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

总结 拟议的工作将确定脂滴相关蛋白CIDEC（也称为FSP 27）在 肝脏和肠道中脂质的代谢命运、循环脂蛋白和肌肉中的氧化脂质代谢 棕色脂肪组织（BAT）脂质代谢失调是一些最常见的 西方人群中的医学疾病，如心血管疾病、高脂血症、脂肪肝疾病， 肥胖和胰岛素抵抗。我们实验室的长期目标是阐明 在生理和病理条件下，控制全身脂质稳态的机制。 CIDEC/FSP 27编码2种亚型a和B，具有严格的组织分布。在这里，我们将利用Fsp 27 bKO小鼠， 揭示了FSP 27 b（在肝脏和肠中表达的唯一FSP 27，以及BAT中的主要同种型）对 用于储存/氧化/分泌的脂质的分配。我们将测试新的想法，FSP 27 b是一个关键的 肝脏APOB脂化和分泌、膳食脂质吸收和餐后脂血症的调节剂，以及脂肪 外周组织中的酸利用。拟议的研究将改变我们对以下问题的理解：i） 调节促动脉粥样硬化脂蛋白的生物发生和分泌的机制; ii）主要的脂质生物学 氧化组织;以及iii）肝脏和其他组织之间的代谢串扰，这是一个在很大程度上已经被 在过去被忽视。 为了实现确定FSP 27 b对脂质代谢的作用的目标，我们计划了三个具体目标。目标1将 检验FSP 27 b促进肝脏中含APOB脂蛋白的脂化和分泌的假设 和肠。目的2将检验肝FSP 27 b限制了PPAR激动剂的可用性的假设， 外周组织目的3将检验FSP 27 b减少棕色脂肪中的能量消耗的假设 组织. 重要的是，一些拟议的研究将纠正FSP 27上已发表的科学记录，该记录基于 一个有缺陷的“Fsp 27-floxed”小鼠。我们的研究的翻译相关性突出的报告显示， FSP 27的多态性与人类空腹血糖升高有关， 功能突变导致5型家族性部分脂肪营养不良（FPLD 5）。总体而言，拟议的 通过定义分子机制，研究将填补全身脂质（病理）生理学知识的巨大空白 脂滴介导的肝、肠、肌肉和棕色脂肪组织中甘油三酯代谢的控制， 特别关注通过循环脂质的多器官代谢串扰。这些研究也可能建立 FSP 27作为有效的药理学靶点来管理脂肪肝疾病、饮食诱导的肥胖症、血脂异常和 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.