Anatomical Regulation of Glucose and Lipid Metabolism by Insulin Signaling in Hepatocytes

肝细胞中胰岛素信号传导对葡萄糖和脂质代谢的解剖调节

• 批准号: 10733836
• 负责人: Rongya Tao
• 金额: $ 45.65万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733836
• 关键词: Anatomy; Candidate Disease Gene; Cells; Data; Diet; Drug Targeting; Exhibits; Fasting; Fatty Liver; Follistatin; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Glucose; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Human; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Impairment; Insulin; Insulin Receptor; Insulin Resistance; Investigation; Knock-in Mouse; Lipids; Liver; Lobule; LoxP-flanked allele; Maps; Mediator; Metabolic; Metabolic Control; Metabolism; Methods; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; PIK3CG gene; Pathogenicity; Pathologic; Patients; Physiological; Physiology; Proteins; Regulation; Regulatory Pathway; Role; Signal Transduction; Specificity; Time; Tissues; Variant; Work; blood glucose regulation; diabetic; experimental study; glucose metabolism; glucose production; in vivo; innovation; insight; insulin regulation; insulin sensitivity; insulin signaling; lipid biosynthesis; lipid metabolism; liver metabolism; mouse model; multitask; non-alcoholic fatty liver disease; novel; prevent; programs; promoter; segregation; transcriptomic profiling; transcriptomics

Abstract This application is entitled ‘Anatomical regulation of glucose and lipid metabolism by insulin signaling in hepatocytes’. The liver is a multitasking organ, performing diverse functions that are critical for maintaining glucose and lipid homeostasis. Previous studies of hepatic insulin signaling have been done with the assumption that all hepatocytes are equivalent. Recently single-cell transcriptomics has revealed that around half of hepatocyte genes are expressed in a zoned manner, in which periportal hepatocytes might coordinate fasting metabolism, whereas pericentral hepatocytes might manage postprandial metabolism. A clear understanding of how insulin signaling coordinates energy homeostasis at spatial levels is necessary. This proposal brings our focus to the important problem of how anatomical segregation of insulin signaling in the liver regulates glucose and lipid metabolism in physiological and pathological conditions. By using promoter knock-in mouse models, we will perform the functional study in vivo by using Gls2CreER mouse line to target periportal hepatocytes and Cyp1a2CreER mouse line to target pericentral hepatocytes. This real-time molecular strategy is innovative as previous work that has relied upon static approaches. By intercrossing with floxed mice targeting insulin signaling components, this project has the potential to reveal important insight into the anatomical segregation of insulin signaling in the liver to control energy homeostasis. First, impaired insulin signal transduction in periportal hepatocytes is expected to promote hepatic glucose production but might retain insulin sensitivity in pericentral hepatocytes for lipid metabolism, producing the pathological combination of hyperglycemia and hyperlipidemia. This strategy might provide an innovative model to investigate the metabolic features of insulin resistance in humans. Second, our preliminary data shows that total hepatic insulin signaling deficiency impairs hepatic de novo lipogenesis and prevents diet-induced fatty liver in mice, which contradicts the excess lipogenesis in insulin-resistant humans. Direct investigation of insulin signaling in pericentral hepatocytes can reveal the relationship between insulin resistance and NAFLD. Third, selective insulin resistance has implications for therapy; however, how to precisely target this paradox is still unresolved. It would be desirable to employ drug targets that could alleviate both T2D and NAFLD. Thus, we propose to identify novel candidate genes that contribute to HFD-induced hyperglycemia and hepatic steatosis. Together, the proposed experiments can discern the function of insulin signaling in the regulation of glucose and lipid metabolism in the periportal and pericentral hepatocytes, which would reveal foundational mechanisms coordinated by hepatic insulin action that moderate glucose and lipid metabolism under physiological and pathological conditions.

摘要 这个应用程序的标题是"解剖调节葡萄糖和脂质代谢的胰岛素 肝细胞的信号传导。肝脏是一个多任务的器官，执行各种功能，这些功能对于 维持葡萄糖和脂质的体内平衡。以前对肝脏胰岛素信号传导的研究已经完成， 假设所有肝细胞都是等效的。最近，单细胞转录组学揭示， 大约一半的肝细胞基因以分区的方式表达，其中门静脉周围肝细胞可能 协调空腹代谢，而中央周围肝细胞可能管理餐后代谢。一 清楚地了解胰岛素信号如何在空间水平上协调能量稳态是必要的。 这一建议使我们关注的重要问题，如何解剖隔离胰岛素信号 在生理和病理条件下调节葡萄糖和脂质代谢。通过使用 启动子敲入小鼠模型，我们将通过使用Gls2CreER小鼠系进行体内功能研究， 靶向门静脉周围肝细胞和靶向中央周围肝细胞的Cyp1a2CreER小鼠系。这种实时 分子策略是创新的，因为以前的工作依赖于静态的方法。通过与 floxed小鼠靶向胰岛素信号传导成分，该项目有可能揭示重要的见解， 胰岛素信号在肝脏中的解剖学分离以控制能量稳态。第一，受损的胰岛素 门脉周围肝细胞中的信号转导预期促进肝葡萄糖产生，但可能 在中心周围肝细胞中保持胰岛素敏感性以进行脂质代谢，产生病理性组合 高血糖和高脂血症。这一战略可能提供一个创新的模式，以调查 人类胰岛素抵抗的代谢特征。其次，我们的初步数据显示， 胰岛素信号传导缺陷损害肝脏从头脂肪生成并防止小鼠中饮食诱导的脂肪肝， 这与胰岛素抵抗人群中的过量脂肪生成相矛盾。胰岛素信号转导的直接研究 中心周围肝细胞可以揭示胰岛素抵抗与NAFLD的关系。第三，选择性 胰岛素抵抗对治疗有影响;然而，如何精确地靶向这一矛盾仍然没有解决。 期望采用可以缓解T2D和NAFLD两者的药物靶标。因此，我们建议 鉴定导致HFD诱导的高血糖症和肝脂肪变性的新候选基因。 总之，所提出的实验可以辨别胰岛素信号传导在调节胰岛素分泌中的功能。 门静脉周围和中央周围肝细胞的葡萄糖和脂质代谢，这将揭示基础的 由肝脏胰岛素作用协调的机制，在低血糖下调节葡萄糖和脂质代谢， 生理和病理条件。