De Novo Lipogenesis and Metabolic Disease

描述（由申请人提供）：脂肪酸合成酶（FAS）是一种多功能酶，用于脂肪的新生生成，在常见的代谢性疾病中发生改变。我们最近发现FAS反应的产物优先激活肝脏中过氧化物酶体增殖物激活受体α (ppar α)。ppar是已知影响葡萄糖和脂质代谢的核受体，它们是饮食和药物治疗改变与代谢性疾病相关的异常环境的有吸引力的靶点。我们现在使用Cre-Lox技术建立了几个新的动物模型，并证明FAS似乎也影响巨噬细胞、内皮和下丘脑中的ppar依赖过程，对血管疾病、炎症（包括对内毒素诱导死亡的易感性）和肥胖具有显著的组织特异性作用。该项目将测试由FAS介导的从头脂肪生成通过激活ppar来调节与炎症相关的代谢紊乱（如动脉粥样硬化、肥胖和脂肪肝）的易感性的假设。具体目标是：确定巨噬细胞FAS失活小鼠（FASKOM小鼠）对血管疾病的保护是否由巨噬细胞lxrα（另一种核受体）介导。2. 确定pparα激活是否可以预防内皮细胞FAS失活小鼠（FASKOE小鼠）内毒素诱导的死亡，以及这些小鼠对炎症刺激的反应增加是否会加速饮食诱导的动脉粥样硬化。3. 为了确定食物摄入减少的下丘脑FAS失活小鼠（FASKOHyp小鼠）是否对饮食诱导的肥胖有抵抗力，以及这些小鼠的贪食表型是否可以通过激活ppar来逆转。4. 通过比较对照组小鼠和FAS失活小鼠（FASKOL小鼠）肝脏中ppar相关脂质谱，鉴定FAS产生的潜在内源性ppar配体。肥胖及其合并症是一个巨大的公共卫生问题。这些研究的发现有可能为治疗与肥胖相关的常见代谢紊乱建立新的药理学和饮食方法。

DESCRIPTION (provided by applicant): Fatty acid synthase (FAS), the multifunctional enzyme required for de novo lipogenesis, is altered in common metabolic diseases. We recently discovered that the products of the FAS reaction preferentially activate peroxisome proliferator-activated receptor alpha (PPARalpha) in liver. PPARs are nuclear receptors known to affect glucose and lipid metabolism, and they represent attractive targets for diet and drug therapy to alter the abnormal milieu associated with metabolic diseases. We have now generated several new animal models using Cre-Lox technology and demonstrated that FAS also appears to affect PPARalpha-dependent processes in macrophages, endothelium and hypothalamus with striking tissue-specific effects on vascular disease, inflammation (including susceptibility to endotoxin-induced death), and obesity. This project will test the hypothesis that de novo lipogenesis mediated by FAS modulates susceptibility to metabolic disorders associated with inflammation such as atherosclerosis, obesity and fatty liver in part by activating PPARalpha. We will pursue the following specific aims: 1. To determine in mice with FAS inactivation in macrophages (FASKOM mice) if protection from vascular disease is mediated by macrophage LXRalpha, another nuclear receptor. 2. To determine if endotoxin-induced death in mice with FAS inactivation in endothelium (FASKOE mice) is prevented by PPARalpha activation and if diet-induced atherosclerosis is accelerated in these mice with an increased response to inflammatory stimuli. 3. To determine if mice with FAS inactivation in hypothalamus (FASKOHyp mice) with decreased food intake are resistant to diet-induced obesity and if the hypophagic phenotype in these mice can be reversed by PPARalpha activation. 4. To identify potential endogenous PPARalpha ligands produced by FAS by comparing PPARalpha-associated lipid spectra between control mice and mice with FAS inactivation in liver (FASKOL mice). Obesity and its co-morbidities represent an enormous public health problem. Findings from these studies have the potential to establish novel pharmacologic and dietary approaches for the treatment of common metabolic disorders associated with obesity.