基于单细胞转录组的基因富集方法分析星形胶质细胞与阿尔茨海默病的关系*

目的:通过生物信息学方法分析阿尔茨海默病(Alzheimer disease, AD)中与星形胶质细胞相关的糖代谢通路,为揭示AD患者的星形胶质细胞在大脑中的糖代谢过程提供理论基础。方法:首先根据细胞特异性表达基因将AD患者和健康人脑组织单细胞转录组学测序结果进行降维分析,再根据星形胶质细胞不同亚型的基因表达特征进行细胞分群,对星形胶质细胞差异表达基因进行基因注释(Gene Ontology. GO)、信号通路分析(Kyoto Encyclopedia of Genes and Genomes, KEGG)以及基因集富集分析(Gene Set Enrichment Analysis, GSEA),采用转录调控网络分析与AD的星形胶质细胞相关的转录辅助因子。结果:所有细胞降维分析结果显示AD患者脑内星形胶质细胞和兴奋性神经元数量显著减少;星形胶质细胞降维分析结果显示其可以被进一步分为6个亚群,其中在AD患者中减少的星形胶质细胞主要为RASGEF1B⁺SLC26A3⁺亚群和NRGN⁺CALM1⁺亚群;GO分析结果显示AD患者与健康对照星形胶质细胞差异表达基因主要与轴突发生、神经元的迁移、胶质细胞分化、体内锌离子稳态、突触传递的正调控、血管运输有关。KEGG结果显示,上述差异基因主要与PI3K-Akt信号通路、AMPK信号通路、钙信号通路有关。GSEA分析结果显示,AD患者差异基因在糖酵解/糖异生通路中得到富集,其中丙酮酸激酶PKM、PFKL、ACSS1、乳酸脱氢酶LDHB在AD患者星形胶质细胞中下调。转录调控网络分析结果显示,星形胶质细胞中差异表达转录辅助因子有5个,其中PKM、SOX2、SOX9在AD患者星形胶质细胞中下调。SREBF1和BCL6在AD患者星形胶质细胞中上调。结论:AD患者脑内兴奋性神经元和星形胶质细胞数量降低,以及星形胶质细胞糖酵解相关基因下调。结合星形胶质细胞作为神经元的主要乳酸供应细胞,其数量减少和糖酵解能力减低提示星形胶质细胞供能不足可能是AD发生的机制之一。     

星形胶质细胞和神经元之间谷氨酸-谷氨酰胺的代谢偶联

谷氨酸-谷氨酰胺循环是星形胶质细胞和神经元代谢偶联最重要的途径之一。在中枢神经系统中葡萄糖经糖酵解和三羧酸循环,合成三羧酸循环的中间产物。神经元因缺乏丙酮酸羧化酶,不能由葡萄糖直接合成谷氨酸,而必须依赖于星形胶质细胞的三羧酸循环来产生作为谷氨酸前体的三羧酸循环中间代谢产物。星形胶质细胞的谷氨酸载体从突触间隙摄取谷氨酸,在星形胶质细胞中转变成谷氨酰胺并释放到细胞外,然后重新被神经元摄取,转变成谷氨酸进入新一轮的循环。本文介绍了该循环,以及星形胶质细胞谷氨酸载体的功能、特性及调控。     

胶质细胞中葡萄糖转运机制研究进展

脑内神经元的能量主要依赖神经胶质细胞利用葡萄糖代谢产物乳酸供应;脑内星形胶质细胞和少突胶质细胞主要通过葡萄糖转运体途径和钠依赖性葡萄糖转运蛋白途径摄取葡萄糖,同时也可通过连接蛋白介导的缝隙连接或半通道途径形式在细胞间进行葡萄糖转运。这些途径的异常与某些神经系统疾病的病理生理学特性密切相关,故深入了解葡萄糖进入胶质细胞及其在胶质细胞之间的转运机制对脑代谢异常相关疾病的防治有重要的指导意义。     

脑能量代谢：星形胶质细胞-神经元耦合

脑是能量需求旺盛器官,能量底物的传递保证了神经元正常活化。星形胶质细胞在脑能量的产生、传递、利用和储存中具有重要功能。星形胶质细胞和神经元相互作用是脑能量代谢的核心,也是神经能量学研究的重点。本文简要综述星形胶质细胞和神经元各自的代谢特点及两者之间的代谢耦合和代谢机制。     

