Molecular Mechanisms of Mitigation of Insulin Induction of SREBP-1c by N-3 PUFA

N-3 PUFA 减轻 SREBP-1c 胰岛素诱导的分子机制

• 批准号: 8305416
• 负责人: MARSHALL B ELAM
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305416
• 关键词: ADD-1 protein; Adult; Atherosclerosis; Binding; Binding Sites; Blood; Blood Glucose; Blood Pressure; Blood Vessels; Caring; Chronic; Complement; Complex; Development; Disease; Down-Regulation; Dyslipidemias; Enzymes; Fatty acid glycerol esters; Fish Oils; Gene Expression; Genetic Transcription; Healthcare; Healthcare Systems; Heart Diseases; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; Histone Deacetylase; Hormones; Hydroxycholesterols; Hypertriglyceridemia; Individual; Insulin; LXRalpha protein; Laboratories; Lead; Ligands; Lipids; Liver; Mediating; Metabolic syndrome; Metabolism; Modality; Modification; Molecular; Morbidity - disease rate; Myocardial Infarction; N-3 polyunsaturated fatty acid; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Proteins; Obesity; Overweight; Polyunsaturated Fatty Acids; Population; Post-Translational Protein Processing; Prevalence; Production; Proteins; Rattus; Regulation; Research; Response Elements; Risk; Risk Factors; Sterols; Stroke; Testing; Triglycerides; Unsaturated Fatty Acids; Veterans; base; cis acting element; cost; effective therapy; loss of function; mortality; nuclear receptor coactivator 1; prevent; promoter; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Understanding the mechanistic basis of chronic aberrant regulation of SREBP-1c and its downstream lipogenic enzyme targets in chronic hyperinsulinemic states has been a focus of research in our laboratory. Specifically, we have been studying the insulin-responsive cis-acting elements of the rat SREBP-1c promoter and have found that its full response requires participation of multiple cis-acting sites that bind to LXR1, NF-Y, Sp1 and SREBP-1c itself. As a logical extension of our ongoing studies we now propose to examine the molecular mechanisms by which polyunsaturated fatty acids (PUFA), specifically n-3 PUFA, reduce transcription of SREBP-1c, thereby effectively mitigating the effect of insulin to induce lipogenic enzyme expression and hepatic lipid overproduction in hyperinsulinemic states. To systematically examine the cellular and molecular mechanisms by which n-3 PUFA mitigate induction of SREBP-1c gene expression we propose a three- pronged hypothesis: (i) n-3 PUFA modulate the interaction of LXR1 with transcription factors (Sp1, SREBP- 1c), co-activators (SRC-1, CBP), and co-repressors (NcoR, SMRT, HDAC), (ii) n-3 PUFA alter binding and/or metabolism of endogenous ligands of LXR1 and (iii) the full complement of nuclear factors and their posttranslational modifications that modulate SREBP-1c promoter by insulin and PUFA remain to be defined. POTENTIAL IMPACT ON VETERAN'S HEALTH CARE: The prevalence of obesity and Type II Diabetes is extraordinarily high among veterans receiving health care within the VA Health Care System. The dyslipidemia that accompanies these disorders is a significant risk factor for atherosclerotic vascular disease which is also highly prevalent in the VA population. The combined effects of vascular complications of obesity and Type II Diabetes in the Veteran population results in significant morbidity and mortality among Veterans. Further, providing care related to these complications entails significant cost to the VA Health Care System. Effective treatment modalities for the dyslipidemia that accompanies obesity, Type II Diabetes, and Metabolic Syndrome, primarily hypertriglyceridemia and low HDLC, are needed. Research such as the proposed studies that examines the molecular mechanisms underlying dyslipidemia in hyperinsulinemic states will provide needed information for development of new, effective treatments. PUBLIC HEALTH RELEVANCE: Both obesity and adult onset (Type II) diabetes increase the risk of heart attack and stroke. Risk factors for heart disease in such individuals include increased blood sugar, increased blood pressure, increased levels of blood fat, specifically triglyceride, and decreased levels of "good" cholesterol (HDL). We are studying the underlying mechanisms by which the hormone insulin increases blood triglyceride levels in individuals who are overweight or have type II diabetes. Such individuals have high insulin levels. Our hypothesis is that insulin increases production of fat (triglyceride) in such individuals by increasing levels of a protein called sterol regulatorybinding-protein-1c or SREBP-1c. We are examining the ability of highly unsaturated fatty acids (Polyunsaturated Fatty Acids or PUFA) derived from fish oil to reduce fat production in the liver by decreasing levels of SREBP-1c. Understanding how PUFA causes this will lead to more effective treatments for high triglyceride levels in individuals with obesity and type II diabetes to reduce risk of heart attack and stroke.

