Acetyl-CoA metabolism and nutrient sensing in adipocytes

脂肪细胞中的乙酰辅酶A代谢和营养感应

• 批准号: 10304153
• 负责人: David A Guertin
• 金额: $ 48.58万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-06 至 2023-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304153
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acetylation; Adipocytes; Adipose tissue; Bioinformatics; Biology; Brown Fat; Carbohydrates; Carbon; Cell Nucleus; Cells; Chromatin; Chronic; Consumption; Cytosol; Data; Development; Diabetes Mellitus; Diet; Dietary Carbohydrates; Enzymes; Fatty acid glycerol esters; Feedback; Female; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Glucose; Health; Histone Acetylation; Incidence; Individual; Insulin; Lead; Left; Link; Lipids; Lysine; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Metabolism; Modality; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutrient; Nutritional status; Obesity; Obesity Epidemic; Phenotype; Play; Production; Proteins; Public Health; Recording of previous events; Regulation; Regulator Genes; Research; Risk; Role; Signal Pathway; Signal Transduction; Sucrose; Testing; Therapeutic; Thermogenesis; Tissues; United States; adipocyte biology; adiponectin; base; carbohydrate metabolism; detection of nutrient; fatty liver disease; feeding; glucose metabolism; improved; in vivo; insight; insulin sensitivity; lipid biosynthesis; lipid metabolism; male; metabolomics; novel; nutrient metabolism; nutrition; programs; response; transcription factor; uptake

Rates of obesity and associated metabolic diseases such as type 2-diabetes and fatty liver disease have risen steadily in recent decades. Nutrient metabolism within adipose tissue is essential for whole body metabolic health. While recent studies have pointed towards a bidirectional relationship between signaling and metabolic pathways, the role of nutrient metabolism in modulating signaling and gene expression in adipocytes is poorly understood. Novel insights into this relationship could point towards therapeutic strategies for obesity and diabetes. Nuclear-cytoplasmic pools of acetyl-CoA are crucial for de novo synthesis of lipids and for protein lysine acetylation. Recent studies have revealed that acetylation of histones and other cellular proteins is sensitive to acetyl-CoA availability, and that acetylation may thus serve as a mechanism to modulate gene expression in a nutrient-sensitive manner. ATP-citrate lyase (ACLY) is the major enzyme responsible for generating nuclear-cytoplasmic acetyl-CoA from glucose. ACLY is suppressed in adipose tissue in obesity or upon high fat feeding and is conversely induced by carbohydrates. Our previous studies implicated ACLY in regulating histone acetylation and expression of glucose metabolism genes in adipocytes, in a nutrient-dependent manner. We have generated mice lacking Acly in all adipose tissues (Aclyf/f; Adiponectin-Cre) and specifically in brown adipose tissue (Aclyf/f; Ucp1-Cre). ACLY deficiency results in altered gene expression patterns and lipid metabolism in both white and brown adipose tissue. Based on extensive preliminary data, we propose to test the hypothesis that glucose-dependent acetyl-CoA production by ACLY enables nutrient-dependent gene regulation in adipocytes, serving as a key control mechanism for carbohydrate handling and insulin response, as well as for thermogenesis. Specifically, we will test ACLY’s role in fat-specific and systemic carbohydrate metabolism and define the mechanisms through which ACLY regulates gene expression in white adipocytes. We will define the role of ACLY in cold-induced BAT remodeling and elucidate the mechanisms by which acetyl-CoA metabolism promotes thermogenesis. We propose that disruption of acetyl-CoA metabolism is a feature of metabolic disease, and that by defining the roles of the key acetyl-CoA producer ACLY in adipocytes, these studies will point to new strategies to improve the metabolic health of individuals with or at risk for metabolic diseases.

