Utilization of Phytochemicals to Ameliorate Fructose-Induced Fatty Liver through

描述(申请人提供)：果糖消费量急剧上升，研究表明，果糖可导致多种不良反应，如诱导胰岛素抵抗，体重增加，和瘦素抵抗动物和人类。特别是，果糖被证明可以增加肝脏脂肪合成，减少肝脏脂肪氧化，这表明果糖参与了非酒精性脂肪性肝病的发病机制。我们已经发现，果糖的快速代谢可能是导致果糖不良反应的关键机制。因此，我们假设抑制KHKC为开发治疗果糖诱导的脂肪肝的药物提供了一个新的靶点。[我们建议使用两种植物成分，肉桂和茶树变种。Asamica(锡兰茶)，已被鉴定为对KHKC具有体外抑制作用。]本项目的目的是确定肉桂和茶的植物化学物质抑制KHKC在改善(1)果糖诱导的ATP耗竭，(2)果糖诱导的肝脏脂肪合成增加和减少肝脏脂肪氧化，以及(3)果糖诱导的脂肪肝的发展方面的有效性。这些研究的结果将通过确认KHKC作为预防和治疗果糖诱导的脂肪肝的治疗方法的重要目标来促进我们的理解。在拟议的5年授权期内，申请者将发展新的技能，并增加她在药物发现和开发领域的知识，特别是将植物作为治疗来源的工作。该奖项将通过教学计划和讲座，以及通过促进与不同部门和机构的研究人员的互动，为申请者提供成为独立科学家所需的培训。申请者已经建立了一个咨询委员会，将为她提供极好的指导。作为她的主要导师，理查德·约翰逊博士是果糖和尿酸诱导的内皮功能障碍、代谢综合征、肾脏疾病和脂肪肝疾病的主要研究人员之一。作为科罗拉多大学安舒茨医学院肾脏疾病和高血压科主任，约翰逊博士将为申请者提供必要的设施和设备，以顺利完成她提出的学习。此外，药学系副研究教授兼药物化学核心设施主任Michael Wempe博士在药物化学方面拥有丰富的经验。作为她的联合导师，温佩博士将监督申请者在药物发现和开发方面的培训。此外，科罗拉多州立大学食品科学与人类营养学系助理教授蒂凡尼·韦尔博士也将成为勒博士的联合导师。她在使用传统的生物活性导向分离和代谢组学方法分离和鉴定植物性化合物方面拥有广泛的背景，因此，她将在天然产品的分离和表征方面培训Le博士。申请者还将依靠医学和免疫学教授、胃肝科主任雨果·罗森博士和肾脏内科助理研究教授米格尔·兰纳斯帕-加西亚博士的专业知识。罗森博士将为脂肪肝的组织学分析提供咨询，拉纳斯帕-加西亚博士将为体外和体内研究的设计提供咨询。

DESCRIPTION (provided by applicant): Fructose consumption has sharply risen and studies have shown that fructose can cause a variety of adverse effects, such as inducing insulin resistance, weight gain, and leptin resistance in animals and humans. In particular, fructose has been shown to increase hepatic fat synthesis and decrease hepatic fat oxidation, suggesting that fructose contributes to the pathogenesis of nonalcoholic fatty liver disease. We have identified that the rapid metabolism of fructose by ketohexokinase-C (KHKC) may be the key mechanism driving the adverse effects of fructose. Thus, we hypothesize that inhibition of KHKC provides a novel mechanism as a target for the development of a therapeutic agent to ameliorate fructose-induced fatty liver. [We propose to utilize two botanicals, Cinnamomum cassia (cinnamon) and Camillia sinensis var. assamica (Ceylon tea), which have been identified to have in vitro inhibitory effects on KHKC.] The objectives of the project are to determine the effectiveness of inhibiting KHKC by phytochemicals of cinnamon and tea on ameliorating (1) fructose-induced ATP depletion, (2) fructose-induced increase in hepatic fat synthesis and decrease in hepatic fat oxidation, and (3) the development of fructose-induced fatty liver. The findings from these studies will advance our understanding by validating KHKC as an important target for the development of therapies to prevent and treat fructose-induced fatty liver. During the proposed 5-year award period, the applicant will develop new skills and will increase her knowledge in the field of drug discovery and development, in particular working with botanicals as a therapeutic source. The award will provide the applicant the necessary training to become an independent scientist through both didactic programs and lectures and by facilitating interactions with researchers in different departments and institutions. The applicant has established an advisory committee that will provide her with excellent mentorship. As her primary mentor, Dr. Richard Johnson is one of the leading researchers in fructose- and uric acid-induced pathways in endothelial dysfunction, metabolic syndrome, kidney disease, and fatty liver disease. As Head of the Division of Renal Diseases and Hypertension at the University of Colorado Anschutz Medical Campus, Dr. Johnson will provide the applicant access to the necessary facilities and equipment to successfully complete her proposed studies. In addition, Dr. Michael Wempe, Associate Research Professor in the Department of Pharmaceutical Sciences and Director of the Medicinal Chemistry Core Facility, has extensive experience in medicinal chemistry. As her co-mentor, Dr. Wempe will supervise the applicant's training in drug discovery and development. In addition, Dr. Tiffany Weir, an Assistant Professor in the Department of Food Science and Human Nutrition at Colorado State University, will also be Dr. Le's co-mentor. She has extensive background in isolating and identifying plant-based compounds using both traditional bio-activity guided fractionation as well as metabolomics approaches, and thus, will train Dr. Le in the isolation and characterization of natural products. The applicant will also rely on the expertise of Dr. Hugo Rosen, Professor of Medicine and Immunology and Division Head of Gastro & Hepatology, and Dr. Miguel Lanaspa-Garcia, Assistant Research Professor in the Department of Renal Medicine. Dr. Rosen will consult on the histological analysis of fatty liver and Dr. Lanaspa-Garcia will consult on the design of in vitro and in vivo studies.