Longevity foods, SIRT activation and diabetic dyslipidemia.

描述(申请人提供)：肥胖症在美国已经达到流行的程度，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，阿育吠陀一直建议使用苦瓜或苦瓜(BM)作为一种功能食品来预防和治疗糖尿病及相关并发症。在人类中，摄入BM会降低糖尿病患者的葡萄糖耐量和餐后血糖，并降低糖化血红蛋白。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。我们最近证实，BM汁(BMJ)能降低人肝细胞株HepG2的载脂蛋白B(ApoB)、apoC-III和TG的合成和分泌。我们的初步数据表明，BMJ改善了肝脏胰岛素信号转导通路，并激活了哺乳动物长寿基因sirtuin(Sirt1)。我们的长期目标是了解功能性食品改善肥胖及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Sirt1激活的分子靶点和途径，以及TG和apoB的调节机制，并基于生物活性导向分级来表征BMJ的活性成分。根据Sirt1通过叉头转录因子(FOXO)改善脂肪和葡萄糖代谢的事实以及我们的初步数据，BMJ增加了小鼠肝脏中Sirt1蛋白的表达，我们假设BMJ通过Sirt1激活调节肝脏甘油三酯和葡萄糖代谢，特别是通过FOXO途径。我们将使用生物活性引导的BMJ分级来鉴定活性成分，这些活性成分将被用来通过体内和体外实验来验证我们的假设。我们的具体目的是研究BMJ相关的-1)Sirt1激活对FOXO蛋白调节甘油三酯和葡萄糖代谢的影响，2)激活PI3K途径调节apoB代谢的作用。这是一项独特而新颖的研究，它将证明功能食品具有调节长寿基因Sirt1的能力。从这项研究中获得的知识有望被用于在人类身上进行转化研究，以缓解糖尿病血脂异常。传统功能食品将容易被文化敏感人群接受，将提高生活质量，并将在全球范围内为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/功能特性的食品，可能会通过减少与肥胖和2型糖尿病和心血管疾病相关疾病相关的发病率和死亡率，在促进健康和长寿方面产生重大影响。

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.