Fatty Liver Preventive Effects and High Dose Hepatotoxicity of Tea Polyphenols

茶多酚的脂肪肝预防作用及高剂量肝毒性

• 批准号: 7883667
• 负责人: JOSHUA D LAMBERT
• 金额: $ 35.43万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883667
• 关键词: Accounting; Adverse effects; Alanine Transaminase; Applications Grants; Aspartate Transaminase; Biochemical; Body Weight decreased; CCL2 gene; Camellia sinensis; Carbohydrates; Carbon; Carnitine; Case Study; Chronic; Cirrhosis; Clinical Trials; Complication; Consumption; Data; Deoxyguanosine; Development; Diet; Dietary Intervention; Dosage Forms; Dose; Drug Kinetics; Enzymes; Epidemic; Epigallocatechin Gallate; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fatty-acid synthase; Future; Genetic; Genetic Models; Green tea; Health; Hepatic; Hepatotoxicity; Histones; Hyperglycemia; Incidence; Individual; Inflammation; Insulin Resistance; Interleukin-15; Interleukin-18; Liquid substance; Literature; Liver; Liver diseases; Measures; Mediating; Medical; Metabolic syndrome; Metabolism; Metallothionein I; Methods; Modeling; Monocyte Chemoattractant Proteins; Mus; Necrosis; Obesity; Oxidative Stress; Plasma; Preparation; Preventive; Primary carcinoma of the liver cells; Public Health; Research; Risk Factors; Role; Safety; Sampling; Serum Markers; Severities; Steatohepatitis; Stress; Tea; Testing; Toxic effect; Transferase; Tumor Necrosis Factor-alpha; Tyrosine; absorption; base; db/db mouse; design; dietary supplements; feeding; gallocatechol; insight; isoprostaglandin F2alpha type-III; lipid metabolism; mouse model; non-alcoholic fatty liver; oxidation; polyphenol; pre-clinical; prevent; protective effect; public health relevance; response

DESCRIPTION (provided by applicant): The beneficial health effects of tea (Camellia sinensis) and its major polyphenolic constituent, (-)- epigallocatechin-3-gallate (EGCG), have been extensively studied and publicized. Recently, green tea polyphenols have been used as dietary supplements for weight reduction, however, the efficacy of such preparations remains debatable. Of concern, emerging case reports associate liver toxicity with consumption of green tea-based supplements. Our preliminary studies have indicated that whereas high doses of EGCG are hepatotoxic, moderate doses protect against development of obesity and metabolic syndrome in high-fat fed mice. More importantly, dietary EGCG also prevented the development of obesity-related fatty liver disease (ORFLD). ORFLD is emerging as a serious health problem and represents a significant risk factor for the development of cirrhosis. We hypothesize that dietary administration of EGCG can prevent and reverse the development of ORFLD, but high doses of EGCG are hepatotoxic and the toxicity is potentiated by ORFLD. The protective effects are mediated by the ability EGCG to alter fat absorption and hepatic fat metabolism. The toxic effects arise from the pro-oxidative activity of high dose EGCG. We propose to test these hypotheses as follows: 1. To determine the preventive effects of low dose chronic EGCG against the development of ORFLD in both dietary and genetic mouse models. 2. To determine the mechanisms by which EGCG prevents the development of ORFLD in dietary and genetic mouse models. 3. To characterize the hepatotoxic effects of high doses of EGCG and determine whether this toxicity is potentiated by ORFLD in mice. Successful completion of this grant application will enhance our understanding of the efficacy of green tea polyphenols as ORFLD preventive agents and the mechanisms involved. Further, the dose-response of beneficial versus potential toxic effects of EGCG to the liver will be established, allowing rational design of future pre-clinical and clinical trials. Given the growing obesity epidemic and the increased use of green tea-based dietary supplements for weight loss, the present studies are expected to have significant public health impact. PUBLIC HEALTH RELEVANCE: The rate of obesity and the related complication of fatty liver disease are increasing at a rapid pace; dietary interventions, such as green tea polyphenols, could have significant public health impact. However, the increased use of green tea-based dietary supplements, in which tea extracts are concentrated and/or purified represents a situation in which unforeseen adverse effects could, and have, occurred due to alterations in dose, dosage form, and pharmacokinetics. In this study, we will study the efficacy and mechanisms of action of epigallocatechin-3-gallate (EGCG), the major tea polyphenol, as fatty liver disease preventive agents, as well as the hepatotoxicity of high doses of EGCG. Successful completion of this research will provide important insight into the fatty liver preventive effects of EGCG, establish an upper safety limit for EGCG dose, and identify potential medical situations (i.e. preexisting fatty liver disease) in which individuals may be sensitized to the hepatotoxic effects of EGCG.

描述（由申请人提供）：茶（Camellia sinensis）及其主要的多酚成分的有益健康影响，（ - ） - epigallocatechin-3-gallate（EGCG），已被广泛研究和宣传。最近，绿茶多酚已被用作减轻体重的饮食补充剂，但是，这种制剂的功效仍然值得商bat。令人担忧的是，新兴病例报告将肝脏毒性与消费基于绿茶的补充剂有关。我们的初步研究表明，高剂量的EGCG是肝毒性，中等剂量的预防剂，以防止高脂喂养小鼠的肥胖和代谢综合征的发展。更重要的是，饮食EGCG还阻止了与肥胖相关脂肪肝病（ORFLD）的发展。 ORFLD正在成为严重的健康问题，代表了肝硬化发展的重要危险因素。我们假设饮食中的EGCG可以预防和扭转ORFLD的发展，但是高剂量的EGCG是肝毒性的，毒性受ORFLD增强。保护作用是通过EGCG改变脂肪吸收和肝脂肪代谢的能力来介导的。毒性作用来自高剂量EGCG的促氧化活性。我们建议对这些假设进行如下：1。确定低剂量慢性EGCG对饮食和遗传小鼠模型中ORFLD发展的预防作用。 2。确定EGCG阻止饮食和遗传小鼠模型中ORFLD发展的机制。 3。为了表征高剂量的EGCG的肝毒性作用，并确定这种毒性是否被小鼠中的ORFLD增强。成功完成此赠款应用程序将增强我们对绿茶多酚作为ORFLD预防剂和所涉及的机制的理解。此外，将建立有益的有益剂量与潜在毒性作用的剂量反应对肝脏的毒性作用，从而可以合理地设计未来的临床前和临床试验。鉴于肥胖的流行越来越多，并且增加了基于绿茶的饮食补充剂以减轻体重，因此目前的研究有望产生重大的公共卫生影响。公共卫生相关性：肥胖率和脂肪肝病的相关并发症的速度正在迅速增加；饮食干预（例如绿茶多酚）可能会产生重大的公共卫生影响。然而，增加基于绿茶的饮食补充剂的使用，其中茶提取物被浓缩和/或纯化代表了一种情况，在这种情况下，由于剂量，剂型形式和药代动力学的改变，不可预见的不良影响可能并且发生了。在这项研究中，我们将研究表瓜蛋白3-gallate（EGCG），主要茶多酚作为脂肪肝病预防剂以及高剂量EGCG的肝毒性的作用疗效和机制。这项研究的成功完成将为EGCG的脂肪肝预防作用，建立EGCG剂量的上限限制，并确定潜在的医疗情况（即先前存在的脂肪肝病），其中可能对EGCG的肝毒性效应敏感。