Lipogenesis, lipoprotein flux & CVD risk: role of meal composition & frequency

描述（由申请人提供）：过去几十年预示着一个高碳水化合物（CHO）饮食的时代，其中一些现在已知会恶化血脂谱并增加心血管疾病（CVD）的风险。膳食组成和进餐频率均影响脂质合成和动力学，但具体机制尚不清楚。我们将检验以下假设：CHO转化为脂肪（从头脂肪生成[DNL]）是导致血清TG水平升高和血脂异常的餐后甘油三酯（TG）和脂蛋白通量的主要决定因素。我们建议进行控制代谢研究，使用饮食组成和膳食频率来调节餐后DNL，并评估其对TG和载脂蛋白（apo）B通量、脂质谱和脂蛋白颗粒分布的影响。我们将通过测量极低密度脂蛋白（VLDL;来自肝脏）和乳糜微粒（chylos，来自肠道）对超重和肥胖志愿者（有CVD风险的人群）餐后总脂蛋白-TG产生和清除的个体贡献来实现这一目标。我们将使用稳定同位素示踪剂和复杂的数学模型，比较用两种等热量饮食（随机分配）喂养7天对餐后DNL、VLDL-TG和chylo-TG以及载脂蛋白B100和B48通量的影响，所述等热量饮食为高蔗糖或高脂肪。在被分配到每种饮食的参与者中使用随机交叉设计，我们还将比较连续7天食用少量频繁膳食（啃食）和每日摄入2餐之间的差异幅度，每个参与者作为他/她自己的对照。受试者将被安置在代谢病房，并喂食恒定的体重维持饮食，以确保饮食依从性和控制活动。将通过磁共振（MR）光谱测量肝脏脂质储存，通过MR成像测量内脏脂肪，通过双能X线吸收测定法测量瘦体重和脂肪质量。为了进一步将动态通量与致动脉粥样硬化风险联系起来，将使用专有的HPLC方法和凝胶电泳测量VLDL和乳糜残留物的组成、脂蛋白颗粒大小、小而密的低密度脂蛋白和高密度脂蛋白。我们预计，这些新的研究将使我们能够确定，第一次，膳食组成和频率影响餐后apoB和TG通量和相关的脂质谱的机制。这些发现可以为开发循证干预措施和饮食指导以减轻CVD风险的努力提供信息。

DESCRIPTION (provided by applicant): The past few decades heralded an era of high carbohydrate (CHO) diets, some of which are now known to worsen lipid profiles and increase risk of cardiovascular disease (CVD). Both diet composition and meal frequency affect lipid synthesis and kinetics, but the specific mechanisms remain unsettled. We will test the hypothesis that the conversion of CHO to fat (de novo lipogenesis [DNL]) is a major determinant of postprandial triglyceride (TG) and lipoprotein fluxes leading to higher levels of serum TG and dyslipidemia. We propose to perform controlled metabolic studies that use diet composition and meal frequency to modulate postprandial DNL and assess its impact on TG and apolipoprotein (apo) B fluxes, lipid profiles and lipoprotein particle distribution. We will do so by measuring th individual contributions of very low density lipoprotein (VLDL; from the liver) and chylomicrons (chylos, from the intestine) to overall postprandial lipoprotein-TG production and clearance in overweight and obese volunteers, a population that is at risk for CVD. We will compare the effects of 7 days feeding with two isocaloric diets (randomly assigned) that are either high in sucrose or high in fat on postprandial DNL, VLDL-TG and chylo-TG, and apolipoprotein B100 and B48 fluxes using stable isotope tracers and sophisticated mathematical modeling. Using a randomized crossover design in participants assigned to each diet, we will also compare the magnitude of differences between successive 7-day periods of consuming small frequent meals (nibbling) and ingesting 2 daily meals, with each participant serving as his/her own control. Participants will be housed in a metabolic ward and fed constant weight-maintaining diets to assure dietary adherence and control activity. Liver lipid storage will be measured by magnetic resonance (MR) spectroscopy, visceral fat by MR imaging, and lean and fat mass by dual energy X-ray absorptiometry. To further link the dynamic fluxes to atherogenic risk, the composition of VLDL and chylo remnants, lipoprotein particle sizes, small dense low density lipoprotein and high density lipoprotein will be measured using proprietary HPLC methods and gel electrophoresis. We anticipate that these novel studies will allow us to identify, for the firs time, the mechanisms by which meal composition and frequency affect postprandial apoB and TG fluxes and associated lipid profiles. These findings could inform efforts to develop evidence-based interventions and dietary guidance to mitigate CVD risk.