Novel regulation of insulin action in the liver

肝脏中胰岛素作用的新调节

• 批准号: 10549322
• 负责人: Bo Wang
• 金额: $ 33.4万
• 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/10549322
• 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; 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; biophysical properties; blood glucose regulation; diet-induced obesity; enzyme activity; fibroblast growth factor 21; 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.

项目摘要 胰岛素抵抗和2型糖尿病（T2DM）已向公共卫生和 经济越来越多。 T2DM的特征是胰腺引起的相对胰岛素缺乏症 代谢器官中的β细胞功能障碍和胰岛素抵抗。肝脏在调节系统性方面起着核心作用 葡萄糖和脂质稳态。异常的肝胰岛素作用被认为是胰岛素的主要驱动力 胰岛素无法充分抑制肝葡萄糖产生（HGP），而增强 脂肪生成和甘油三酸酯分泌，这种现象称为选择性胰岛素抵抗。虽然 下游信号传导级联介导胰岛素对葡萄糖和脂质代谢的控制已是 广泛研究了胰岛素耐药性及其发展的分子机制及 对葡萄糖和脂质代谢的差异作用尚不清楚。我们以前已经确定了关键 脂质磷脂酰胆碱酰基转移酶3（LPCAT3），一种磷脂（PL）重塑酶的功能，在脂质中 肝脏中的代谢。 LPCAT3的损失有选择地降低膜中的多不饱和PL，导致精制 膜的流动性和曲率。膜动力学的变化导致SREBP-1C处理受损和 脂肪生成，减少肝脏中的甘油三酸酯分泌。该提议的总体目标是定义 胰岛素信号传导以及全身脂质和葡萄糖代谢中的Hepati LPCAT3和PL组成及其 对胰岛素抵抗发展的贡献。在AIM 1中，我们将阐明PL的机制 组成调节胰岛素敏感性。在AIM 2中，我们将研究LPCAT3表达的失调是否失调 介导T2DM中的选择性胰岛素抵抗。在AIM 3中，我们将测试靶向LPCAT3的治疗潜力 用于T2DM中的高血糖和高甘油三酯血症。这项工作的结果将提高我们对 膜组成如何调节肝脏中的胰岛素敏感性和葡萄糖代谢，以及如何变化 膜生物物理特性有助于胰岛素抵抗的发病机理。