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: 8018135
• 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/8018135
• 关键词: ADD-1 protein; Adult; Affect; Animal Model; Animals; Antiatherogenic; Apolipoproteins B; Atherogenic Diet; Attenuated; Biochemical; Biological Assay; Blood Glucose; Blood Pressure; Body Weight decreased; CD36 gene; Cardiovascular Diseases; Cell model; Central obesity; Cholelithiasis; Cholesterol; Clinical; Combined Modality Therapy; Developing Countries; Development; Diabetes Mellitus; Drug Combinations; Dyslipidemias; Electrophoretic Mobility Shift Assay; Enzymes; Epidemic; Event; FABP1 gene; Fatty Acids; 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 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; Peroxisome Proliferator-Activated Receptors; 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; diacylglycerol O-acyltransferase; fatty acid-transport protein; feeding; follow-up; improved; in vivo; insulin sensitivity; lipid biosynthesis; lipid metabolism; mortality; non-alcoholic fatty liver; overexpression; oxidation; particle; 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显着增加糖尿病和心血管疾病风险的危险因素。代谢综合征包括向心性肥胖、动脉粥样硬化性血脂异常、血压和血糖升高以及促血栓和促炎症状态。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。随着肥胖和糖尿病的患病率以惊人的速度上升，这种病态综合征的发病率预计在美国和世界范围内将继续增长，因此，更需要开发新的安全有效的治疗方法药物组合、更有效的药物以及多功能药物可用作治疗该综合征的各个组成部分的有价值的临床工具。该实验室之前的研究表明，沙漠植物 Larrea tridentata（杂酚油布什）衍生的去甲二氢愈创木酸 (NDGA) 是一种有效的脂氧合酶 (LO) 抑制剂，对代谢综合征的多个组成部分具有深远的影响，包括降低血糖、游离在几种胰岛素抵抗、2 型糖尿病、血脂异常和高血压的啮齿动物模型中，脂肪酸 (FFA) 和甘油三酯水平、血压升高的减弱和胰岛素敏感性的改善。该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核转录因子的活性来发挥其降血脂作用，从而改善肝脏脂质代谢，特别是通过抑制肝脏脂肪生成和增加脂肪酸氧化通道，所有其中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 还可能直接影响 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。目标 1 将描述 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。目标 2 将确定 NDGA 对肝脏从头脂肪生成 (DNL) 的抑制作用机制。目标 3 将评估 NDGA 对肝脏 VLDL-TG 产生、组装和分泌的影响。更好地了解 NDGA 发挥降血脂作用的分子机制可能会提供重要线索，最终可能导致 NDGA（或其衍生物）发展成为一种新的、有效的治疗药物。血脂异常和代谢综合征的其他可能的核心组成部分。公共卫生相关性：代谢综合征已成为一系列危险因素，可显着增加 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在以惊人的速度上升，这种病态综合征的发病率预计在美国和世界范围内将继续增长，因此，更需要开发新的安全有效的药物药物组合、更有效的药物以及多功能药物可作为治疗该综合征的宝贵临床工具。该项目的目标是阐明NDGA通过改善肝脏脂质代谢来降低升高的血脂的分子机制。更好地了解 NDGA 发挥降血脂作用的分子机制可能会提供重要线索，最终可能导致 NDGA（或其某种形式的衍生物）发展成为一种新的、有效的治疗药物。血脂异常和代谢综合征的其他可能的核心组成部分。