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，肥胖和相关代谢疾病（例如 2 型糖尿病和脂肪肝疾病）的发病率稳步上升，而脂肪组织内的营养代谢对于全身代谢健康至关重要，而最近的研究表明信号传导与代谢之间存在双向关系。尽管人们对营养代谢在调节脂肪细胞信号传导和基因表达中的作用知之甚少，但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。用于脂质的从头合成和蛋白质赖氨酸乙酰化最近的研究表明，组蛋白和其他细胞蛋白质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调节营养敏感的基因表达的机制。 ATP-柠檬酸裂解酶 (ACLY) 是负责从葡萄糖生成核细胞质乙酰辅酶 A 的主要酶，ACLY 在脂肪中受到抑制。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的组蛋白乙酰化和葡萄糖代谢基因的表达，并且在所有脂肪组织中都缺乏 Acly。（Aclyf/f；脂联素-Cre），特别是棕色脂肪组织（Aclyf/f；Ucp1-Cre）缺乏会导致基因表达模式和脂质代谢改变。基于大量的初步数据，我们建议检验这样的假设：ACLY 产生的葡萄糖依赖性乙酰辅酶 A 能够实现脂肪细胞中营养依赖性基因调节，作为碳水化合物处理和胰岛素的关键控制机制。具体来说，我们将测试 ACLY 在脂肪特异性和碳水化合物系统代谢中的作用，并确定 ACLY 调节白色脂肪细胞中基因表达的机制。我们将确定 ACLY 在寒冷诱导中的作用。 BAT 重塑并阐明乙酰辅酶 A 代谢促进产热的机制我们认为乙酰辅酶 A 代谢是代谢疾病的一个特征，并且通过定义破坏脂肪细胞中关键乙酰辅酶 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

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）

Advances into understanding metabolites as signaling molecules in cancer progression.

在理解代谢物作为癌症进展中的信号分子方面取得的进展。

DOI：
10.1016/j.ceb.2020.01.013
发表时间：
2020-02-22
期刊：
Current opinion in cell biology
影响因子：
7.5
作者：
Joyce Liu;K. Wellen
通讯作者：
K. Wellen

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

内源性 RICTOR 的邻近标记可识别 ADP 核糖基化因子 ARF1 对 mTOR 复合物 2 的调节。

DOI：
发表时间：
2022-10
期刊：
影响因子：
0
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?

我们是否应该考虑代谢物的亚细胞区室化？如果是，我们如何测量它们？

DOI：
10.1097/mco.0000000000000580
发表时间：
2019-09-01
期刊：
Current Opinion in Clinical Nutrition & Metabolic Care
影响因子：
3.1
作者：
K. Wellen;N. Snyder
通讯作者：
N. Snyder

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

动态蛋白质脱乙酰化是乙酰辅酶A依赖性代谢的有限碳源。

DOI：
发表时间：
2023-06
期刊：
影响因子：
0
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

Subcellular metabolic pathway kinetics are revealed by correcting for artifactual post harvest metabolism.

通过校正人工收获后代谢来揭示亚细胞代谢途径动力学。

DOI：
发表时间：
2019-12
期刊：
影响因子：
8.1
作者：
Trefely, Sophie;Liu, Joyce;Huber, Katharina;Doan, Mary T;Jiang, Helen;Singh, Jay;von Krusenstiern, Eliana;Bostwick, Anna;Xu, Peining;Bogner;Wellen, Kathryn E;Snyder, Nathaniel W
通讯作者：
Snyder, Nathaniel W