Utilization of Phytochemicals to Ameliorate Fructose-Induced Fatty Liver through

利用植物化学物质改善果糖诱导的脂肪肝

• 批准号: 8768130
• 负责人: MyPhuong T Le
• 金额: $ 13.07万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768130
• 关键词: Adverse effects; Advisory Committees; Animals; Automobile Driving; Award; Biological Factors; Botanicals; Cells; Cholesterol; Cinnamomum cassia; Cinnamon - dietary; Colorado; Consult; Consumption; Core Facility; Crude Extracts; Data; Development; Disease; Effectiveness; Enzymes; Equipment; Fatty Liver; Fatty acid glycerol esters; Fractionation; Fructose; Goals; Head; Health; Hepatic; Hepatology; Hepatotoxicity; Human; Immunology; In Vitro; Institution; Insulin Resistance; Intake; Ketohexokinase; Kidney; Kidney Diseases; Knowledge; Leptin resistance; Liver diseases; Longitudinal Studies; Medical; Medicine; Mentors; Mentorship; Metabolic syndrome; Metabolism; Modeling; Parents; Pathogenesis; Pathway interactions; Pharmaceutical Chemistry; Pharmacologic Substance; Phosphorylation; Phytochemical; Plants; Postdoctoral Fellow; Prevention; Process; Production; Protein Isoforms; Rattus; Renal Hypertension; Reporting; Research; Research Personnel; Science; Scientist; Serum; Source; Sri Lanka; Tea; Testing; Therapeutic; Therapeutic Agents; Training; United States; Universities; Uric Acid; Weight Gain; Work; base; design; drug development; drug discovery; endothelial dysfunction; experience; feeding; food science; glycogenesis; in vitro Assay; in vivo; inhibitor/antagonist; innovation; lectures; lipid biosynthesis; liver injury; metabolomics; new therapeutic target; non-alcoholic fatty liver; novel; novel therapeutic intervention; nutrition; oxidation; prevent; professor; programs; public health relevance; skills; therapy development

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.

描述（申请人提供）：果糖消费量急剧上升，研究表明果糖会引起多种不良影响，例如诱导动物和人类的胰岛素抵抗、体重增加和瘦素抵抗。特别是，果糖已被证明可以增加肝脏脂肪合成并减少肝脏脂肪氧化，这表明果糖有助于非酒精性脂肪肝的发病机制。我们发现酮己糖激酶-C (KHKC) 对果糖的快速代谢可能是驱动果糖不良反应的关键机制。因此，我们假设 KHKC 的抑制提供了一种新的机制作为开发改善果糖诱导的脂肪肝治疗剂的靶点。 [我们建议使用两种植物，Cinnamomum cassia（肉桂）和Camillia sinensis var。 assamica（锡兰茶），已被鉴定对 KHKC 具有体外抑制作用。] 该项目的目标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 消耗方面的有效性， (2) 果糖诱导的肝脂肪合成增加和肝脂肪氧化减少，以及 (3) 果糖诱导的脂肪形成 肝。这些研究的结果将验证 KHKC 是开发预防和治疗果糖诱导的脂肪肝疗法的重要靶点，从而加深我们的理解。 在拟议的 5 年奖励期内，申请人将发展新技能并增加药物发现和开发领域的知识，特别是使用植物作为治疗来源。该奖项将通过教学计划和讲座以及促进与不同部门和机构的研究人员的互动，为申请人提供成为独立科学家所需的培训。申请人成立了一个咨询委员会，将为她提供良好的指导。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途径的领先研究人员之一。作为科罗拉多大学安舒茨医学校区肾脏疾病和高血压科主任，约翰逊博士将为申请人提供必要的设施和设备，以成功完成她拟议的研究。此外，药物科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。作为她的共同导师，Wempe 博士将监督申请人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系助理教授Tiffany Weir博士也将担任Le博士的共同导师。她在使用传统的生物活性引导分馏和代谢组学方法分离和鉴定植物基化合物方面拥有丰富的背景，因此将在天然产物的分离和表征方面对 Le 博士进行培训。申请人还将依赖医学和免疫学教授兼胃肠病学和肝病科主任 Hugo Rosen 博士以及肾脏医学系助理研究教授 Miguel Lanaspa-Garcia 博士的专业知识。 Rosen 博士将就脂肪肝的组织学分析提供咨询，Lanaspa-Garcia 博士将就体外和体内研究的设计提供咨询。