Lipid Droplets and Transcriptional Regulation of Metabolism

脂滴和代谢的转录调控

• 批准号: 10696383
• 负责人: ROBERT V FARESE
• 金额: $ 52.16万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696383
• 关键词: Attenuated; Binding; Biochemical; Buffers; Carbohydrates; Cells; Cellular Metabolic Process; Cellular biology; Data; Dietary Fatty Acid; Dimerization; Esterification; Family; Fatty Acids; Gene Expression; Genetic; Genetic Transcription; Glucose; Health; Hepatocyte; Homeostasis; Human; Intervention; Knowledge; Link; Lipids; Liver; Membrane; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Mus; Nutrient; Obesity; Organelles; Organism; Physiological; Physiology; Process; Regulation; Role; Surface; Testing; Therapeutic; Transcriptional Activation; Transcriptional Regulation; Triglycerides; Williams Syndrome; alpha-glycerophosphoric acid; developmental disease; fascinate; glucose metabolism; glucose uptake; insight; lipid biosynthesis; lipid metabolism; member; novel; pandemic disease; response; transcription factor

Abstract Lipid storage is a fundamental process for organisms to buffer fluctuations in the availability and need for metabolic energy. Lipids are predominantly stored as neutral lipids, such as triacylglycerols (TGs), in organelles called lipid droplets (LDs). In conditions of excess metabolic energy, cells convert carbohydrates to fatty acids and esterify them, along with dietary fatty acids, to glycerol-3-phosphate to form TG. Conversely, when fatty acids are needed as metabolic fuel or as precursors for membrane components, TGs are hydrolyzed. Whether or not cells have lipid stores directly impacts their ability to grow and divide, as well as their physiology and need to import nutrients. Through a combination of unbiased genetic and biochemical screens, we recently found that all members of the MLX family of transcription factors localize to the LD surfaces as LDs accumulate in cells. These transcription factors include MLX and its obligate dimerization partners, MLXIP/MondoA or MLXIPL/MondoB/ChREBP, which detect glucose derivatives and are key regulators of glucose and lipid metabolism. Deficiency of ChREBP has also been linked to the developmental disorder Williams-Beuren syndrome and to features of the metabolic syndrome. Based on extensive preliminary data, we suggest a model in which the accumulation of LDs serves to attenuate the transcriptional response of MLX:ChREBP or MLX:MondoA targets in response to glucose. We will test this model defining the mechanism and regulation of MLX-type transcription factor targeting to LDs and elucidating how this modulates their response to glucose. Completing these aims will reveal a fundamental aspect of metabolic coordination through a fascinating, novel paradigm of transcriptional control. It may also have important implications for human health. Overaccumulation of LDs is the hallmark of metabolic disease linked to obesity, a problem of pandemic proportions. Our findings will shed new light on physiological sequelae of LD accumulation, possibly providing therapeutic avenues for intervention.

抽象的 脂质储存是生物体缓冲可用性和需求波动的基本过程 代谢能量。脂质主要以中性脂质形式储存，例如三酰甘油 (TG) 称为脂滴（LD）的细胞器。在代谢能量过剩的情况下，细胞会转化碳水化合物 脂肪酸并将其与膳食脂肪酸一起酯化为 3-磷酸甘油以形成 TG。 相反，当需要脂肪酸作为代谢燃料或作为膜成分的前体时， TG 被水解。细胞是否储存脂质直接影响其生长和分裂的能力， 以及他们的生理机能和需要输入的营养物质。通过公正的遗传和 生化筛选，我们最近发现转录因子MLX家族的所有成员都定位 当 LD 在细胞中积累时，到达 LD 表面。这些转录因子包括 MLX 及其专性 二聚化伙伴，MLXIP/MondoA 或 MLXIPL/MondoB/ChREBP，可检测葡萄糖衍生物并 是葡萄糖和脂质代谢的关键调节因子。 ChREBP 缺乏也与 发育障碍 Williams-Beuren 综合征和代谢综合征的特征。 基于广泛的初步数据，我们提出了一个模型，其中 LD 的积累有助于 减弱 MLX:ChREBP 或 MLX:MondoA 靶标对葡萄糖的转录反应。 我们将测试这个模型，该模型定义了 MLX 型转录因子靶向的机制和调节 LD 并阐明其如何调节其对葡萄糖的反应。 完成这些目标将通过令人着迷的、 转录控制的新范式。它也可能对人类健康产生重要影响。 LD 的过度积累是与肥胖相关的代谢性疾病的标志，肥胖是一个大流行问题 比例。我们的研究结果将为 LD 积累的生理后遗症提供新的线索，可能 提供干预的治疗途径。