Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA

描述（由申请人提供）：代谢综合征已成为一系列显著增加糖尿病和心血管疾病风险的危险因素。代谢综合征包括中枢性肥胖、动脉粥样硬化性血脂异常、血压和血糖升高、血栓形成前和炎症前状态。它使患心血管疾病的风险增加2倍，使患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将在美国和世界范围内继续增长，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，这些药物可以作为有价值的临床工具，用于管理这种综合征的各个组成部分。该实验室之前的研究表明，沙漠植物Larrea tridentata （Creosote Bush）衍生的去二氢木酚木酸（NDGA）是一种有效的脂氧合酶（LO）抑制剂，对代谢综合征的多种成分有深远的影响，包括降低血糖、游离脂肪酸（FFA）和甘油三酯水平，降低血压升高和改善胰岛素敏感性。血脂异常和高血压。本项目的总体目标是阐明NDGA在肝脏中发挥其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其降血脂作用，进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生产/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。为了验证这些假设，提出了三个具体目标。目的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。目的2将确定NDGA对肝脏新生脂肪生成（DNL）的抑制作用机制。目的3将评估NDGA对肝脏VLDL-TG产生、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会提供重要的线索，最终可能导致NDGA（或其衍生物）作为一种新的、有效的治疗血脂异常和代谢综合征的其他核心成分的药物的发展。

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.