脑星形胶质细胞生物学功能研究进展

脑星形胶质细胞是中枢神经系统（CNS）内在数目占绝对优势的一类大胶质细胞,被认为在神经元的整个发育过程中起重要作用。本文主要就参与星形胶质细胞调节神经元活动的主要功能分子,星形胶质细胞在中枢神经系统的生物学功能,及其与疾病的关系作一简要回顾。     

乳酸在中枢神经系统中的作用及其与相关疾病的关系

一直以来,乳酸在脑中被视作代谢废物,对其功能认识严重滞后。近年来,越来越多的证据表明,乳酸在多种生理与病理过程中扮演重要角色。在神经细胞中,星形胶质细胞是产生和释放乳酸的主要细胞源,该细胞通过有氧糖酵解过程生成乳酸,随后经跨膜通道释放至胞外进入神经元为其供能。在中枢神经系统中,乳酸对稳态调节发挥着十分重要的作用。乳酸主要通过两种途径,即代谢途径(作为能量底物)与信号途径(作为信号分子)调控神经元的功能活动,广泛参与神经元能量代谢、兴奋性、可塑性、学习记忆及神经系统发育等生理过程调节,亦参与抑郁行为、阿尔兹海默病(AD)和脑损伤等病理过程的调节。在脑组织中,存在着乳酸特异性受体(GPR81),乳酸与其结合后调控胞内的第二信使。此外,还发现乳酸可通过未知受体调节神经元的兴奋性以及作为信号分子的其他作用。本文就乳酸作为能量底物和信号分子及其参与相关神经疾病的研究进展进行阐述,旨在为相关中枢神经系统疾病防治提供新思路。     

胆固醇代谢异常与神经系统疾病关系的研究进展

胆固醇是一种广泛存在于动物体内的常见小分子脂类物质,是构成细胞膜和血浆脂蛋白的重要成分。其在中枢神经系统内的含量尤为丰富,与神经元突起的产生、发育和形成,星形胶质细胞的增生,神经元的存活,神经的修复重塑以及发育相关的信号通路的传递等活动紧密相关。由于血脑屏障的隔离,脑内胆固醇主要由星形胶质细胞合成,其代谢需要通过转化为可透过血脑屏障的分子才能排出脑外。正常情况下,脑内胆固醇的浓度维持在相对稳定的范围内,对中枢神经系统的生长发育以及正常功能的维持起着至关重要的作用,其代谢异常可以诱多种神经系统疾病,因此以维持脑内胆固醇代谢的稳态为靶标可以为许多神经系统疾病的防治提供新思路。本文综述了脑内胆固醇的合成、代谢以及其与中枢神经系统疾病的相关性。     

星形胶质细胞引起神经元超激发的作用机制分析

实验发现,星形胶质细胞表面膜上有多种神经递质受体,能积极参与脑内的信号传导,并与多种神经性疾病相关.在锥体神经元和星形胶质细胞的耦合网络中,星形胶质细胞能接受外部刺激.本文研究了在神经元和胶质细胞耦合系统中,将谷氨酸刺激加载在星形胶质细胞上的情况,发现神经元出现超激发现象,而神经元超激发是癫痫疾病的一个重要特征之一;并...     

星形胶质细胞在阿尔茨海默病中的功能变化及分子机制

星形胶质细胞在脑内数量最多,分布最广,对神经元有营养支持的作用,并且能够调控神经元的活性。越来越多的证据表明星形胶质细胞激活参与阿尔茨海默病(Alzheimer's disease,AD)的发生和发展。在AD病理情况下,星形胶质细胞在多种因子如β淀粉样蛋白(beta-amyloid,Aβ)和促炎细胞因子的作用下被激活,激活的星形胶质细胞进一步释放一氧化氮(Nitric oxide,NO)和多种炎性因子增强炎症级联反应。功能失常的星形胶质细胞会促进Aβ的产生,减弱对Aβ的摄取和清除,导致Aβ聚集沉积形成老年斑。激活的星形胶质细胞释放的炎症因子还能显著增加神经元内tau蛋白的异常过度磷酸化,产生神经纤维缠结。本文对星形胶质细胞在AD中参与神经变性的功能变化和分子机制进行总结,为星形胶质细胞作为靶点预防及治疗AD提供一定的理论依据。     

