FATTY ACID TRANSPORTER: REGULATION, IDENTIFICATION

描述（由申请人提供）：CD36是一种膜清道夫受体，可识别几种配体，包括天然和氧化脂蛋白和长链脂肪酸。该基金支持的研究已经鉴定出CD36是关键代谢组织摄取长链脂肪酸的重要促进剂。在上一个资助期，我们研究了CD36水平基因改变的动物模型，以研究介导脂肪酸和葡萄糖代谢之间相互作用的分子机制，以及这种机制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PPARgamma激活和瘦素和脂联素的分泌。最后，我们记录了脂肪酸和转录因子fox01在肌肉细胞中CD36膜定位和功能调控中的作用。我们最近的研究发现，CD36通过棕榈酰化和羧基结构域残基泛素化的复杂加工，介导了配体（脂肪酸和氧化脂蛋白）或调节剂（胰岛素和fox01）对其的急性调节。我们的假设是，这种调节过程影响了蛋白质在膜上的分选及其细胞再分配。我们提出，CD36的配体脂肪酸和OxLDL的泛素化是一种保护机制，通过诱导CD36降解来限制这些脂质的过量摄取，该机制的功能障碍将导致病理。我们建议研究CD36加工调控的机制及其与脂肪酸代谢和胰岛素抵抗的关系。我们还将探讨CD36的细胞内运输如何影响脂肪细胞中脂滴的生物发生和成熟水平的脂质储存。我们将验证脂肪组织CD36由于正能量平衡而在病理生理方面发挥保护作用的假设，通过促进脂肪PPARgamma和脂质储存的激活，从而最大限度地减少异位脂肪积累。本研究具有潜在的临床意义。在人类中，CD36基因的多态性是常见的，CD36变异与血脂、代谢综合征易感性和心血管疾病有关。更好地了解CD36在FA摄取和加工中的分子调节功能将有助于设计更好的治疗方法，防止或逆转功能失调的FA代谢及其有害后果。公共卫生相关性：膜蛋白CD36促进关键代谢组织（如肌肉、脂肪组织、心脏和肠道）对长链脂肪酸的摄取。我们最近的数据表明，脂肪酸通过其泛素化作用急剧增强CD36的周转，其目标是降解。我们认为这种保护机制的功能障碍会导致过量脂肪酸摄取的病理结果。提出的工作将探索调节CD36周转的机制及其对胰岛素抵抗的影响。本研究具有潜在的临床意义。在人类中，脂肪酸代谢异常与细胞膜上CD36水平异常相关。此外，CD36基因的常见变异与血脂、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.