Novel regulation of insulin action in the liver

肝脏中胰岛素作用的新调节

• 批准号: 10365731
• 负责人: Bo Wang
• 金额: $ 42.48万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365731
• 关键词: ADD-1 protein; Acute; Acyltransferase; Affect; Antisense Oligonucleotides; Binding; Binding Proteins; Biochemical; Biological; Cell membrane; Cells; Data; Development; Endocytosis; Energy Metabolism; Enzymes; FGF21 gene; Feedback; Functional disorder; Glucose; Goals; Hepatic; High Fat Diet; Homeostasis; Hormones; Hyperglycemia; Hypertriglyceridemia; Impairment; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Insulin deficiency; Intervention; Knock-out; Light; Lipids; Liver; Lysophosphatidylcholines; Lysophospholipids; Measures; Mediating; Membrane; Membrane Fluidity; Metabolic; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obese Mice; Organ; Pathogenesis; Peroxisome Proliferator-Activated Receptors; Phospholipids; Physiology; Play; Polyunsaturated Fatty Acids; Prevalence; Public Health; Regulation; Research; Role; Series; Signal Transduction; Site; Structure of beta Cell of islet; Testing; Thermogenesis; Triglycerides; Very low density lipoprotein; Work; base; biophysical properties; blood glucose regulation; diet-induced obesity; enzyme activity; fluidity; glucose metabolism; glucose production; glucose tolerance; glucose uptake; improved; insulin regulation; insulin sensitivity; insulin signaling; lipid biosynthesis; lipid metabolism; microscopic imaging; novel; novel therapeutic intervention; overexpression; therapeutic evaluation

PROJECT SUMMARY Insulin resistance and type 2 diabetes mellitus (T2DM) have presented an enormous burden to public health and economy with increasing prevalence. T2DM is characterized by relative insulin deficiency caused by pancreas β cells dysfunction and insulin resistance in metabolic organs. The liver plays a central role in regulating systemic glucose and lipid homeostasis. Aberrant hepatic insulin action is believed to be a primary driver of insulin resistance, in which insulin fails to adequately suppress hepatic glucose production (HGP), while enhances lipogenesis and triglyceride secretion, a phenomenon referred to as selective insulin resistance. Although downstream signaling cascades mediating insulin's control of glucose and lipid metabolism have been extensively studied, the molecular mechanisms underlying the development of insulin resistance and its differential effect on glucose and lipid metabolism are not well understood. We previously have identified critical functions of lysophosphatidylcholine acyltransferase 3 (Lpcat3), a phospholipid (PL) remodeling enzyme, in lipid metabolism in liver. Loss of Lpcat3 selectively reduces polyunsaturated PL in membranes, leading to decreased membrane fluidity and curvature. Changes in membrane dynamics result in impaired SREBP-1c processing and lipogenesis, and reduced triglyceride secretion in liver. The overall goal of this proposal is to define the roles of hepatic Lpcat3 and PL composition in insulin signaling and systemic lipid and glucose metabolism, and their contribution to the development of insulin resistance. In Aim 1, we will elucidate the mechanisms by which PL composition regulates insulin sensitivity. In Aim 2, we will investigate whether dysregulation of Lpcat3 expression mediates selective insulin resistance in T2DM. In Aim 3, we will test the therapeutic potential of targeting Lpcat3 for hyperglycemia and hypertriglyceridemia in T2DM. The results of this work will advance our understanding of how membrane composition modulates insulin sensitivity and glucose metabolism in liver, and how changes in membrane biophysical properties contribute to the pathogenesis of insulin resistance.

项目总结 胰岛素抵抗和2型糖尿病(T2 DM)给公众健康和 日益盛行的经济。2型糖尿病的特点是胰腺引起的相对胰岛素缺乏。 β细胞功能障碍与代谢器官的胰岛素抵抗。肝脏在全身调节中起着核心作用。 糖和脂的动态平衡。肝脏胰岛素的异常作用被认为是胰岛素的主要驱动因素 抵抗，即胰岛素不能充分抑制肝糖生成(HGP)，而增强 脂肪生成和甘油三酯分泌，这一现象称为选择性胰岛素抵抗。虽然 介导胰岛素控制糖脂代谢的下游信号级联反应一直是 胰岛素抵抗发生的分子机制及其影响因素的研究进展 对糖和脂代谢的不同影响还不清楚。我们之前已经确定了关键的 磷脂重塑酶溶血磷脂酰基转移酶3(Lpcat3)在脂质中的作用 肝脏的新陈代谢。Lpcat3的丢失选择性地减少了膜中的多不饱和PL，导致减少 膜的流动性和曲率。膜动力学的变化导致SREBP-1c加工受损和 脂肪生成，并减少肝脏甘油三酯的分泌。该提案的总体目标是定义 肝脏Lpcat3和PL在胰岛素信号转导和全身脂、糖代谢中的组成及其 对胰岛素抵抗的发展有贡献。在目标1中，我们将阐明PL的机制 成分调节胰岛素敏感性。在目标2中，我们将研究Lpcat3表达的失调 介导T2 DM患者选择性胰岛素抵抗。在目标3中，我们将测试靶向Lpcat3的治疗潜力 适用于2型糖尿病患者的高血糖、高甘油三酯血症。这项工作的成果将促进我们对 膜成分如何调节肝脏的胰岛素敏感性和葡萄糖代谢，以及如何改变 膜生物物理特性参与了胰岛素抵抗的发病机制。