脑损伤后星形胶质细胞的重编程及意义

脑损伤后神经元的死亡及凋亡使脑组织功能受损,是患者出现肢体、语言功能障碍等后遗症的主要原因。因此,修复受损脑组织的神经元是治疗的关键。近年研究表明,星形胶质细胞能发生重编程转化为神经元,其重编程的方式有去分化和转分化两种。去分化主要在体外诱导星形胶质细胞形成神经球,但这种神经球移植回体内后并不能产生神经元。转分化方式,包括直接转分化和间接转分化。间接转分化过程产生新生神经元的周期较长,且存在形成肿瘤的风险;直接转分化尤其是体内的直接转分化方式既避免了细胞移植的复杂过程,又能避免间接转分化方式形成肿瘤的风险,是脑损伤后新生神经元最安全有效的方法。该文就正常星形胶质细胞与脑损伤后反应性星形胶质细胞的重编程的机制和意义进行综述。     

Astrocytes and energy metabolism

Astrocytes are glial cells, which play a significant role in a number of processes, including the brain energy metabolism. Their anatomical position between blood vessels and neurons make them an interface for effective glucose uptake from blood. After entering astrocytes, glucose can be involved in different metabolic pathways, e.g. in glycogen production. Glycogen in the brain is localized mainly in astrocytes and is an important energy source in hypoxic conditions and normal brain functioning. The portion of glucose metabolized into glycogen molecules in astrocytes is as high as 40%. It is thought that the release of gliotransmitters (such as glutamate, neuroactive peptides and ATP) into the extracellular space by regulated exocytosis supports a significant part of communication between astrocytes and neurons. On the other hand, neurotransmitter action on astrocytes has a significant role in brain energy metabolism. Therefore, understanding the astrocytes energy metabolism may help understanding neuron-astrocyte interactions.     

Reconstruction and flux analysis of coupling between metabolic pathways of astrocytes and neurons: application to cerebral hypoxia

Background

It is a daunting task to identify all the metabolic pathways of brain energy metabolism and develop a dynamic simulation environment that will cover a time scale ranging from seconds to hours. To simplify this task and make it more practicable, we undertook stoichiometric modeling of brain energy metabolism with the major aim of including the main interacting pathways in and between astrocytes and neurons.

Model

The constructed model includes central metabolism (glycolysis, pentose phosphate pathway, TCA cycle), lipid metabolism, reactive oxygen species (ROS) detoxification, amino acid metabolism (synthesis and catabolism), the well-known glutamate-glutamine cycle, other coupling reactions between astrocytes and neurons, and neurotransmitter metabolism. This is, to our knowledge, the most comprehensive attempt at stoichiometric modeling of brain metabolism to date in terms of its coverage of a wide range of metabolic pathways. We then attempted to model the basal physiological behaviour and hypoxic behaviour of the brain cells where astrocytes and neurons are tightly coupled.

Results

The reconstructed stoichiometric reaction model included 217 reactions (184 internal, 33 exchange) and 216 metabolites (183 internal, 33 external) distributed in and between astrocytes and neurons. Flux balance analysis (FBA) techniques were applied to the reconstructed model to elucidate the underlying cellular principles of neuron-astrocyte coupling. Simulation of resting conditions under the constraints of maximization of glutamate/glutamine/GABA cycle fluxes between the two cell types with subsequent minimization of Euclidean norm of fluxes resulted in a flux distribution in accordance with literature-based findings. As a further validation of our model, the effect of oxygen deprivation (hypoxia) on fluxes was simulated using an FBA-derivative approach, known as minimization of metabolic adjustment (MOMA). The results show the power of the constructed model to simulate disease behaviour on the flux level, and its potential to analyze cellular metabolic behaviour in silico.

Conclusion

The predictive power of the constructed model for the key flux distributions, especially central carbon metabolism and glutamate-glutamine cycle fluxes, and its application to hypoxia is promising. The resultant acceptable predictions strengthen the power of such stoichiometric models in the analysis of mammalian cell metabolism.     

