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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、代谢综合征和II型糖尿病的慢性高胰岛素血症通过脂肪生成酶的转录上调维持肝脏脂肪生成的增加。这导致肝脏产生过量的VLDL，导致血浆中积累致动脉粥样硬化的富含甘油三酯的脂蛋白。胰岛素诱导的脂肪生成是由甾醇调节元件结合蛋白1c （SREBP-1c）通过转录上调介导的。SREBP-1c是作为一种定位于内质网的完整膜蛋白合成的，它与其伴侣蛋白（SCAP）和调节蛋白（Insig2, Sec24）相关。我们发现，除了促进新生SREBP-1c的转录外，胰岛素还刺激SREBP-SCAP复合物转运到高尔基体，在高尔基体中进行蛋白水解裂解，释放SREBP-1c的转录活性n端片段（SREBP-1c加工），从而放大胰岛素的转录作用。相反，cAMP（胰高血糖素的替代物）阻止SREBP-1c的加工。因此，SREBP-1c的加工是胰岛素和其他因子调节这一关键转录因子的一个新的、潜在重要的额外水平。尽管胆固醇调节异构体SREBP-2通过固醇平衡加工的机制已被广泛研究，但胰岛素和cAMP对SREBP-1c加工的调节知之甚少。我们还发现新生的SREBP-1c在胰岛素存在下通过MAPK和PI-3K依赖途径被磷酸化。这些途径的抑制剂可阻止SREBP-1c的磷酸化和胰岛素诱导的加工，这表明SREBP-1c的磷酸化（可能还有其他参与蛋白）可能介导胰岛素对加工的影响。因此，我们建议通过确定(1)SREBP-1c上被胰岛素磷酸化的位点，(2)介导胰岛素刺激和cAMP抑制作用的信号通路，以及(3)磷酸化对SREBP-1c加工调节的功能意义，来描述胰岛素和cAMP调节SREBP-1c蛋白水解加工的机制。我们还将确定胰岛素调节ER膜胆固醇含量和Insig2表达在SREBP-1c加工中的其他作用。这些研究将在体外原代大鼠肝细胞和体内高胰岛素血症模型（肥胖的JCR:LA-cp大鼠）中进行。相关性：在肥胖、代谢综合征和成人发病的糖尿病中，高胰岛素水平促进肝脏形成脂肪（甘油三酯）。由此导致的血浆中甘油三酯水平升高会增加心脏病发作和中风的风险。本研究探讨了一种重要的调节蛋白SREBP-1c在肝脏对高胰岛素水平的反应中的作用。本研究的目的是通过了解胰岛素调节该蛋白的机制来确定高脂血症的新治疗方法。