DE NOVO LIPOGENESIS AND METABOLIC DISEASE

描述（由申请人提供）：脂肪酸合成酶（FAS）合成棕榈酸和其他脂肪酸。在成人中，FAS被认为在生理上并不重要。这一观点受到了挑战，因为我们证明FAS通过激活核受体PPAR？影响几种组织的代谢。在肝脏中，FAS依赖性激活部分由作为PPAR？配体的磷脂酰胆碱类介导。FAS还驱动一个独立于PPAR的信号传导过程。内皮FAS缺乏导致内皮型一氧化氮合酶（eNOS）棕榈酰化受损引起的血管功能障碍。添加棕榈酸酯，FAS的直接产物，在FAS缺乏的情况下不能恢复有缺陷的PPAR？或eNOS信号传导。我们的研究结果表明，FAS被划分在一个集成的盒产生信号主管脂质，可能会影响代谢疾病。 本申请的长期目标是通过调节FAS信号传导功能来改善糖尿病和肥胖症患者的健康。本项目将测试FAS传输生理信号的假设。这些脂质信号通过离散的信号传导节点、分子伴侣和FAS本身的共价修饰而被区室化以影响代谢疾病。具体目标是：1.通过使用从对照小鼠和肝脏特异性FAS缺陷小鼠肝脏中纯化的PC-TP比较PC-TP相关的脂质谱，暗示PC-TP作为参与细胞核中FAS依赖性内源性配体与PPAR？结合的伴侣。 2.确定肝脏和内皮中CEPT 1（FAS信号传导的假定节点）组织特异性失活的小鼠是否具有模拟FAS组织特异性失活小鼠的表型。 3.鉴定FAS相互作用蛋白，这些蛋白可能参与将FAS引导至不同的细胞区室，并将其酶产物区室化至离散的信号节点。 4.确定营养调节的磷酸化位点以及FAS中的其他共价修饰是否介导FAS酶活性和细胞生理学。 通过建立区室化FAS作为生理信号的介导者，该项目可以通过确定与糖尿病和肥胖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.