Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA

杂酚油布什衍生的 NDGA 的降血脂作用

• 批准号: 7602882
• 负责人: Salman Azhar
• 金额: $ 35.8万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602882
• 关键词: Adult; Affect; Animals; Antiatherogenic; Apolipoproteins B; Atherogenic Diet; Attenuated; Biochemical; Biological Assay; Blood Glucose; Blood Pressure; Body Weight decreased; Cardiovascular Diseases; Cell model; Central obesity; Cholelithiasis; Cholesterol; Clinical; Combined Modality Therapy; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Drug Combinations; Dyslipidemias; Electrophoretic Mobility Shift Assay; Enzymes; Epidemic; Event; FABP1 gene; Fatty Acids; Follow-Up Studies; Fructose; Glucose; Glucose Intolerance; Goals; Gout; Health; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; Hyperlipidemia; Hypertension; In Vitro; Incidence; Individual; Infertility; Inflammatory; Insulin Resistance; Intervention; Kidney Diseases; Laboratories; Laboratory Study; Larrea; Lead; Life Style; Lipids; Lipoxygenase; Lipoxygenase Inhibitors; Liver; Liver diseases; Low-Density Lipoproteins; Malignant Neoplasms; Measurement; Mediating; Mediator of activation protein; Medical; Mental disorders; Messenger RNA; Metabolic; Metabolic syndrome; Mitochondria; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nordihydroguaiaretic Acid; Nuclear; Nuclear Receptors; Obesity; Ovarian; Pharmaceutical Preparations; Physical activity; Plants; Plasma; Population; Prevalence; Production; Proteins; Rattus; Reporter; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Rodent Model; Role; Syndrome; Techniques; Testing; Therapeutic Agents; Transactivation; Transgenic Mice; Triglycerides; United States; Very low density lipoprotein; Western Blotting; Work; aminoglycoside N1-acetyltransferase; attenuation; blood lipid; cardiovascular disorder risk; coping; diabetes risk; fatty acid-transport protein; feeding; improved; in vivo; insulin sensitivity; lipid biosynthesis; lipid metabolism; mortality; non-alcoholic fatty liver; overexpression; oxidation; particle; public health relevance; tool; transcription factor; uptake; very low density lipoprotein triglyceride

DESCRIPTION (provided by applicant): The metabolic syndrome has emerged as a constellation of risk factors that markedly increase the risk of diabetes and cardiovascular disease. The metabolic syndrome consists of central obesity, atherogenic dyslipidemia, elevations of blood pressure and plasma glucose, and prothrombotic and pro-inflammatory states. It increases the risk for cardiovascular disease by 2-fold and raises the risk for type 2 diabetes by approximately 5-fold. As the prevalence of obesity and diabetes is rising at an alarming rate, the incidence of this morbid syndrome is expected to continue to grow both in the United States and worldwide, and thus, there is a greater need for the development of new safe and effective combinations of drugs, more efficacious drugs as well as multifunctional drugs that can be used as valuable clinical tools in the management of individual components of this syndrome. Previous studies from this laboratory have shown that the desert plant, Larrea tridentata (Creosote Bush) derived nordihydroguaiaretic Acid (NDGA), a potent lipoxygenase (LO) inhibitor, has profound effects on multiple components of the metabolic syndrome including lowering of blood glucose, free fatty acids (FFA) and triglyceride levels, attenuation of elevated blood pressure and improvement in insulin sensitivity in several rodent models of insulin resistance, type 2 diabetes, dyslipidemia and hypertension. The overall goal of this project is to elucidate the molecular mechanism by which NDGA exerts its hypolipidemic action in the liver. The central hypothesis is that NDGA exerts its hypolipidemic actions by altering the activity of key lipid-sensitive nuclear transcription factors, which, in turn, improve hepatic lipid metabolism, particularly through an inhibition of hepatic lipogenesis and increased channeling of fatty acids toward oxidation, all of which severely curtail the supply of fatty acids needed for triglyceride (TG) synthesis, TG storage and VLDL-TG production/ secretion. Additionally, NDGA may also directly impact VLDL-TG production, assembly and secretion. To test these hypotheses three specific aims are proposed. Aim 1 will characterize the effects of NDGA on molecular, biochemical and metabolic events associated with hepatic fatty acid uptake and oxidation in animal and cell models of hyperlipidemia. Aim 2 will determine the mechanism of inhibitory action of NDGA on hepatic de novo lipogenesis (DNL). Aim 3 will evaluate the effects of NDGA on hepatic VLDL-TG production, assembly and secretion. A greater understanding of the molecular mechanism(s) by which NDGA exerts its hypolipidemic action is likely to provide important clues which eventually may lead to the development of NDGA (or its derivative(s)) as a new, effective therapeutic agent in the management of dyslipidemia and possibly other central components of the metabolic syndrome. PUBLIC HEALTH RELEVANCE: Metabolic syndrome has emerged as a constellation of risk factors that markedly increase the risk of type 2 diabetes and cardiovascular disease (CVD). Because the prevalence of diabetes and obesity is rising at an alarming rate, the incidence of this morbid syndrome is expected to continue to grow both in the United States and worldwide, and thus, there is a greater need for the development of new safe and effective combinations of drugs, more efficacious drugs as well as multifunctional drugs that can be used as valuable clinical tools in the management of this syndrome. The goal of this project is to elucidate the molecular mechanism by which NDGA lowers elevated blood lipids by improving the lipid metabolism in the liver. A greater understanding of the molecular mechanism(s) by which NDGA exerts its hypolipidemic action is likely to provide important clues which eventually may lead to the development of NDGA (or some form of its derivative) as a new, effective therapeutic agent in the management of dyslipidemia and possibly other central components of the metabolic syndrome.

