Hyperinsulinemia, mTOR activity and plasma lipoproteins

高胰岛素血症、mTOR 活性和血浆脂蛋白

• 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
• 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

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和VLDL脂质和apoB分泌的影响保持敏感。在与Accili博士的合作研究中，我们发现肝脏胰岛素受体（IR）水平遗传降低的Ldlr-/-小鼠VLDL分泌减少，动脉粥样硬化。然而，在具有功能性LDLR的小鼠中，限制性肝脏胰岛素信号传导也导致LDLR水平降低，表明胰岛素信号传导增加VLDL分泌的能力被LDLR水平增加所抵消。最近的研究表明，通过胰岛素信号传导调节VLDL分泌和LDLR水平可能是通过影响肝脏mTOR活性来介导的。有趣的是，已经发现mTOR信号转导抑制Sort（最近在CAD和LDL水平的GWAS中鉴定的基因）的表达，导致VLDL甘油三酯和apoB分泌增加。初步结果表明，这些影响可能是介导的mTOR诱导的ER压力，导致增加表达的ATF 3，转录抑制排序。相比之下，LDLR的水平似乎受到mTOR下游独特途径的调节，导致Pcsk 9表达降低和LDLR转录后增加。拟议的研究将检验肝脏mTOR信号传导作为整合来自胰岛素和营养因子的信号以调节VLDL分泌和LDLR水平的中心枢纽的假设。将使用最近获得的肝脏特异性敲除调节肝脏mTOR活性的关键分子的小鼠，即Li-Tsc 1 KO（mTOR 1活性增加）和Li-RapKO小鼠（mTOR 1活性降低），对该假设进行检验。与Drs Accili和塔巴斯一起，我们将试图表明影响VLDL分泌和LDLR的胰岛素信号传导的遗传操作作用于mTOR的上游，而ER应激、ATF 3和Sort作用于mTOR的下游以调节VLDL apoB和脂质分泌。与塔巴斯博士一起，我们将分析肥胖和消瘦受试者的肝脏样本，以确定人类是否存在类似的Sort调节。这些研究将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的血脂异常的特征在于VLDL的过度产生，但LDL胆固醇的水平相对正常。然而，对潜在的机制仍然知之甚少。拟议的研究应提供新的见解，在这些条件下的VLDL分泌和LDLR水平的调节。