Regulation of SREBP-1c Processing by Insulin and Cyclic-AMP

胰岛素和环磷酸腺苷对 SREBP-1c 加工的调节

基本信息

批准号：
7259573
负责人：
MARSHALL B ELAM
金额：
$ 26.83万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7259573
关键词：
1-Phosphatidylinositol 3-Kinase ADD-1 protein Abbreviations Acyl Coenzyme A Acyltransferase Address Animals Binding Proteins Bucladesine COPII-Coated Vesicles Cell Nucleus Cell membrane Ceramides Cholesterol Chronic Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Dyslipidemias Elements Enzymes Equilibrium Fatty acid glycerol esters Fatty-acid synthase Figs - dietary Functional disorder Genes Genetic Transcription Genetic Translation Glucagon Glycogen Glycogen Synthase Kinase 3 Goals Golgi Apparatus Hepatic Hepatocyte Hour Hyperinsulinism Hyperlipidemia In Vitro Insulin Integral Membrane Protein Length Lipids Lipoproteins Liver Localized MAP Kinase Gene MEKs Marshal Mediating Membrane Membrane Proteins Metabolic Metabolic syndrome Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases Modification Molecular Chaperones Myocardial Infarction N-terminal Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity PD-98059 Pathogenesis Pathway interactions Phosphatidylinositide 3-Kinase Inhibitor Phosphatidylinositols Phosphorylation Phosphotransferases Plasma Polyunsaturated Fatty Acids Post-Translational Regulation Process Protein Isoforms Protein Kinase C Proteins Proteolytic Processing Rattus Regulation Regulatory Element Research Research Personnel Risk Role SCAP protein SRE-2 binding protein SREBP-1a Signal Pathway Site Sphingolipids Sphingomyelinase Sterol O-Acyltransferase Sterols Stroke Testing Triglycerides Up-Regulation Very low density lipoprotein Vesicle base genetic regulatory protein in vivo in vivo Model inhibitor/antagonist inorganic phosphate lipid biosynthesis novel novel therapeutics particle prevent programs promoter protein kinase A kinase response sterol esterase therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): The chronic hyperinsulinemia that accompanies obesity, metabolic syndrome, and type II diabetes mellitus sustains increased hepatic lipogenesis via transcriptional upregulation of lipogenic enzymes. This results in overproduction of VLDL by the liver with resulting accumulation of atherogenic triglyceride-rich lipoproteins in the plasma. Induction of lipogenesis by insulin is mediated by sterol regulatory element binding protein-1c (SREBP-1c) via transcriptional upregulation. SREBP-1c is synthesized as an integral membrane protein localized in the ER where it is associated with its chaperone (SCAP) and regulatory proteins (Insig2, Sec24). We have found that, in addition to promoting transcription of nascent SREBP-1c, insulin also stimulates transport of the SREBP-SCAP complex to the golgi where it undergoes proteolytic cleavage to release the transcriptionally active N-terminal fragment of SREBP-1c (SREBP-1c processing), thereby amplifying the transcriptional effects of insulin. Conversely, cAMP (a surrogate for glucagon) prevents processing of SREBP-1c. Thus, processing of SREBP-1c is a novel and potentially important additional level by which insulin and other factors regulate this pivotal transcription factor. Although the mechanisms by which processing of the cholesterol regulating isoform, SREBP-2, by sterol balance have been extensively studied, little is known about regulation of SREBP-1c processing by insulin and cAMP. We have also found that nascent SREBP-1c is phosphorylated in the presence of insulin via MAPK and PI-3K dependent pathways. Inhibitors of these pathways prevent both phosphorylation of SREBP-1c and insulin induced processing indicating that phosphorylation of SREBP-1c (and possibly of other participating proteins) may mediate the effect of insulin on processing. We therefore propose to delineate the mechanism(s) by which insulin and cAMP regulate proteolytic processing of SREBP-1c by identifying (1) the sites on SREBP-1c that are phosphorylated by insulin, (2) the signaling pathways that mediate the effect of insulin to stimulate and cAMP to inhibit processing, and (3) the functional significance of phosphorylation for regulation of SREBP-1c processing. We will also determine the additional roles of regulation of ER membrane cholesterol content and Insig2 expression by insulin in SREBP-1c processing. These studies will be carried out both in vitro in primary rat hepatocytes and in an in vivo model of hyperinsulinemia, the corpulent JCR:LA-cp rat. Relevance: in obesity, metabolic syndrome, and adult-onset diabetes mellitus, high insulin levels promote formation of fat (triglyceride) by the liver. The resulting elevated levels of triglyceride in the plasma increase the risk of heart attack and stroke. This research examines the role of an important regulatory protein, SREBP-1c in the response of the liver to high insulin levels. The goal of this research is to identify new treatments for hyperlipidemia by understanding the mechanisms by which insulin regulates this protein.

描述（由申请人提供）：伴随肥胖症，代谢综合征和II型糖尿病伴随的慢性高胰岛素血症，通过脂肪酶的转录上调，增加了肝脂肪生成。这会导致肝脏过量生产VLDL，导致血浆中富含动脉粥样硬糖甘油三酸酯的脂蛋白的积累。胰岛素诱导脂肪生成是由固醇调节元素结合蛋白1C（SREBP-1C）通过转录上调介导的。 SREBP-1C合成为与其伴侣（SCAP）和调节蛋白相关的ER中的整合膜蛋白（Insig2，sec24）。我们发现，除了促进新生SREBP-1C的转录外，胰岛素还刺激了Srebp-SCAP复合物向高尔基体的转运，在那里它经历了蛋白水解裂解以释放Srebp-1c的转录活性N末端片段（Srebp-P-1C） 1C处理），从而扩增胰岛素的转录作用。相反，CAMP（胰高血糖素的代理）可防止SREBP-1C的处理。因此，SREBP-1C的处理是一种新颖且潜在的额外水平，胰岛素和其他因素调节该关键转录因子。尽管已经对固醇平衡的胆固醇调节同工型SREBP-2的处理的机制进行了广泛的研究，但人们对通过胰岛素和CAMP对SREBP-1C加工的调节鲜为人知。我们还发现，在通过MAPK和PI-3K依赖途径的胰岛素存在下，新生的SREBP-1C被磷酸化。这些途径的抑制剂可以防止SREBP-1C和胰岛素诱导的加工磷酸化，表明SREBP-1C的磷酸化（可能是其他参与蛋白）可以介导胰岛素对加工的作用。因此，我们建议描述胰岛素和cAMP通过识别（1）SREBP-1C上的位点通过胰岛素磷酸化的位点来调节SREBP-1C的蛋白水解处理的机制，（2）介导介导的信号传导途径介导介导的信号传导途径胰岛素刺激和扎营以抑制加工，以及（3）磷酸化对SREBP-1C加工调节的功能意义。我们还将确定胰岛素在SREBP-1C加工中的ER膜胆固醇含量和INIG2表达的调节的其他作用。这些研究将在原发性大鼠肝细胞和高胰岛素血症的体内模型（肥胖的JCR：LA-CP大鼠）中进行体外进行。相关性：在肥胖，代谢综合征和成年糖尿病中，高胰岛素水平促进肝脏促进脂肪（甘油三酸酯）的形成。血浆中甘油三酸酯水平的升高增加了心脏病发作和中风的风险。这项研究研究了重要的调节蛋白SREBP-1C在肝脏对高胰岛素水平的反应中的作用。这项研究的目的是通过了解胰岛素调节该蛋白质的机制来鉴定高脂血症的新疗法。