De Novo Lipogenesis and Metabolic Disease

描述(申请人提供)：脂肪酸合成酶(FAS)是一种新生脂肪生成所需的多功能酶，在常见的代谢性疾病中会发生改变。我们最近发现，Fas反应产物优先激活肝脏中的过氧化物酶体增殖物激活受体α(PPARpha)。PPAR是已知的影响糖脂代谢的核受体，它们是改变与代谢性疾病相关的异常环境的饮食和药物治疗的有吸引力的靶点。我们现在已经使用Cre-Lox技术建立了几个新的动物模型，并证明了Fas似乎也影响巨噬细胞、内皮和下丘脑中PPARpha依赖的过程，在血管疾病、炎症(包括内毒素诱导死亡的易感性)和肥胖方面具有显著的组织特异性作用。该项目将检验这样一个假设，即Fas介导的从头脂肪生成在一定程度上通过激活PPARpha来调节与炎症相关的代谢紊乱的易感性，如动脉粥样硬化、肥胖和脂肪肝。我们将追求以下特定目标：1.在巨噬细胞Fas失活的小鼠(FASKOM小鼠)中，确定对血管疾病的保护是否由另一种核受体-巨噬细胞LXRpha介导。2.确定内毒素诱导的内皮Fas失活小鼠(FASKOE小鼠)的死亡是否被PPARpha激活所预防，以及饮食诱导的动脉粥样硬化是否在这些小鼠对炎症刺激的反应增强的情况下加速。3.确定进食量减少的下丘脑Fas失活小鼠(FASKOHyp小鼠)是否对饮食诱导的肥胖具有抵抗力，以及PPARpha激活是否能逆转这些小鼠的低吞噬表型。4.通过比较正常小鼠和Fas失活小鼠(FASKOL小鼠)的PPARpha相关脂谱，鉴定Fas可能产生的内源性PPARpha配体。肥胖及其并存是一个巨大的公共卫生问题。这些研究的结果有可能建立新的药理和饮食方法来治疗与肥胖相关的常见代谢紊乱。

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.