DE NOVO LIPOGENESIS AND METABOLIC DISEASE

描述(申请人提供)：脂肪酸合成酶(FAS)合成棕榈酸和其他脂肪酸。在成年人中，Fas被认为在生理上并不重要。我们的研究表明，Fas通过激活核受体PPAR？影响几个组织中的新陈代谢，这一观点受到了挑战。在肝脏中，Fas依赖的激活在一定程度上是由作为PPAR？配体的磷脂酰胆碱介导的。Fas还驱动独立于PPAR的信令流程。内皮型Fas缺乏症是由于内皮型一氧化氮合酶(ENOS)棕榈酰化受损而导致的血管功能障碍。在Fas缺乏的情况下，添加Fas的直接产物棕榈酸酯并不能恢复有缺陷的PPAR或eNOS信号。我们的发现表明，Fas被分隔在一个整合的盒中，产生可能影响代谢性疾病的具有信号能力的脂类。该应用的长期目标是通过调节Fas信号功能来改善糖尿病和肥胖者的健康。这个项目将检验Fas传递生理信号的假设。这些脂质信号通过离散的信号节点、伴侣和Fas本身的共价修饰来影响代谢性疾病。其具体目的是：1.通过比较对照组小鼠和肝脏特异性Fas缺陷小鼠肝脏磷脂酰胆碱转移蛋白(PC-TP)的脂谱，推测PC-TP是参与Fas依赖的内源性PPAR配体在细胞核内结合的伴侣。2.确定肝脏和内皮中CEPT1(Fas信号转导的假定节点)组织特异性失活的小鼠是否具有与组织特异性Fas失活小鼠相似的表型。3.鉴定与Fas相互作用的蛋白，这些蛋白可能参与将Fas定向到不同的细胞室，并将其酶产物区隔到不同的信号节点。4.确定Fas中营养调节的磷酸化位点以及其他共价修饰是否调节Fas酶的活性和细胞生理。通过建立分隔的Fas作为生理信号的媒介，该项目可以通过确定与糖尿病和肥胖症相关的广泛代谢紊乱的新治疗靶点来改善人类健康。

DESCRIPTION (provided by applicant): Fatty acid synthase (FAS) synthesizes palmitate and other fatty acids. In adults, FAS has not been thought to be physiologically important. This notion was challenged by our demonstration that FAS affects metabolism in several tissues by activating the nuclear receptor PPAR¿. In liver, FAS-dependent activation is mediated in part by a phosphatidylcholine species that serves as a PPAR¿ ligand. FAS also drives a PPAR¿- independent signaling process. Endothelial FAS deficiency results in vascular dysfunction caused by impaired palmitoylation of endothelial nitric oxide synthase (eNOS). Addition of palmitate, the direct product of FAS, does not restore defective PPAR¿ or eNOS signaling in the setting of FAS deficiency. Our findings suggest that FAS is compartmentalized within an integrated cassette generating signaling-competent lipids that could affect metabolic disease. The long-term objective of this application is to improve the health of people with diabetes and obesity by modulating FAS signaling functions. This project will test the hypothesis that FAS transmits physiological signals. These lipid signals are compartmentalized through discrete signaling nodes, chaperones, and covalent modification of FAS itself to impact metabolic disease. The specific aims are: 1. To implicate phosphatidylcholine transfer protein (PC-TP) as a chaperone involved in the binding of an FAS-dependent endogenous ligand for PPAR¿ in the nucleus by comparing PC-TP-associated lipid spectra using PC-TP purified from livers of control mice and liver-specific FAS-deficient mice. 2. To determine if mice with tissue-specific inactivation of CEPT1 (a putative node for FAS signaling) in the liver and at the endothelium have phenotypes that mimic those of mice with tissue-specific inactivation of FAS. 3. To identify FAS-interacting proteins potentially involved in directing FAS to distinct cellular compartments and compartmentalizing its enzymatic product to discrete signaling nodes. 4. To determine if nutritionally regulated phosphorylation sites as well as other covalent modifications in FAS mediate FAS enzyme activity and cellular physiology. By establishing compartmentalized FAS as a mediator of physiological signals, this project could improve human health by identifying novel therapeutic targets for a wide range of metabolic disorders associated with diabetes and obesity.