Hyperinsulinemia, mTOR activity and plasma lipoproteins

高胰岛素血症、mTOR 活性和血浆脂蛋白

基本信息

批准号：
8275590
负责人：
ALAN richard TALL
金额：
$ 38.63万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-16 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8275590
关键词：
Adenoviruses Affect Albumins Alleles Apolipoprotein E Apolipoproteins B Apoptosis Atherosclerosis Cell Line Complication Diet Dyslipidemias Fatty acid glycerol esters Figs - dietary Foam Cells Genes Genetic Glucose Hepatic Hepatocyte Human Hyperinsulinism Insulin Insulin Receptor Insulin Resistance Insulin Signaling Pathway LDL Cholesterol Lipoproteins Leptin Link Lipids Lipoproteins Liver Low-Density Lipoproteins Maps Mediating Metabolic syndrome Minor Modeling Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Nutritional Obesity Pathway interactions Plasma Production Proto-Oncogene Proteins c-akt Raptors Regulation Repression Risk Role Sampling Signal Transduction Sirolimus Sorting - Cell Movement Stimulus Stress Testing Transcription Repressor/Corepressor Up-Regulation Very low density lipoprotein atherogenesis cytokine feeding genetic manipulation genome wide association study human FRAP1 protein inhibitor/antagonist insight insulin signaling lipid biosynthesis macrophage promoter research study response very low density lipoprotein triglyceride

项目摘要

DESCRIPTION (provided by applicant): In Type 2 diabetes and metabolic syndrome, the liver appears to remain sensitive to the effects of insulin on lipogenesis and VLDL lipid and apoB secretion. In collaborative studies with Dr Accili, we showed that Ldlr-/- mice with genetically reduced levels of insulin receptors (IRs) in liver had decreased VLDL secretion and atherosclerosis. However, in mice with functioning LDLRs, restricted hepatic insulin signaling also led to diminished LDLR levels, indicating that the ability of insulin signaling to increase VLDL secretion is offset by an increase in LDLR levels. Recent studies have shown that the regulation of VLDL secretion and LDLR levels by insulin signaling may be mediated via effects on hepatic mTOR activity. Interestingly, mTOR signaling has been found to repress expression of Sort (a gene recently identified in GWAS of CAD and LDL levels), leading to increased VLDL triglyceride and apoB secretion. Preliminary results indicate that these effects may be mediated by mTOR-induced ER stress, leading to increased expression of ATF3, a transcriptional repressor of Sort. In contrast, the levels of LDLR appear to be regulated by a distinctive pathway downstream of mTOR that leads to decreased expression of Pcsk9 and a post-transcriptional increase in LDLR. The proposed studies will test the hypothesis that hepatic mTOR signaling acts as a central hub integrating signals from insulin and nutritional factors to regulate VLDL secretion and LDLR levels. This hypothesis will be tested using recently available mice with liver-specific knock-outs of key molecules regulating hepatic mTOR activity i.e. Li-Tsc1KO (increased mTOR1 activity) and Li-RapKO mice (reduced mTOR1 activity). With Drs Accili and Tabas, we will seek to show that genetic manipulations of insulin signaling that affect VLDL secretion and LDLR act upstream of mTOR, while ER stress, ATF3 and Sort act downstream of mTOR to regulate VLDL apoB and lipid secretion. With Dr Tabas, we will analyze liver samples from obese and lean subjects to determine if similar regulation of Sort occurs in humans. These studies should provide new insights into the regulation of VLDL secretion and LDLR levels in subjects with obesity and hyperinsulinemia. PUBLIC HEALTH RELEVANCE: The dyslipidemia of Type 2 diabetes and metabolic syndrome is characterized by excessive production of VLDL but relatively normal levels of LDL cholesterol. However, the underlying mechanisms have remained poorly understood. The proposed studies should provide new insights into the regulation of VLDL secretion and LDLR levels in these conditions.

描述（由申请人提供）：在2型糖尿病和代谢综合征中，肝脏似乎对胰岛素对脂肪生成以及VLDL脂质和apoB分泌的影响仍然敏感。在与 Accili 博士的合作研究中，我们发现，肝脏中胰岛素受体 (IR) 水平基因降低的 Ldlr-/- 小鼠，VLDL 分泌减少，动脉粥样硬化也减少。然而，在具有功能性 LDLR 的小鼠中，肝脏胰岛素信号传导受限也导致 LDLR 水平降低，这表明胰岛素信号传导增加 VLDL 分泌的能力被 LDLR 水平的增加所抵消。最近的研究表明，胰岛素信号对 VLDL 分泌和 LDLR 水平的调节可能是通过影响肝脏 mTOR 活性来介导的。有趣的是，mTOR 信号传导被发现可以抑制 Sort（最近在 CAD 和 LDL 水平的 GWAS 中发现的一种基因）的表达，导致 VLDL 甘油三酯和 apoB 分泌增加。初步结果表明，这些效应可能是由 mTOR 诱导的 ER 应激介导的，导致 ATF3（一种转录抑制因子）的表达增加。相比之下，LDLR 的水平似乎受到 mTOR 下游独特途径的调节，该途径导致 Pcsk9 表达降低和 LDLR 转录后增加。拟议的研究将检验以下假设：肝脏 mTOR 信号传导作为整合来自胰岛素和营养因子的信号来调节 VLDL 分泌和 LDLR 水平的中枢。这一假设将使用最近获得的小鼠进行测试，这些小鼠肝脏特异性敲除调节肝脏 mTOR 活性的关键分子，即 Li-Tsc1KO（mTOR1 活性增加）和 Li-RapKO 小鼠（mTOR1 活性降低）。我们将与 Accili 和 Tabas 博士一起，力图证明影响 VLDL 分泌和 LDLR 的胰岛素信号传导的基因操作作用于 mTOR 的上游，而 ER 应激、ATF3 和 Sort 则作用于 mTOR 的下游，以调节 VLDL apoB 和脂质分泌。我们将与塔巴斯博士一起分析肥胖和瘦受试者的肝脏样本，以确定类似的 Sort 调节是否发生在人类身上。这些研究应该为肥胖和高胰岛素血症受试者的 VLDL 分泌和 LDLR 水平的调节提供新的见解。公共卫生相关性：2 型糖尿病和代谢综合征引起的血脂异常的特点是 VLDL 生成过多，但 LDL 胆固醇水平相对正常。然而，人们对潜在的机制仍然知之甚少。拟议的研究应该为这些条件下 VLDL 分泌和 LDLR 水平的调节提供新的见解。