Differential metabolic adaptation to acute and long-term hypoxia in rat primary cortical astrocytes

Brain astrocytes provide structural and metabolic support to surrounding cells during ischemia. Glucose and oxygen are critical to brain function, and glucose uptake and metabolism by astrocytes are essential to their metabolic coupling to neurons. To examine astrocyte metabolic response to hypoxia, cell survival and metabolic parameters were assessed in rat primary cortical astrocytes cultured for 3 weeks in either normoxia or in either 1 day or 3 weeks sustained hypoxia (5% O2). Although cell survival and proliferation were not affected by the mildly hypoxic environment, substantial differences in glucose consumption and lactate release after either acute or prolonged hypoxia suggest that astrocyte metabolism may contribute to their adaptation. Hypoxia over a period of 1 day increased glucose uptake, lactate release, and glucose transporter 1 (GLUT1) and monocarboxylate transporter 1 (MCT1) expression, whereas hypoxia over a period of 3 weeks resulted in a decrease of all parameters. Furthermore, increased glucose uptake at 1 day of hypoxia was not inhibited by cytochalasin B suggesting the involvement of additional glucose transporters. We uncovered hypoxia-regulated expression of sodium-dependent glucose transporters (SGLT1) in astrocytes indicating a novel adaptive strategy involving both SGLT1 and GLUT1 to regulate glucose intake in response to hypoxia. Overall, these findings suggest that although increased metabolic response is required for the onset of astrocyte adaptation to hypoxia, prolonged hypoxia requires a shift to an energy conservation mode. These findings may contribute to the understanding of the relative tolerance of astrocytes to hypoxia compared with neurons and provide novel therapeutic strategies aimed at maintaining brain function in cerebral pathologies involving hypoxia.     

Astrocytic energetics during excitatory neurotransmission: What are contributions of glutamate oxidation and glycolysis?

Astrocytic energetics of excitatory neurotransmission is controversial due to discrepant findings in different experimental systems in vitro and in vivo. The energy requirements of glutamate uptake are believed by some researchers to be satisfied by glycolysis coupled with shuttling of lactate to neurons for oxidation. However, astrocytes increase glycogenolysis and oxidative metabolism during sensory stimulation in vivo, indicating that other sources of energy are used by astrocytes during brain activation. Furthermore, glutamate uptake into cultured astrocytes stimulates glutamate oxidation and oxygen consumption, and glutamate maintains respiration as well as glucose. The neurotransmitter pool of glutamate is associated with the faster component of total glutamate turnover in vivo, and use of neurotransmitter glutamate to fuel its own uptake by oxidation-competent perisynaptic processes has two advantages, substrate is supplied concomitant with demand, and glutamate spares glucose for use by neurons and astrocytes. Some, but not all, perisynaptic processes of astrocytes in adult rodent brain contain mitochondria, and oxidation of only a small fraction of the neurotransmitter glutamate taken up into these structures would be sufficient to supply the ATP required for sodium extrusion and conversion of glutamate to glutamine. Glycolysis would, however, be required in perisynaptic processes lacking oxidative capacity. Three lines of evidence indicate that critical cornerstones of the astrocyte-to-neuron lactate shuttle model are not established and normal brain does not need lactate as supplemental fuel: (i) rapid onset of hemodynamic responses to activation delivers oxygen and glucose in excess of demand, (ii) total glucose utilization greatly exceeds glucose oxidation in awake rodents during activation, indicating that the lactate generated is released, not locally oxidized, and (iii) glutamate-induced glycolysis is not a robust phenotype of all astrocyte cultures. Various metabolic pathways, including glutamate oxidation and glycolysis with lactate release, contribute to cellular energy demands of excitatory neurotransmission.     

Neighborly interactions of metabolically-activated astrocytes in vivo

Metabolic responses of brain cells to a stimulus are governed, in part, by their enzymatic specialization and interrelationships with neighboring cells, and local shifts in functional metabolism during brain activation are likely to be influenced by the neurotransmitter system, subcellular compartmentation, and anatomical structure. Selected examples of functional activation illustrate the complexity of metabolic interactions in working brain and of interpretation of changes in brain lactate levels. The major focus of this article is the disproportionately higher metabolism of glucose compared to oxygen in normoxic brain, a phenomenon that occurs during activation in humans and animals. The glucose utilized in excess of oxygen is not fully explained by accumulation of glucose, lactate, or glycogen in brain or by lactate efflux from brain to blood. Thus, any lactate derived from the excess glucose could not have been stoichiometrically exported to and metabolized by neighboring neurons because oxygen consumption would have otherwise increased and matched that of glucose. Metabolic labeling of tricarboxylic acid cycle-derived amino acids increased during brief sensory stimulation, reflecting a rise in oxidative metabolism. Brain glycogen is mainly in astrocytes, and its level falls throughout the stimulus and early post-activation interval. Glycogenolysis cannot be accounted for by lactate accumulation or oxidation; there must be rapid product clearance. Glycogen restoration is slow and diversion of glucose from oxidative pathways for its re-synthesis could reduce the global O(2)/glucose uptake ratio; astrocytes could downshift this ratio for up to an hour after 5 min stimulus. Morphological studies of astrocytes reveal a paucity of cytoplasm and organelles in the fine processes that surround synapses and form gap junction connections with neighboring astrocytes. Specialized regions of astrocytes, e.g. their endfeet and thin peripheral lamellae, are likely to have compartmentalized metabolic activities. Anatomical constraints imposed upon the fine processes might require preferential utilization of glycolysis to satisfy their energy demands, but rapid lactate clearance would then be essential, since its accumulation would inhibit glycolysis. Gap junctional connections between neighboring astrocytes provide a mechanism for rapid metabolite spreading via the astrocytic syncytium and elimination of by-products. Local structure-function relationships need to be incorporated into experimental models of neuron-astrocyte and astrocyte-astrocyte interactions in working brain.     

