FATTY ACID TRANSPORTER: REGULATION, IDENTIFICATION

描述(申请人提供)：CD36是一种膜清道夫受体，可识别几种配体，包括天然和氧化的脂蛋白和长链脂肪酸。由这笔赠款支持的研究已经确定CD36是关键代谢组织摄取长链脂肪酸的重要促进剂。在上一次资助期间，我们研究了CD36水平发生遗传变化的动物模型，以检验调节脂肪酸和葡萄糖代谢之间相互作用的分子机制，以及这如何影响胰岛素抵抗的易感性。我们探索了CD36在交叉脂肪组织中的作用，我们发现它影响PPARγ的激活以及瘦素和脂联素的分泌。最后，我们证明了脂肪酸和转录因子FoxO1在调节CD36膜在肌肉细胞中的定位和功能中的作用。这一应用延续了我们最近的发现，即CD36通过棕榈酰化和其羧基残基的泛素化进行复杂的加工，介导其受到配体(脂肪酸和氧化脂蛋白)或调节剂(胰岛素和FoxO1)的急性调节。我们的假设是，这种受调控的过程会影响蛋白质到膜上的分类及其细胞重新分布。我们认为，CD36被其配体脂肪酸和OxLDL泛素化是一种保护性机制，通过诱导CD36的降解来限制这些脂类的过度摄取，而这种机制的功能障碍将导致病理。我们建议研究参与调节CD36加工的机制及其对脂肪酸代谢和胰岛素抵抗的影响。我们还将探索CD36在细胞内的运输如何在脂肪细胞的生物发生和脂滴成熟的水平上影响脂肪的储存。我们将验证这一假设，即脂肪组织CD36通过促进脂肪PPARγ的激活和脂肪的储存，从而最大限度地减少异位脂肪积累，从而在正能量平衡的基础上发挥病理生理学保护作用。提出的工作具有潜在的临床意义。在人类中，CD36基因的多态很常见，CD36变异与高脂血症、代谢综合征和心血管疾病的易感性有关。更好地了解CD36在FA摄取和加工过程中的分子调节作用将有助于设计更好的治疗方法，以防止或逆转FA代谢障碍及其有害后果。与公众健康相关：膜蛋白CD36促进关键代谢组织，如肌肉、脂肪组织、心脏和肠道摄取长链脂肪酸。我们最近的数据表明，脂肪酸通过泛素化显著提高CD36的周转率，而泛素化是针对CD36的降解。我们认为，这种保护机制的功能障碍会导致过度摄取脂肪酸而导致病理改变。这项拟议的工作将探索CD36周转的调节机制及其对胰岛素抵抗的影响。这项工作具有潜在的临床意义。在人类中，脂肪酸代谢的异常与膜上CD36水平的异常相关。此外，CD36基因的常见变异还与血脂异常、代谢综合征易感性和心血管疾病有关。

DESCRIPTION (provided by applicant): CD36 is a membrane scavenger receptor that recognizes several ligands including native and oxidized lipoproteins and long chain fatty acids. Research supported by this grant has resulted in the identification of CD36 as an important facilitator of long-chain fatty acid uptake by key metabolic tissues. In the last funding period we studied animal models with genetically altered CD36 levels to examine the molecular mechanims that mediate the interaction between the metabolisms of fatty acids and glucose and how this impacts susceptibility to insulin resistance. We explored the role of CD36 in cross adipose tissue where we showed that it influences PPARgamma activation and the secretion of leptin and adiponectin. Finally we documented the role of fatty acids and the transcription factor FoxO1 in regulation of CD36 membrane localization and function in muscle cells. This application follows up on our recent findings that complex processing of CD36 via palmitoylation and ubiquitination of residues in its carboxyl domain mediates its acute regulation by ligands (fatty acids and oxidized lipoproteins) or regulators (insulin and FoxO1). Our hypothesis is that this regulated processing influences sorting of the protein to the membrane and its cellular redistribution. We propose that ubiquitination of CD36 by its ligands fatty acids and OxLDL is a protective mechanism that limits excess uptake of these lipids via inducing CD36 degradation and dysfunction of this mechanism would lead to pathology. We propose to examine the mechanisms involved in regulation of CD36 processing and the implications with respect to fatty acid metabolism and insulin resistance. We will also explore how intracellular trafficking of CD36 influences lipid storage at the level of biogenesis and maturation of lipid droplet in adipocytes. We will test the hypothesis that adipose tissue CD36 exerts a protective effect with respect to pathophysiology due to positive energy balance by promoting activation of adipose PPARgamma and lipid storage which minimizes ectopic fat accumulation. The work proposed has potential clinical significance. In humans, polymorphisms in the CD36 gene are common and CD36 variants have been linked to dylipidemia, susceptibility to the metabolic syndrome and to cardiovascular disease. A better understanding of the molecular regulators of CD36 function in FA uptake and processing will help in designing better therapies that prevent or reverse dysfunctional FA metabolism and its deleterious consequences. PUBLIC HEALTH RELEVANCE: The membrane protein CD36 facilitates long chain fatty acid uptake by key metabolic tissues, e.g. muscle, adipose tissue, heart and intestine. Our recent data indicate that fatty acids acutely enhance CD36 turnover via its ubiquitination, which targets it to degradation. We propose that dysfunction of this protective mechanism would lead to pathology as a result of excess fatty acid uptake. The work proposed will explore the mechanisms regulating CD36 turnover and their implications with respect to insulin resistance. The work has potential clinical significance. In humans, abnormalities in fatty acid metabolism correlate with abnormal CD36 levels at the membrane. In addition common variants in the CD36 gene have been linked to dylipidemia, susceptibility to the metabolic syndrome and to cardiovascular disease.