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: 8597358
• 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/8597358
• 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）： 了解慢性高胰岛素状态下 SREBP-1c 及其下游脂肪生成酶靶标的慢性异常调节的机制基础一直是我们实验室的研究重点。具体来说，我们一直在研究大鼠 SREBP-1c 启动子的胰岛素响应顺式作用元件，发现其完全响应需要与 LXR1、NF-Y、Sp1 和 SREBP-1c 本身结合的多个顺式作用位点的参与。作为我们正在进行的研究的逻辑延伸，我们现在建议检查多不饱和脂肪酸（PUFA），特别是n-3 PUFA，减少SREBP-1c转录的分子机制，从而有效减轻胰岛素在高胰岛素状态下诱导脂肪生成酶表达和肝脂质过量产生的作用。为了系统地研究 n-3 PUFA 减轻 SREBP-1c 基因表达诱导的细胞和分子机制，我们提出了一个三管齐下的假设：（i）n-3 PUFA 调节 LXR1 与转录因子（Sp1、SREBP-1c）、共激活因子（SRC-1、CBP）和共阻遏因子（NcoR、 SMRT、HDAC)，(ii) n-3 PUFA 改变 LXR1 内源配体的结合和/或代谢，以及 (iii) 通过胰岛素和 PUFA 调节 SREBP-1c 启动子的完整核因子及其翻译后修饰仍有待定义。对退伍军人医疗保健的潜在影响：在 VA 医疗保健系统内接受医疗保健的退伍军人中，肥胖和二型糖尿病的患病率非常高。伴随这些疾病的血脂异常是动脉粥样硬化性血管疾病的重要危险因素，这种疾病在 VA 人群中也非常普遍。退伍军人群体中肥胖和 II 型糖尿病的血管并发症的综合影响导致退伍军人中显着的发病率和死亡率。此外，提供与这些并发症相关的护理会给 VA 医疗保健系统带来巨大的成本。需要有效的治疗方法来治疗伴随肥胖、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。拟议的研究（例如检查高胰岛素状态下血脂异常的分子机制）将为开发新的有效治疗方法提供所需的信息。 公共卫生相关性： 肥胖和成人发病（II 型）糖尿病都会增加心脏病发作和中风的风险。这些人患心脏病的危险因素包括血糖升高、血压升高、血脂（特别是甘油三酯）水平升高以及“好”胆固醇（HDL）水平降低。我们正在研究胰岛素激素增加超重或患有 II 型糖尿病的个体血液甘油三酯水平的潜在机制。这些人的胰岛素水平很高。我们的假设是，胰岛素通过增加一种称为甾醇调节结合蛋白-1c 或 SREBP-1c 的蛋白质的水平来增加这些个体的脂肪（甘油三酯）的产生。我们正在研究从鱼油中提取的高度不饱和脂肪酸（多不饱和脂肪酸或 PUFA）通过降低 SREBP-1c 水平来减少肝脏脂肪产生的能力。了解 PUFA 如何导致这一现象将有助于对肥胖和 II 型糖尿病患者的高甘油三酯水平进行更有效的治疗，从而降低心脏病发作和中风的风险。