Longevity foods, SIRT activation and diabetic dyslipidemia.

长寿食品、SIRT 激活和糖尿病血脂异常。

• 批准号: 7501261
• 负责人: Pratibha V Nerurkar
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7501261
• 关键词: Animals; Apolipoproteins B; Apolipoproteins C; Back; Body fat; Cardiovascular Diseases; Clinical Trials; Consumption; Data; Deacetylase; Developed Countries; Developing Countries; Diabetes Mellitus; Diet; Disease; Disease Management; Dyslipidemias; Epidemic; Event; Fatty acid glycerol esters; Figs - dietary; Food; Fractionation; Glucose; Glycosylated Hemoglobin; Goals; Health; Hepatic; Hepatocyte; Human; In Vitro; Insulin Receptor; Insulin Resistance; Intervention; Juice; Knowledge; Link; Lipids; Lipoproteins; Liver; Living Wills; Longevity; Measures; Melons; Messenger RNA; Metabolic Diseases; Metabolism; Molecular; Molecular Target; Momordica charantia; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Plant Roots; Plasma; Population; Prevention strategy; Production; Property; Proteins; Quality of life; Regulation; Research; Small Interfering RNA; Testing; Time; Translational Research; Triglyceride Metabolism; Triglycerides; Triton; United States; Very low density lipoprotein; Very low density lipoprotein cholesterol; Work; apolipoprotein B-100; apolipoprotein B-48; ayurveda; base; blood glucose regulation; cost; diabetic; drug discovery; feeding; forkhead protein; functional food; glucose metabolism; glucose tolerance; improved; in vivo; inhibitor/antagonist; insulin sensitivity; insulin signaling; lipid metabolism; longevity gene; mRNA Expression; mortality; multidisciplinary; novel; prevent; research study

DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions in the United States and is closely linked to type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). For centuries, Ayurveda has recommended the use of Momordica charantia or bitter melon (BM) as a functional food to prevent and treat diabetes and associated complications. In humans, consumption of BM reduced glucose tolerance and postprandial glucose in diabetic patients as well as glycosylated hemoglobin. In animal studies, we, and others have demonstrated that BM not only improves glucose metabolism, but also reduces body fat, plasma triglyceride (TG), cholesterol, and very low density lipoprotein (VLDL) levels. We recently demonstrated that BM juice (BMJ) reduces apolipoprotein B (apoB), apoC-III and TG synthesis, and secretion in human liver cells, HepG2. Our preliminary data indicates that BMJ improves hepatic insulin signaling cascade and activates the mammalian longevity gene, sirtuin (Sirt1). Our long-term goal is to understand the molecular mechanisms of functional foods to ameliorate obesity and associated metabolic disorders of diabetes and dyslipidemia. The objective of the proposed research is to investigate the molecular targets and pathways of BM-associated Sirt1 activation and mechanisms of TG and apoB regulation as well as to characterize active components of BMJ based on bioactivity-guided fractionation. Based on the fact that Sirt1 improves lipid and glucose metabolism via forkhead transcription factors (Foxo) and our preliminary data that BMJ increases Sirt1 protein in mouse liver, we hypothesize that BMJ regulates hepatic TG and glucose metabolism via Sirt1 activation, specifically through Foxo pathways. We will employ bioactivity-guided fractionation of BMJ to identify the active components which will be used to test our hypothesis using in-vivo and ex-vivo experiments. Our specific aims are to investigate the effects of BMJ-associated- 1) Sirt1 activation on Foxo proteins to regulate TG and glucose metabolism, and 2) -activation of PI3K pathway to regulate apoB metabolism. This is a unique and novel study, which will demonstrate that functional foods have the capacity to regulate the longevity gene, Sirt1. Knowledge obtained from this study is expected to be utilized to conduct translational research in humans to alleviate diabetic dyslipidemia. Traditional functional foods will be readily acceptable by culturally sensitive population, will improve quality of life, and will offer a cost-effective treatment or preventive strategy for diabetic dyslipidemia globally. Understanding molecular events of functional foods has strong potential for developing drugs for obesity- associated metabolic disorders. "Going back to our cultural roots" and identifying foods with not only nutritional but also medicinal/functional properties, may have a significant impact on promoting health and longevity by reducing morbidity and mortality associated with obesity and associated disorders of type 2 diabetes and cardiovascular diseases.

描述（由申请人提供）：肥胖在美国已达到流行比例，并与2型糖尿病（T2 DM）和心血管疾病（CVD）密切相关。几个世纪以来，阿育吠陀一直推荐使用苦瓜或苦瓜（BM）作为预防和治疗糖尿病及相关并发症的功能性食物。在人类中，BM的消耗降低了糖尿病患者的葡萄糖耐量和餐后葡萄糖以及糖化血红蛋白。在动物研究中，我们和其他人已经证明，BM不仅可以改善葡萄糖代谢，还可以降低体脂、血浆甘油三酯（TG）、胆固醇和极低密度脂蛋白（VLDL）水平。我们最近证明，BM汁（BMJ）减少载脂蛋白B（apoB），apoC-III和TG的合成，并在人肝细胞，HepG 2分泌。我们的初步数据表明，BMJ改善肝脏胰岛素信号级联，激活哺乳动物长寿基因，sirtuin（Sirt 1）。我们的长期目标是了解功能性食品改善肥胖和相关的糖尿病和血脂异常代谢紊乱的分子机制。本研究的目的是研究BM相关Sirt 1激活的分子靶点和途径以及TG和apoB调节的机制，并基于生物活性指导的分级来表征BMJ的活性成分。基于Sirt 1通过叉头转录因子（Foxo）改善脂质和葡萄糖代谢的事实以及我们的初步数据BMJ增加小鼠肝脏中Sirt 1蛋白，我们假设BMJ通过Sirt 1活化调节肝脏TG和葡萄糖代谢，特别是通过Foxo途径。我们将采用生物活性指导的BMJ分馏，以确定将用于测试我们的假设，使用体内和体外实验的活性成分。我们的具体目标是研究BMJ相关的1）Sirt 1激活Foxo蛋白以调节TG和葡萄糖代谢，以及2）PI 3 K通路激活以调节apoB代谢的作用。这是一项独特而新颖的研究，它将证明功能性食品具有调节长寿基因Sirt 1的能力。从本研究中获得的知识预计将用于在人类中进行转化研究，以缓解糖尿病血脂异常。传统功能性食品将容易被文化敏感人群接受，将改善生活质量，并将为全球糖尿病血脂异常提供具有成本效益的治疗或预防策略。了解功能性食品的分子事件对于开发治疗肥胖相关代谢紊乱的药物具有很大的潜力。“回到我们的文化根源”，并确定不仅具有营养而且具有药用/功能特性的食物，可能会对促进健康和长寿产生重大影响，因为它可以减少与肥胖和2型糖尿病和心血管疾病相关疾病有关的发病率和死亡率。