Lipid Droplets and Transcriptional Regulation of Metabolism

脂滴和代谢的转录调控

• 批准号: 10356853
• 负责人: ROBERT V FARESE
• 金额: $ 47万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 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 2022-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356853
• 关键词: Attenuated; Binding; Biochemical; Buffers; Carbohydrates; Cells; Cellular Metabolic Process; Cellular biology; Data; Dietary Fatty Acid; Dimerization; Family; Fatty Acids; Gene Expression; Genetic; Genetic Transcription; Glucose; Health; Hepatocyte; Homeostasis; Human; Intervention; Knowledge; Light; 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; base; 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获得性和需要的波动的基本过程 新陈代谢能量。脂类主要以中性脂的形式储存，如三酰甘油(TGS)，在 细胞器称为脂滴(LDS)。在代谢能量过剩的情况下，细胞将碳水化合物 将脂肪酸与饮食中的脂肪酸一起酯化成甘油-3-磷酸，形成甘油三酯。 相反，当脂肪酸需要作为代谢燃料或作为膜组件的前体时， TGS被水解。细胞是否有脂肪储存直接影响它们的生长和分裂能力， 以及他们的生理和需要进口的营养。通过不偏不倚的基因和 生化筛查，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在细胞中的积累，LD表面也会发生变化。这些转录因子包括MLX及其专一性 二聚体伙伴，MLXIP/Mondoa或MLXIPL/MondoB/ChREBP，它们检测葡萄糖衍生物和 是糖和脂代谢的关键调节者。ChREBP的缺乏也与 发育障碍威廉姆斯-博伦综合征和代谢综合征的特征。 基于大量的初步数据，我们建议了一个模型，在该模型中，LDS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，定义MLX型转录因子靶向于 并阐明这一点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，通过一个迷人的， 转录控制的新范例。它还可能对人类健康产生重要影响。 LDS的过度积累是与肥胖有关的代谢性疾病的标志，这是一个大流行的问题 比例。我们的发现将为研究LD积聚的生理后遗症提供新的线索，可能 为干预提供治疗途径。