regards to DG, the most significant changes occurred in the plasma. DG species containing fatty acids with lengths 16:1 or 18:1 were significantly decreased in PF+Exe and DCR groups when compared to sedentary controls. Due to the significant role of TG in energy storage and DG in cellular signaling, our findings of the effects of weight control on individual TG and DG species in plasma and skin tissue following exposure to a tumor promoter, may provide insight into the mechanism of weight control on cancer prevention.     

GSK3β Overexpression in Dentate Gyrus Neural Precursor Cells Expands the Progenitor Pool and Enhances Memory Skills

In restricted areas of the adult brain, like the subgranular zone of the dentate gyrus (DG), there is continuous production of new neurons. This process, named adult neurogenesis, is involved in important cognitive functions such as memory and learning. It requires the presence of newborn neurons that arise from neuronal stem cells, which divide and differentiate through successive stages in adulthood. In this work, we demonstrate that overexpression of glycogen synthase kinase (GSK) 3β in neural precursor cells (NPCs) using the glial fibrillary acidic protein promoter during DG development produces an increase in the neurogenic process, increasing NPCs numbers. Moreover, the transgenic mice show higher DG volume and increased number of mature granule neurons. In an attempt to compensate for these alterations, glial fibrillary acidic protein/GSK3β-overexpressing mice show increased levels of Dkk1 and sFRP3, two inhibitors of the Wnt-frizzled complex. We have also found behavioral differences between wild type and transgenic mice, indicating a higher rating in memory tasks for GSK3β-overexpressing mice compared with wild type mice. These data indicate that GSK3β is a crucial kinase in NPC physiology and suggest that this molecule plays a key role in the correct development of DG and adult neurogenesis in this region.     

Modification by diacylglycerol of the structure and interaction of various phospholipid bilayer membranes

The effects of incorporating diacylglycerol (DG) derived from egg phosphatidylcholine (PC) into PC, egg phosphatidylethanolamine (PE), and bovine phosphatidylserine (PS) have been measured. In excess solution DG induces a multilamellar-to-hexagonal (L-H) structural transition in PE and PC that is temperature dependent. At 37 degrees C it begins at about 3 and 30 mol%, respectively. In PC at lower DG concentrations a modified lamellar phase is formed; at about 70 mol% DG a single primitive cubic phase forms. An L-H transition induced by 20-30 mol% DG in PS is dependent on ionic strength and degree of lipid hydration, with the appearance of crystalline acyl chains at the higher DG levels. Calcium precipitates of DG/PS (1/1) mixtures have melted chains. Structural parameters were derived for the lamellar phases at subtransition levels of DG in PE and PC. The area per polar group is increased, but by contrast with cholesterol, the polar group spreading is not accompanied by an increase in bilayer thickness. DG does not affect the equilibrium separation of PC or PE bilayers. Measured interbilayer forces as they vary with bilayer separation show that DG at 20 mol% does not effect closer apposition of PC bilayers at any separation. Spreading the polar groups may effect the binding of protein kinase C or the activation of phospholipases; the nonlamellar phases may be linked to the biochemical production of DG in cellular processes involving membrane fusion.     

Pyruvate protection against endothelial cytotoxicity induced by blockade of glucose uptake

We have previously demonstrated that the redox reactant pyruvate prevents apoptosis in the oxidant model of bovine pulmonary artery endothelial cells (BPAEC), and that the anti-apoptotic mechanism of pyruvate is mediated in part via the mitochondrial matrix compartment. However, cytosolic mechanisms for the cytoprotective feature of pyruvate remain to be elucidated. This study investigated the pyruvate protection against endothelial cytotoxicity when the glycolysis inhibitor 2-deoxy-D-glucose (2DG) was applied to BPAEC. Millimolar 2DG blocked the cellular glucose uptake in a concentration- and time-dependent manner with >85% inhibition at > or =5 mM within 24 h. The addition of 2DG evoked BPAEC cytotoxicity with a substantial increase in lipid peroxidation and a marked decrease in intracellular total glutathione. Exogenous pyruvate partially prevented the 2DG-induced cell damage with increasing viability of BPAEC by 25-30%, and the total glutathione was also modestly increased. In contrast, 10 mM L-lactate, as a cytosolic reductant, had no effect on the cytotoxicity and lipid peroxidation that are evoked by 2DG. These results suggest that 2DG toxicity may be a consequence of the diminished potential of glutathione antioxidant, which was partially restored by exogenous pyruvate but not L-lactate. Therefore, pyruvate qualifies as a cytoprotective agent for strategies that attenuate the metabolic dysfunction of the endothelium, and cellular glucose oxidation is required for the functioning of the cytosolic glutathione/NADPH redox system.     

The contribution of the Drosophila model to lipid droplet research

Intracellular lipid droplets have long been misconceived as evolutionarily conserved but functionally frugal components of cellular metabolism. An ever-growing repertoire of functions has elevated lipid droplets to fully-fledged cellular organelles. Insights into the multifariousness of these organelles have been obtained from a range of model systems now employed for lipid droplet research including the fruit fly, Drosophila melanogaster. This review summarizes the progress in fly lipid droplet research along four main avenues: the role of lipid droplets in fat storage homeostasis, the control of lipid droplet structure, the lipid droplet surface as a dynamic protein-association platform, and lipid droplets as mobile organelles. Moreover, the research potential of the fruit fly model is discussed with respect to the prevailing general questions in lipid droplet biology.