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.

摘要 脂质储存是生物体缓冲可用性和需求波动的基本过程， 代谢能脂质主要以中性脂质形式储存，例如三酰基甘油（TG）， 称为脂滴（LDs）的细胞器。在代谢能量过剩的情况下，细胞将碳水化合物 转化为脂肪酸，并将其与膳食脂肪酸一起沿着转化为甘油-3-磷酸以形成TG。 相反，当需要脂肪酸作为代谢燃料或作为膜组分的前体时， TG被水解。细胞是否有脂质储存直接影响它们的生长和分裂能力， 以及它们的生理和输入营养的需要。通过结合无偏见的遗传学和 通过生物化学筛选，我们最近发现MLX转录因子家族的所有成员都定位于 随着LD在细胞中积累，这些转录因子包括MLX及其专性转录因子。 二聚化伴侣，MLXIP/MondoA或MLXIPL/MondoB/ChREBP，其检测葡萄糖衍生物， 是葡萄糖和脂质代谢的关键调节剂。ChREBP的缺乏也与 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靶标响应于葡萄糖的转录应答。 我们将测试这个模型，定义MLX型转录因子靶向的机制和调节， 并阐明这如何调节它们对葡萄糖的反应。 完成这些目标将揭示代谢协调的一个基本方面， 转录控制的新范例。它还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疾病的标志，肥胖是一个流行病问题 比例。我们的研究结果将揭示新的光生理后遗症LD积累，可能 为干预提供治疗途径。