描述（由申请人提供）：代谢综合征已成为一系列危险因素，显著增加糖尿病和心血管疾病的风险。代谢综合征包括向心性肥胖、致动脉粥样硬化性血脂异常、血压和血糖升高以及血栓形成前和促炎症状态。它使心血管疾病的风险增加2倍，使2型糖尿病的风险增加约5倍。由于肥胖症和糖尿病的患病率正以惊人的速度上升，预计这种病态综合征的发病率在美国和全世界都将继续增长，因此，更需要开发新的安全有效的药物组合，更有效的药物以及多功能药物，可以用作有价值的临床工具，在管理的个别组成部分，这综合征这个实验室以前的研究表明，沙漠植物，Larrea tridentata（杂酚油灌木）衍生的去甲二氢愈创木酸（NDGA），一种有效的脂氧合酶（LO）抑制剂，对代谢综合征的多个组分具有深远的影响，包括降低血糖、游离脂肪酸（FFA）和甘油三酯水平，在胰岛素抵抗、2型糖尿病、血脂异常和高血压的几种啮齿动物模型中，降低血压升高和改善胰岛素敏感性。本项目的总体目标是阐明NDGA在肝脏中发挥降血脂作用的分子机制。核心假设是NDGA通过改变关键脂质敏感性核转录因子的活性来发挥其降血脂作用，这反过来又改善了肝脏脂质代谢，特别是通过抑制肝脏脂肪生成和增加脂肪酸向氧化的通道，所有这些都严重减少了甘油三酯（TG）合成、TG储存和VLDL-TG产生/分泌所需的脂肪酸供应。此外，NDGA也可能直接影响VLDL-TG的产生、组装和分泌。为了检验这些假设，提出了三个具体目标。目的1将表征NDGA对高脂血症动物和细胞模型中与肝脂肪酸摄取和氧化相关的分子、生化和代谢事件的影响。目的2探讨NDGA抑制肝脏新生脂肪生成（DNL）的机制.目的3研究NDGA对肝脏VLDL-TG生成、组装和分泌的影响。对NDGA发挥其降血脂作用的分子机制的更深入了解可能提供重要线索，最终可能导致NDGA（或其衍生物）开发为一种新的有效治疗药物，用于管理血脂异常和代谢综合征的其他可能的中心组分。公共卫生关系：代谢综合征已成为一系列危险因素，显着增加2型糖尿病和心血管疾病（CVD）的风险。由于糖尿病和肥胖症的患病率正以惊人的速度上升，预计这种病态综合征的发病率在美国和全世界都将继续增长，因此，更需要开发新的安全有效的药物组合、更有效的药物以及多功能药物，其可用作治疗这种综合征的有价值的临床工具。本项目的目的是阐明NDGA通过改善肝脏脂质代谢来降低血脂升高的分子机制。对NDGA发挥其降血脂作用的分子机制的更深入了解可能提供重要线索，最终可能导致NDGA（或其衍生物的某种形式）作为一种新的有效治疗药物在血脂异常和代谢综合征的其他可能的中心组分的管理中的发展。