Xanthohumol and Metabolic Syndrome

描述（由申请人提供）：最近的估计显示，超过5000万美国人患有代谢综合征（MetS），并且有患心血管疾病和2型糖尿病的风险。导致MetS的危险因素包括动脉粥样硬化性血脂异常和葡萄糖耐受不良。许多参与血脂异常和糖代谢的基因都是通过调节法内酯X受体（FXR）来调节的。黄腐酚（Xanthohumol， XN）是啤酒花（Humulus lupulus）的主要烯丙基类黄酮，可调节FXR，并在MetS小鼠模型中显示出降低血浆甘油三酯和葡萄糖的作用。膳食XN补充剂最近已在市场上出售，以“改善一般健康”，但对其在人体中的功效和安全性知之甚少。我们的长期目标是确定XN和相关的烯丙基类黄酮对人体的健康益处。本应用程序的目的是确定XN对培养肝癌细胞和诊断为met的人的甘油三酯，胆固醇和葡萄糖稳态的影响。我们的中心假设是XN通过调节FXR对脂质和葡萄糖代谢产生影响。这项研究的基本原理是，研究的成功完成将为XN作为一种新型CAM模式治疗met相关疾病的治疗潜力提供评估。在Specific Aim 1中，XN对HepG2肝癌细胞中甘油三酯、胆固醇和葡萄糖水平的总体影响将被确定。我们的工作假设是XN通过调节FXR剂量依赖性地影响甘油三酯、胆固醇和葡萄糖代谢。在Specific Aim 2中，XN对MetS标记物的总体影响将在人类中确定。将对36名确诊为MetS的受试者进行双盲、随机、安慰剂对照研究，以确定两种剂量XN （20mg和60mg XN一次/天）的安全性和有效性，其对生物标志物的影响程度将与XN及其代谢物的稳态血浆水平有关。临床试验之前将进行单剂量药代动力学（PK）研究，目的是确定PK参数并计算每个人类受试者的稳态血浆XN水平。提出的研究具有创新性，因为XN之前没有被评估为改善人类MetS的生物活性剂。鉴于成千上万的美国人在不了解XN的功效和安全性的情况下长时间服用XN补充剂，人体数据是迫切需要的。

DESCRIPTION (provided by applicant): Recent estimates show that over 50 million Americans have metabolic syndrome (MetS) and are at risk for developing cardiovascular disease and type-2 diabetes. Risk factors that contribute to MetS include atherogenic dyslipidemia and glucose intolerance. Many genes involved in dyslipidemia and glucose metabolism are regulated by modulation of the farnesoid X receptor (FXR). Xanthohumol (XN), the principal prenylflavonoid of hops (Humulus lupulus), modulates FXR and was shown to lower plasma triglycerides and glucose in a mouse model of MetS. Dietary XN supplements have recently become available on the market to 'improve general health', but little is known regarding their efficacy and safety in humans. Our long-term goal is to determine the health benefits of XN and related prenylflavonoids in humans. The objective of this application is to determine the effects of XN on triglyceride, cholesterol and glucose homeostasis in cultured hepatoma cells and in humans diagnosed with MetS. Our central hypothesis is that XN exerts its effects on lipid and glucose metabolism by modulation of FXR. The rationale for the proposed research is that successful completion of the studies will provide an assessment of the therapeutic potential of XN as a novel CAM modality in the treatment of MetS-related disorders. In Specific Aim 1, the overall effect of XN on triglyceride, cholesterol and glucose levels will be determined in HepG2 hepatoma cells. Our working hypothesis is that XN dose-dependently affects triglyceride, cholesterol, and glucose metabolism by modulation of FXR. In Specific Aim 2, the overall effect of XN on markers of MetS will be determined in humans. A double-blinded, randomized, placebo-controlled study of 36 subjects with diagnosed MetS will be conducted to determine safety and efficacy of XN at two doses (20 mg and 60 mg XN once/day) and the magnitude of the effect on the biomarkers will be related to steady-state plasma levels of XN and its metabolites. The clinical trial will be preceded by a single-dose pharmacokinetic (PK) study with the aim to determine PK parameters and to calculate steady-state plasma XN levels for each of the human subjects. The proposed research in innovative, because XN has not previously been evaluated as a biologically active agent in the amelioration of MetS in humans. Human data are urgently needed in view of the fact that thousands of Americans are consuming XN supplements over prolonged periods of time without knowledge of XN's efficacy and safety. PUBLIC HEALTH RELEVANCE: Thousands of Americans are taking dietary supplements containing xanthohumol (XN), a prenylflavonoid from hops (Humulus lupulus), for improving general health, but XN's safety and efficacy have not been investigated in humans. As a modulator of the farnesoid X receptor, XN could be an attractive natural product for the complementary treatment of metabolic syndrome-related disorders and could provide an alternative for currently used antihyperlipidemics and antiglycemics, especially for patients that do not tolerate drugs in these therapeutic classes.