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

基本信息

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
项目类别：
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

项目摘要

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，肥胖和相关的代谢疾病（例如二糖型和脂肪肝疾病）悄悄地上升。脂肪组织中的营养代谢对于全身代谢健康至关重要。尽管最近的研究指出了信号传导与代谢途径之间的双向关系，但养分代谢在调节脂肪细胞中的信号传导和基因表达中的作用知之甚少。对这种关系的新颖见解可能指出肥胖和糖尿病的治疗策略。乙酰辅酶A的核质池对于从头合成脂质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，因此乙酰化可以作为以营养敏感方式调节基因表达的机制。 ATP-柠檬酸裂解酶（ACLY）是负责从葡萄糖产生核胞质乙酰辅酶A的主要酶。 ACLY在肥胖症或高脂肪进食的脂肪组织中抑制，相反，碳水化合物诱导。我们以前的研究以营养依赖性方式确定脂肪细胞中葡萄糖代谢基因的组蛋白乙酰化和表达。我们已经在所有脂肪组织（Aclyf/f; adiponectin-cre）中，特别是在棕色脂肪组织（ACLYF/F; UCP1-CRE）中产生了缺乏丙烯酸的小鼠。伴有白色和棕色脂肪组织中的基因表达模式和脂质代谢改变了基因表达模式和脂质代谢。基于广泛的初步数据，我们建议测试以下假设：糖脂依赖葡萄糖依赖性乙酰-COA可以使脂肪细胞中的营养依赖性基因调节，它是碳氢化物的关键控制机制，我们将在冷bat诱导的bat Repoenting和Elcogen sempoenty co nement and co acetyl-co中定义Acly的作用。我们认为，乙酰-COA代谢的破坏是代谢疾病的一个特征，并且通过定义关键的乙酰-COA生产者在脂肪细胞中的作用，这些研究将指出新的策略，以改善患有或有代谢性疾病风险的个体的代谢健康。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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.

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.

Should we consider subcellular compartmentalization of metabolites, and if so, how do we measure them?