Novel regulation of insulin action in the liver

肝脏中胰岛素作用的新调节

基本信息

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
项目类别：
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

项目摘要

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.

项目概要胰岛素抵抗和 2 型糖尿病 (T2DM) 给公众健康带来了巨大负担 T2DM 的特点是胰腺引起的相对胰岛素缺乏。代谢器官中的β细胞功能障碍和胰岛素抵抗肝脏在调节全身方面发挥着核心作用。葡萄糖和脂质稳态异常被认为是胰岛素的主要驱动因素。抵抗，其中胰岛素无法充分抑制肝葡萄糖生成（HGP），同时增强脂肪生成和甘油三酯分泌，这种现象被称为选择性胰岛素抵抗。下游信号级联介导胰岛素对葡萄糖和脂质代谢的控制经过广泛研究，胰岛素抵抗及其发展的分子机制我们之前尚未确定对葡萄糖和脂质代谢的不同影响。溶血磷脂酰胆碱酰基转移酶 3 (Lpcat3)（一种磷脂 (PL) 重塑酶）在脂质中的功能 Lpcat3 的损失选择性地减少膜中的多不饱和 PL，导致肝脏代谢减少。膜流动性和曲率的变化导致 SREBP-1c 处理和功能受损。该提案的总体目标是确定肝脏中脂肪生成和甘油三酯分泌的减少。肝脏 Lpcat3 和 PL 组成在胰岛素信号传导和全身脂质和葡萄糖代谢中的作用及其在目标 1 中，我们将阐明 PL 的机制。在目标 2 中，我们将研究 Lpcat3 表达是否失调。介导 T2DM 中的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。这项工作的结果将增进我们对 T2DM 中高血糖和高甘油三酯血症的理解。膜成分如何调节肝脏的胰岛素敏感性和葡萄糖代谢，以及膜的生物物理特性有助于胰岛素抵抗的发病机制。