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 脂质存储是生物体缓冲可用性波动和需求的基本过程 代谢能。脂质主要存储为中性脂质，例如三酰基甘油（TGS），在 细胞器称为脂质液滴（LDS）。在过多的代谢能量的条件下，细胞转换碳水化合物 脂肪酸并将其与饮食中的脂肪酸一起酯化，以形成TG甘油-3-磷酸。 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。细胞是否具有脂质存储直接影响其生长和分裂的能力， 以及他们的生理学，需要进口营养。通过公正的遗传和 生化筛选，我们最近发现，MLX转录因子家族的所有成员本地化 当LD在细胞中积聚时，到LD表面。这些转录因素包括MLX及其义务 二聚合作伙伴，mlxip/mondoa或mlxipl/mondob/chrebp，检测葡萄糖衍生物和 是葡萄糖和脂质代谢的关键调节剂。 Chrebp的不足也已与 发育障碍威廉姆斯 - 布伦综合征和代谢综合征的特征。 基于广泛的初步数据，我们建议一个模型，其中LDS的积累用于 减弱MLX的转录响应：CHREBP或MLX：Mondoa靶标在响应葡萄糖时。 我们将测试此模型，以定义MLX型转录因子的机理和调节，该模型的靶向 LDS并阐明这如何调节其对葡萄糖的反应。 完成这些目标将通过迷人的，令人着迷的，揭示代谢协调的基本方面 转录控制的新型范式。它也可能对人类健康具有重要意义。 LDS的过度积累是与肥胖有关的代谢疾病的标志，这是一个大流行的问题 比例。我们的发现将为LD积累的生理后遗症提供新的启示，可能 提供干预的治疗途径。