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 肝脏和肠道中脂质的代谢命运、循环脂蛋白以及肌肉中的氧化脂质代谢 和棕色脂肪组织（BAT）。脂质代谢失调是一些最常见疾病的基础 西方人群的医学疾病，如心血管疾病、高脂血症、脂肪肝疾病、 肥胖、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质稳态的机制。 CIDEC/FSP27 编码 2 个亚型，a 和 b，具有严格的组织分布。在这里，我们将利用 Fsp27bKO 小鼠来 揭示了 FSP27b（在肝脏和肠道中表达的唯一 FSP27，以及 BAT 中的主要亚型）在 脂质的储存/氧化/分泌分配。我们将测试FSP27b是关键的新想法 肝脏 APOB 脂化和分泌、膳食脂质吸收和餐后脂血症以及脂肪的调节剂 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) 控制促动脉粥样硬化脂蛋白的生物发生和分泌的机制； ii）脂质生物学专业 氧化组织； iii）肝脏和其他组织之间的代谢串扰，这一领域已被广泛研究 过去被忽视的。 为了实现明确 FSP27b 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 FSP27b 促进肝脏中含 APOB 脂蛋白的脂化和分泌的假设 和肠道。目标 2 将检验以下假设：肝脏 FSP27b 限制 PPAR 激动剂的可用性 周围组织。目标 3 将检验 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 上已发表的科学记录，该记录基于 在有缺陷的“Fsp27-floxed”小鼠上。报告强调了我们研究的转化相关性 FSP27 的多态性与人类空腹甘油三酯升高有关，并且 功能突变导致家族性部分脂肪营养不良，5 型 (FPLD5)。总体而言，建议的成功 通过定义分子机制，研究将填补全身脂质（病理）生理学的巨大知识空白 脂滴介导的对肝脏、肠、肌肉和棕色脂肪组织中甘油三酯代谢的控制， 特别注意通过循环脂质进行的多器官代谢串扰。这些研究还可能确定 FSP27 作为治疗脂肪肝疾病、饮食引起的肥胖、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.