The role of FSP27b on dietary lipid absorption, lipoprotein secretion, and oxidative metabolism

摘要 拟议的工作将定义脂滴相关蛋白CIDEC(也称为FSP27)在 肝脏和肠道中脂类的代谢去向、循环脂蛋白和肌肉中的氧化脂质代谢 和棕色脂肪组织(BAT)。脂代谢失调是一些最常见的 西方人群中的医疗疾病，如心血管疾病、高脂血症、脂肪肝、 肥胖和胰岛素抵抗。我们实验室的长期目标是阐明分子和细胞 在生理和病理条件下控制全身脂肪动态平衡的机制。 CIDEC/FSP27编码两种异构体，a和b，具有严格的组织分布。在这里，我们将利用Fsp27bKO小鼠 揭示FSP27b(唯一在肝脏和肠道表达的FSP27，以及BAT中的主要异构体)在BAT中的作用 为储存/氧化/分泌而进行的脂类的分配。我们将测试FSP27b是一个关键的新想法 肝脏载脂蛋白B脂肪合成和分泌、膳食脂肪吸收和餐后脂肪的调节因子 外周组织中的酸利用。拟议的研究将改变我们对以下方面的理解：i) 促动脉粥样硬化脂蛋白的生物发生和分泌机制；II)主要 氧化组织；以及三)肝脏和其他组织之间的代谢串扰，这是一个在很大程度上 在过去被忽视了。 为了实现确定FSP27b在脂质代谢中的作用的目标，我们计划了三个具体的目标。目标1将 FSP27b促进肝脏脂化和含载脂蛋白脂蛋白分泌的假说检验 还有肠子。目的2将测试假设，肝脏FSP27b限制PPAR激动剂的可用性 周围组织。目标3将验证FSP27b减少棕色脂肪能量消耗的假设 组织。 重要的是，一些拟议的研究将纠正FSP27上发表的科学记录，这是基于 在有缺陷的“Fsp27-牙线”小鼠身上。我们研究的翻译相关性通过以下报告得到了强调 FSP27基因的多态性与人类空腹甘油三酯血症升高有关，而且-FSP27基因的缺失 功能突变导致家族性5型部分脂营养不良(FPLD5)。总体而言，建议的 研究将通过定义分子机制来填补全身脂质(病理)生理学方面的一大知识空白。 通过脂滴调节肝脏、肠道、肌肉和棕色脂肪组织中的甘油三酯代谢， 并特别注意通过循环脂质的多器官代谢串扰。这些研究还可能建立 FSP27作为有效的药理靶点用于治疗脂肪肝疾病、饮食引起的肥胖、血脂异常，以及 患者的心血管风险。

SUMMARY The proposed work will define the role of the lipid droplet-associated protein CIDEC (also known as FSP27) on the metabolic fate of lipids in liver and intestine, circulating lipoproteins, and oxidative lipid metabolism in muscle and brown adipose tissue (BAT). Dysregulation of lipid metabolism is the basis of some of the most common medical disorders in Western populations, such as cardiovascular disease, hyperlipidemia, fatty liver diseases, obesity, and insulin resistance. The long-term goal in our laboratory is to elucidate molecular and cellular mechanisms governing whole-body lipid homeostasis, both under physiological and pathological conditions. CIDEC/FSP27 encodes 2 isoforms, a and b, with strict tissue distribution. Here we will exploit Fsp27bKO mice to reveal the role of FSP27b (the sole FSP27 expressed in liver and intestine, and the major isoform in BAT) on the partitioning of lipids for storage/oxidation/secretion. We will test the new ideas that FSP27b is a critical regulator of hepatic APOB lipidation and secretion, dietary lipid absorption and postprandial lipemia, and fatty acid utilization in peripheral tissues. The proposed studies will be transformative for our understanding of: i) mechanisms governing the biogenesis and secretion of pro-atherogenic lipoproteins; ii) lipid biology in major oxidative tissues; and iii) metabolic cross-talk between liver and other tissues, an area that has been largely neglected in the past. To achieve the goal of defining the role of FSP27b on lipid metabolism, we plan three specific aims. Aim 1 will test the hypothesis that FSP27b promotes the lipidation and secretion of APOB-containing lipoproteins in liver and intestine. Aim 2 will test the hypothesis that hepatic FSP27b limits the availability of PPAR agonists for peripheral tissues. Aim 3 will test the hypothesis that FSP27b reduces energy expenditure in brown adipose tissue. Importantly, some of the proposed research will correct the published scientific record on FSP27, which is based on a flawed “Fsp27-floxed” mice. The translational relevance of our studies is highlighted by reports showing that polymorphisms in FSP27 are associated with elevated fasting triglyceridemia in humans, and that loss-of- function mutations result in familial partial lipodystrophy, type 5 (FPLD5). Overall, success of the proposed studies will fill a large gap of knowledge in whole-body lipid (patho)physiology, by defining molecular mechanisms of lipid droplet-mediated control of triglyceride metabolism in liver, intestine, muscle, and brown adipose tissue, with particular attention to multi-organ metabolic cross-talk via circulating lipids. These studies may also establish FSP27 as a valid pharmacological target to manage fatty liver diseases, diet-induced obesity, dyslipidemias, and cardiovascular risk in patients.