近几十年来，肥胖和相关代谢疾病（例如 2 型糖尿病和脂肪肝）的发病率稳步上升。脂肪组织内的营养代谢对于全身代谢健康至关重要。虽然最近的研究指出信号传导途径和代谢途径之间存在双向关系，但营养代谢在调节脂肪细胞信号传导和基因表达中的作用却知之甚少。对这种关系的新见解可能会为肥胖和糖尿病的治疗策略指明方向。乙酰辅酶A的核胞质池对于脂质的从头合成和蛋白质赖氨酸乙酰化至关重要。最近的研究表明，组蛋白和其他细胞蛋白的乙酰化对乙酰辅酶A的可用性敏感，因此乙酰化可能作为一种以营养敏感的方式调节基因表达的机制。 ATP-柠檬酸裂解酶 (ACLY) 是负责从葡萄糖生成核胞质乙酰辅酶 A 的主要酶。肥胖或高脂肪喂养时，ACLY 在脂肪组织中受到抑制，而碳水化合物则相反。我们之前的研究表明 ACLY 以营养依赖性方式调节脂肪细胞中组蛋白乙酰化和葡萄糖代谢基因的表达。我们已经培育出所有脂肪组织（Aclyf/f；脂联素-Cre），特别是棕色脂肪组织（Aclyf/f；Ucp1-Cre）都缺乏 Acly 的小鼠。 ACLY 缺乏会导致白色和棕色脂肪组织中基因表达模式和脂质代谢的改变。基于大量的初步数据，我们建议检验以下假设：ACLY 产生的葡萄糖依赖性乙酰辅酶 A 能够在脂肪细胞中实现营养依赖性基因调节，作为碳水化合物处理和胰岛素反应以及生热作用的关键控制机制。具体来说，我们将测试 ACLY 在脂肪特异性和全身碳水化合物代谢中的作用，并确定 ACLY 调节白色脂肪细胞基因表达的机制。我们将定义 ACLY 在寒冷诱导的 BAT 重塑中的作用，并阐明乙酰辅酶 A 代谢促进产热的机制。我们认为乙酰辅酶A代谢的破坏是代谢疾病的一个特征，并且通过定义脂肪细胞中关键的乙酰辅酶A产生者ACLY的作用，这些研究将指出改善患有代谢疾病或有代谢疾病风险的个体的代谢健康的新策略。

项目成果

Dynamic protein deacetylation is a limited carbon source for acetyl-CoA-dependent metabolism.

• DOI: 10.1016/j.jbc.2023.104772
• 发表时间: 2023-06
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Soaita, Ioana;Megill, Emily;Kantner, Daniel;Chatoff, Adam;Cheong, Yuen Jian;Clarke, Philippa;Arany, Zoltan;Snyder, Nathaniel W.;Wellen, Kathryn E.;Trefely, Sophie
• 通讯作者: Trefely, Sophie

Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques.

• DOI: 10.1038/s41467-020-20141-z
• 发表时间: 2020-12-08
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Baardman J;Verberk SGS;van der Velden S;Gijbels MJJ;van Roomen CPPA;Sluimer JC;Broos JY;Griffith GR;Prange KHM;van Weeghel M;Lakbir S;Molenaar D;Meinster E;Neele AE;Kooij G;de Vries HE;Lutgens E;Wellen KE;de Winther MPJ;Van den Bossche J
• 通讯作者: Van den Bossche J

In vivo isotope tracing reveals the versatility of glucose as a brown adipose tissue substrate.

体内同位素追踪揭示了葡萄糖作为棕色脂肪组织底物的多功能性。

• DOI: 10.1016/j.celrep.2021.109459
• 发表时间: 2021-07-27
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Jung SM;Doxsey WG;Le J;Haley JA;Mazuecos L;Luciano AK;Li H;Jang C;Guertin DA
• 通讯作者: Guertin DA

Proximity labeling of endogenous RICTOR identifies mTOR complex 2 regulation by ADP ribosylation factor ARF1.

• DOI: 10.1016/j.jbc.2022.102379
• 发表时间: 2022-10
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Luciano, Amelia K.;Korobkina, Ekaterina D.;Lyons, Scott P.;Haley, John A.;Fluharty, Shelagh M.;Jung, Su Myung;Kettenbach, Arminja N.;Guertin, David A.
• 通讯作者: Guertin, David A.

Integrating adipocyte insulin signaling and metabolism in the multi-omics era.

• DOI: 10.1016/j.tibs.2022.02.009
• 发表时间: 2022-06
• 期刊: TRENDS IN BIOCHEMICAL SCIENCES
• 影响因子: 13.8
• 作者: Calejman, C. Martinez;Doxsey, W. G.;Fazakerley, D. J.;Guertin, D. A.
• 通讯作者: Guertin, D. A.