Antioxidant and bioenergetic coupling between neurons and astrocytes

Oxidative and nitrosative stress underlie the pathogenesis of a broad range of human diseases, in particular neurodegenerative disorders. Within the brain, neurons are the cells most vulnerable to excess reactive oxygen and nitrogen species; their survival relies on the antioxidant protection promoted by neighbouring astrocytes. However, neurons are also intrinsically equipped with a biochemical mechanism that links glucose metabolism to antioxidant defence. Neurons actively metabolize glucose through the pentose phosphate pathway, which maintains the antioxidant glutathione in its reduced state, hence exerting neuroprotection. This process is tightly controlled by a key glycolysis-promoting enzyme and is dependent on an appropriate supply of energy substrates from astrocytes. Thus brain bioenergetic and antioxidant defence is coupled between neurons and astrocytes. A better understanding of the regulation of this intercellular coupling should be important for identifying novel targets for future therapeutic interventions.     

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging.

Despite striking advances in functional brain imaging, the cellular and molecular mechanisms that underlie the signals detected by these techniques are still largely unknown. The basic physiological principle of functional imaging is represented by the tight coupling existing between neuronal activity and the associated local increase in both blood flow and energy metabolism. Positron emission tomography (PET) signals detect blood flow, oxygen consumption and glucose use associated with neuronal activity; the degree of blood oxygenation is currently thought to contribute to the signal detected with functional magnetic resonance imaging, while magnetic resonance spectroscopy (MRS) identifies the spatio-temporal pattern of the activity-dependent appearance of certain metabolic intermediates such as glucose or lactate. Recent studies, including those of neurotransmitter-regulated metabolic fluxes in purified preparations and analyses of the cellular localization of enzymes and transporters involved in energy metabolism, as well as in vivo microdialysis and MRS approaches have identified the neurotransmitter glutamate and astrocytes, a specific type of glial cell, as pivotal elements in the coupling of synaptic activity with energy metabolism. Astrocytes are ideally positioned to sense increases in synaptic activity and to couple them with energy metabolism. Indeed they possess specialized processes that cover the surface of intraparenchymal capillaries, suggesting that astrocytes may be a likely site of prevalent glucose uptake. Other astrocyte processes are wrapped around synaptic contacts which possess receptors and reuptake sites for neurotransmitters. Glutamate stimulates glucose uptake into astrocytes. This effect is mediated by specific glutamate transporters present on these cells. The activity of these transporters, which is tightly coupled to the synaptic release of glutamate and operates the clearance of glutamate from the extracellular space, is driven by the electrochemical gradient of Na+. This Na(+)-dependent uptake of glutamate into astrocytes triggers a cascade of molecular events involving the Na+/K(+)-ATPase leading to the glycolytic processing of glucose and the release of lactate by astrocytes. The stoichiometry of this process is such that for one glutamate molecule taken up with three Na+ ions, one glucose molecule enters an astrocyte, two ATP molecules are produced through aerobic glycolysis and two lactate molecules are released. Within the astrocyte, one ATP molecule fuels one 'turn of the pump' while the other provides the energy needed to convert glutamate to glutamine by glutamine synthase. Evidence has been accumulated from structural as well as functional studies indicating that, under aerobic conditions, lactate may be the preferred energy substrate of activated neurons. Indeed, in the presence of oxygen, lactate is converted to pyruvate, which can be processed through the tricarboxylic acid cycle and the associated oxidative phosphorylation, to yield 17 ATP molecules per lactate molecule. These data suggest that during activation the brain may transiently resort to aerobic glycolysis occurring in astrocytes, followed by the oxidation of lactate by neurons. The proposed model provides a direct mechanism to couple synaptic activity with glucose use and is consistent with the notion that the signals detected during physiological activation with 18F-deoxyglucose (DG)-PET may reflect predominantly uptake of the tracer into astrocytes. This conclusion does not question the validity of the 2-DG-based techniques, rather it provides a cellular and molecular basis for these functional brain imaging techniques.     