描述（由申请人提供）： 了解SREBP-1C的慢性异常调节及其下游脂肪酶靶标在慢性高胰岛素状态状态的机理基础一直是我们实验室研究的重点。具体而言，我们一直在研究大鼠SREBP-1C启动子的胰岛素反应性顺式作用元件，并发现其完整响应需要参与与LXR1，NF-Y，SP1和SREBP-1C结合的多个顺式作用位点本身。作为我们正在进行的研究的逻辑扩展，我们现在建议检查分子机制，通过这些机制，多不饱和脂肪酸（PUFA），特别是N-3 PUFA，减少SREBP-1C的转录，从而有效地降低胰岛素的效果高胰岛素状态中的肝脂质过量产生。为了系统地检查细胞和分子机制，N-3 PUFA减轻SREBP-1C基因表达的诱导诱导我们提出了一个三个提高的假设：（i）N-3 PUFA调节LXR1与转录因子的相互作用（SP1，SREBP-P1，SREBP-P-P1 1C），共激活因子（SRC-1，CBP）和共抑制剂（NCOR，SMRT，HDAC），（ii）N-3 PUFA改变LXR1和（III）内源性配体的结合和/或代谢（iii）通过胰岛素和PUFA调节SREBP-1C启动子的核因素及其翻译后修饰的补充尚待定义。对退伍军人的医疗保健的潜在影响：在VA医疗保健系统内获得医疗保健的退伍军人中，肥胖和II型糖尿病的患病率极高。这些疾病伴随的血脂异常是动脉粥样硬化血管疾病的重要危险因素，在VA人群中也很普遍。肥胖和II型糖尿病血管并发症在退伍军人口中的综合作用导致退伍军人的发病率和死亡率显着。此外，提供与这些并发症相关的护理为VA医疗保健系统带来了巨大的成本。需要对肥胖症，II型糖尿病和代谢综合征（主要是高甘油三酯血症和低HDLC）的血脂异常的有效治疗方法。诸如拟议的研究之类的研究研究了高胰岛素血症状态下血脂异常的分子机制，将为开发新的有效治疗的开发提供所需的信息。 公共卫生相关性： 肥胖和成人发作（II型）糖尿病都会增加心脏病发作和中风的风险。此类个体心脏病的危险因素包括血糖升高，血压升高，血脂水平升高，特异性甘油三酸酯和“好”胆固醇（HDL）的水平降低。我们正在研究激素胰岛素超重或患有II型糖尿病的个体中血液甘油三酸酯水平的潜在机制。这样的个体具有很高的胰岛素水平。我们的假设是，胰岛素通过增加称为固醇调节性蛋白质蛋白1C或SREBP-1C的蛋白质水平来增加此类个体中脂肪（甘油三酸酯）的产生。我们正在研究高度不饱和脂肪酸（多不饱和脂肪酸或PUFA），该能力通过降低SREBP-1C的水平来降低肝脏的脂肪产生。了解PUFA如何导致这将导致对肥胖症和II型糖尿病患者高甘油三酸酯水平的更有效治疗，以降低心脏病发作和中风的风险。