Novel regulation of insulin action in the liver

项目摘要 胰岛素抵抗和2型糖尿病（T2 DM）已经给公共卫生带来了巨大的负担， 经济日益繁荣。2型糖尿病的特征是胰腺引起的相对胰岛素缺乏， 代谢器官中β细胞功能障碍与胰岛素抵抗。肝脏在调节全身性 葡萄糖和脂质体内平衡。异常的肝脏胰岛素作用被认为是胰岛素的主要驱动力 胰岛素抵抗，其中胰岛素不能充分抑制肝葡萄糖产生（HGP），而增强 脂肪生成和甘油三酯分泌，这是一种称为选择性胰岛素抵抗的现象。虽然 调节胰岛素对葡萄糖和脂质代谢的控制的下游信号级联已经被 广泛研究，胰岛素抵抗及其发展的分子机制， 对葡萄糖和脂质代谢不同影响还不清楚。我们之前已经确定了 溶血磷脂酰胆碱酰基转移酶3（Lpcat 3），一种磷脂（PL）重塑酶，在脂质 肝脏代谢。Lpcat 3的损失选择性地减少膜中的多不饱和PL，导致膜中的多不饱和PL减少。 膜流动性和曲率。膜动力学的变化导致SREBP-1c加工受损， 脂肪生成，并减少肝脏中的甘油三酯分泌。本提案的总体目标是界定以下机构的作用： 胰岛素信号传导和全身性脂质和葡萄糖代谢中肝Lpcat 3和PL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 组合物调节胰岛素敏感性。在目标2中，我们将研究Lpcat 3表达的失调是否 介导T2 DM中的选择性胰岛素抵抗。在目标3中，我们将测试靶向Lpcat 3的治疗潜力。 用于T2 DM的高血糖和高甘油三酯血症。这项工作的结果将促进我们对 膜组成如何调节肝脏中胰岛素敏感性和葡萄糖代谢， 膜的生物物理性质有助于胰岛素抵抗的发病机理。

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.