Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA

描述(申请人提供)：代谢综合征已经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。代谢综合征包括中心性肥胖、致动脉粥样硬化性血脂异常、血压和血糖升高，以及血栓前状态和促炎状态。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发病率正在以惊人的速度上升，预计这种病态综合征的发病率在美国和世界范围内都将继续增长，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，这些药物可以作为宝贵的临床工具来管理这种综合征的各个组成部分。本实验室以前的研究表明，从沙漠植物三齿鱼Larrea tridentata(Creosote Bush)中提取的去甲二氢愈创木酸(NDGA)是一种有效的脂氧合酶(LO)抑制剂，对多种代谢综合征成分具有深远的影响，包括降低血糖、游离脂肪酸(FFA)和甘油三酯水平，缓解高血压和改善胰岛素敏感性，包括胰岛素抵抗、2型糖尿病、血脂异常和高血压的几种啮齿动物模型。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通过改变关键的脂敏感核转录因子的活性来发挥降血脂作用，这些转录因子反过来改善肝脏的脂代谢，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，所有这些都严重限制了甘油三酯(TG)合成、TG储存和VLDL-TG产生/分泌所需的脂肪酸供应。此外，NDGA还可能直接影响极低密度脂蛋白-甘油三酯的产生、组装和分泌。为了验证这些假设，本文提出了三个具体目标。目的1研究NDGA对高脂血症动物模型和细胞模型中与肝脏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抑制肝新生脂肪生成的作用机制。目的3评价NDGA对肝脏VLDL-TG生成、组装和分泌的影响。更深入地了解NDGA发挥降血脂作用的分子机制(S)可能会提供重要的线索，最终可能导致NDGA(或其衍生物(S))成为一种新的有效治疗剂，用于治疗血脂异常和代谢综合征的其他中心成分。

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.