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(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极低密度脂蛋白脂质和载脂蛋白B分泌的影响保持敏感。在与Accili博士的合作研究中，我们发现肝脏中胰岛素受体(IRS)水平遗传降低的Ldlr-/-小鼠VLDL分泌减少，并出现动脉粥样硬化。然而，在低密度脂蛋白受体功能正常的小鼠中，限制肝脏胰岛素信号也会导致低密度脂蛋白受体水平降低，这表明胰岛素信号增加极低密度脂蛋白分泌的能力被低密度脂蛋白受体水平增加所抵消。最近的研究表明，胰岛素信号对极低密度脂蛋白分泌和低密度脂蛋白受体水平的调节可能是通过影响肝脏mTOR活性来实现的。有趣的是，mTOR信号已被发现抑制Sort(一种最近在冠心病和低密度脂蛋白水平的GWA中发现的基因)的表达，导致极低密度脂蛋白甘油三酯和载脂蛋白B分泌增加。初步结果表明，这些效应可能是由mTOR诱导的内质网应激，导致转录抑制因子ATF3表达增加所介导的。相反，LDLR的水平似乎受到mTOR下游一条独特的途径的调节，该途径导致PCSK9表达减少，LDLR转录后增加。拟议的研究将检验这样一种假设，即肝脏mTOR信号作为中心枢纽，整合来自胰岛素和营养因素的信号，以调节极低密度脂蛋白的分泌和LDLR水平。这一假设将在最近获得的具有肝脏特异性地敲除调节肝脏mTOR活性的关键分子的小鼠身上进行验证，即Li-Tsc1KO(mTOR1活性增加)和Li-RapKO小鼠(mTOR1活性降低)。通过DRS Accili和Tabas，我们将试图证明影响VLDL分泌和LDLR的胰岛素信号的遗传操作作用于mTOR的上游，而ER应激、ATF3和Sort作用于mTOR的下游，调节VLDL apoB和脂质的分泌。在塔巴斯博士的帮助下，我们将分析肥胖和瘦身受试者的肝脏样本，以确定人类是否也存在类似的调节。这些研究将为肥胖和高胰岛素血症患者的极低密度脂蛋白分泌和低密度脂蛋白受体水平的调节提供新的见解。 与公共卫生相关：2型糖尿病和代谢综合征的血脂异常的特点是极低密度脂蛋白产生过多，但低密度脂蛋白胆固醇水平相对正常。然而，人们对其潜在机制仍知之甚少。拟议的研究应该为在这些条件下调节极低密度脂蛋白分泌和低密度脂蛋白受体水平提供新的见解。