Acetate metabolism in human cytomegalovirus infection.

人类巨细胞病毒感染中的乙酸代谢。

• 批准号: 8731175
• 负责人: YONGJUN YU
• 金额: $ 24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-09 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731175
• 关键词: ATP Citrate (pro-S)-Lyase; Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Area; Carbon; Cells; Cellular Membrane; Citrates; Citric Acid Cycle; Cleaved cell; Coenzyme A; Cytomegalovirus; Cytomegalovirus Infections; Cytosol; Data; Development; Diffuse; Environment; Enzymes; Fasting; Fatty Acids; Fibroblasts; Glucose; Glutamine; Glycolysis; Growth; Human; Hydrolase; Lipids; Mammalian Cell; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Normal Cell; Nutrient; Pathogenesis; Population; Production; Pyruvate; Role; Signal Transduction; Testing; Viral; design; glucose metabolism; lipid biosynthesis; metabolic abnormality assessment; novel; oxidation; pathogen; public health relevance; research study; virology

DESCRIPTION (provided by applicant): Cytosolic acetyl-coenzyme A (Ac-CoA), a central precursor for lipid synthesis, is primarily made from mitochondria-derived citrate by ATP-citrate lyase (ACL) in cells with sufficient nutrients. Alternatively, cytosolic Ac-CoA can be made from acetate by acetyl-CoA synthetase 1 (AceCS1) under fasting conditions. In normal cells, acetate cannot be directly produced from glucose metabolism and ACL is the primary enzyme to synthesize cytosolic Ac-CoA. Previous studies show that HCMV infection dramatically increases glycolysis in the host cells; however, most glucose carbon exits the mitochondria and is used for lipid synthesis to support viral envelope formation, rather than being oxidized to produce energy through the tricarboxylic acid (TCA) cycle. Our preliminary studies show that lipid synthesis is independent of ACL in HCMV-infected human fibroblasts, this differs from that in uninfected cells which are ACL-dependent, indicating that HCMV alters cellular metabolic pathways to generate cytosolic Ac-CoA by using acetate to support lipid synthesis. We hypothesize that HCMV activates mitochondrial acetyl-CoA hydrolase (ACH) to produce acetate from pyruvate-derived Ac-CoA. The specific aims are: 1. Determine acetate production and the carbon fluxes to acetate during HCMV infection; 2. Determine mitochondrial ACH activity, activation during HCMV infection, and its role in acetate production and HCMV-induced lipogenesis; 3. Determine the role of AceCS1 in lipogenesis induced by HCMV infection. Accomplishment of the aims will open a new area of metabolic study and create new metabolic concepts.

描述（由申请人提供）：胞质乙酰辅酶 A (Ac-CoA) 是脂质合成的主要前体，主要由线粒体来源的柠檬酸在营养充足的细胞中通过 ATP-柠檬酸裂解酶 (ACL) 制成。或者，胞质 Ac-CoA 可以在禁食条件下通过乙酰辅酶 A 合成酶 1 (AceCS1) 由乙酸盐制成。在正常细胞中，葡萄糖代谢不能直接产生乙酸，ACL是合成胞质Ac-CoA的主要酶。先前的研究表明，HCMV 感染会显着增加宿主细胞中的糖酵解；然而，大多数葡萄糖碳离开线粒体并用于脂质合成以支持病毒包膜形成，而不是通过三羧酸（TCA）循环被氧化以产生能量。我们的初步研究表明，在HCMV感染的人成纤维细胞中，脂质合成不依赖于ACL，这与未感染的细胞中依赖ACL的脂质合成不同，表明HCMV改变细胞代谢途径，通过使用乙酸盐支持脂质来产生胞质Ac-CoA合成。我们假设 HCMV 激活线粒体乙酰辅酶 A 水解酶 (ACH)，从丙酮酸衍生的 Ac-CoA 中产生乙酸。具体目标是： 1. 确定 HCMV 感染期间乙酸盐的产生和乙酸盐的碳通量； 2. 测定HCMV感染过程中线粒体ACH活性、激活及其在醋酸盐产生和HCMV诱导的脂肪生成中的作用； 3.确定AceCS1在HCMV感染诱导的脂肪生成中的作用。这些目标的实现将开辟代谢研究的新领域并创造新的代谢概念。