Astrocyte Mitochondrial Mechanisms of Ischemic Brain Injury and Neuroprotection

Research on ischemic brain injury has established a central role of mitochondria in neuron death. Astrocytes are also damaged by ischemia, although the participation of mitochondria in their injury is ill defined. As astrocytes are responsible for neuronal metabolic and trophic support, astrocyte dysfunction will compromise postischemic neuronal survival. Ischemic alterations to astrocyte energy metabolism and the uptake and metabolism of the excitatory amino acid transmitter glutamate may be particularly important. Despite the significance of ischemic astrocyte injury, little is known of the mechanisms responsible for astrocyte death and dysfunction. This review focuses on differences between astrocyte and neuronal metabolism and mitochondrial function, and on neuronal-glial interactions. The potential for astrocyte mitochondria to serve as targets of neuroprotective interventions is also discussed.     

Nutrition during brain activation: does cell-to-cell lactate shuttling contribute significantly to sweet and sour food for thought?

Functional activation of astrocytic metabolism is believed, according to one hypothesis, to be closely linked to excitatory neurotransmission and to provide lactate as fuel for oxidative metabolism in neighboring neurons. However, review of emerging evidence suggests that the energetic demands of activated astrocytes are higher and more complex than recognized and much of the lactate presumably produced by astrocytes is not locally oxidized during activation. In vivo activation studies in normal subjects reveal that the rise in consumption of blood-borne glucose usually exceeds that of oxygen, especially in retina compared to brain. When the contribution of glycogen, the brain's major energy reserve located in astrocytes, is taken into account the magnitude of the carbohydrate-oxygen utilization mismatch increases further because the magnitude of glycogenolysis greatly exceeds the incremental increase in utilization of blood-borne glucose. Failure of local oxygen consumption to equal that of glucose plus glycogen in vivo is strong evidence against stoichiometric transfer of lactate from astrocytes to neighboring neurons for oxidation. Thus, astrocytes, not nearby neurons, use the glycogen for energy during physiological activation in normal brain. These findings plus apparent compartmentation of metabolism of glycogen and blood-borne glucose during activation lead to our working hypothesis that activated astrocytes have high energy demands in their fine perisynaptic processes (filopodia) that might be met by glycogenolysis and glycolysis coupled to rapid lactate clearance. Tissue culture studies do not consistently support the lactate shuttle hypothesis because key elements of the model, glutamate-induced increases in glucose utilization and lactate release, are not observed in many astrocyte preparations, suggesting differences in their oxidative capacities that have not been included in the model. In vivo nutritional interactions between working neurons and astrocytes are not as simple as implied by "sweet (glucose-glycogen) and sour (lactate) food for thought."     

The impact of HPV infection on human glycogen and lipid metabolism – a review

Reinterpretation of the Wartburg effect leads to understanding aerobic glycolysis as a process that provides considerable amount of molecular precursors for the production of lipids, nucleotides and amino acids that are necessary for continuous growth and rapid proliferation characteristic for cancer cells.Human papilloma virus (HPV) is a number one cause of cervical carcinoma with 99% of the cervical cancer patients being HPV positive. This tight link between HPV and cancer raises the question if and how HPV impact cells to reprogram their metabolism? Focusing on early phase proteins E1, E2, E5, E6 and E7 we demonstrate that HPV activates plethora of metabolic pathways and directly influences enzymes of the glycolysis pathway to promote the Warburg effect by increasing glucose uptake, activating glycolysis and pentose phosphate pathway, increasing the level of lactate dehydrogenase A synthesis and inhibiting β-oxidation. Our considerations lead to conclusion that HPV is substantially involved in metabolic cell reprogramming toward neoplastic phenotype and its metabolic activity is the fundamental reason of its oncogenicity.