Saturated Fatty Acid and Cardiovascular Disease

描述（由申请人提供）：本提案要测试的中心假设是饱和脂肪酸与SR-BI的结合激活AMP激酶，导致eNOS依赖性过氧亚硝酸盐的产生，并随后增加动脉粥样硬化病变。几十年来，减少膳食脂肪摄入总量一直被用作降低冠心病风险的方法；然而，大量研究表明，脂肪的类型可能比饮食中脂肪的总量更重要。不饱和脂肪，例如 n-3 和 n-6 脂肪酸被认为具有抗动脉粥样硬化作用，而具有 14-16 个碳原子的饱和脂肪酸（即肉豆蔻酸和棕榈酸）被认为具有促动脉粥样硬化作用。饱和脂肪酸被认为是促动脉粥样硬化的，部分原因是导致血浆总胆固醇水平增加。虽然血浆胆固醇水平明显影响动脉粥样硬化病变的发展，但胆固醇只是动脉粥样硬化多因素疾病的因素之一。我们的初步研究表明，饱和脂肪酸可以导致动脉粥样硬化的增加，而与血浆胆固醇水平的变化无关。该提案的目标是确定饱和脂肪酸在不改变血浆胆固醇的情况下促进动脉粥样硬化的机制。初步数据表明，饱和脂肪酸存在一种新的信号传导机制，涉及 SR-BI、caveolin、AMP 激酶和 eNOS，随后导致促动脉粥样硬化化合物过氧亚硝酸盐的生成。提出了三个具体目标。目标 1：确定 SR-BI 内与饱和脂肪酸和小窝蛋白相互作用的结构域，并确定小窝蛋白内与 SR-BI 相互作用的结构域。目标 2：阐明 Caveolin 中被磷酸化的残基以及 Caveolin 和 AMP 激酶中相互作用的结构域。目标 3：确定内皮特异性小窝蛋白缺失小鼠是否能够免受饱和脂肪酸诱导的过氧亚硝酸盐产生以及随后的动脉粥样硬化的影响。

DESCRIPTION (provided by applicant): The central hypothesis to be tested in this proposal is that binding of saturated fatty acid to SR-BI activates AMP kinase which results in the production of eNOS-dependent peroxynitrite and subsequently an increase in atherosclerotic lesions. Reducing total dietary fat intake has been used as a method for reducing the risk of coronary heart disease for decades; however, numerous studies have demonstrated that the type of fat may be more important than the total amount of fat in the diet. Unsaturated fats, such as, n-3 and n-6 fatty acids are thought to be anti-atherogenic whereas saturated fatty acids with 14-16 carbon atoms (i.e., myristic acid and palmitic acid) are considered to be pro-atherogenic. Saturated fatty acids are thought to be pro-atherogenic, in part, by causing an increase in total plasma cholesterol levels. Although plasma cholesterol levels clearly influence the development of atherosclerotic lesions cholesterol is only one factor in the multi-factorial disease of atherosclerosis. Our preliminary studies demonstrate that saturated fatty acid can cause an increase in atherosclerosis independent of changes in plasma cholesterol levels. The goal of this proposal is to determine the mechanism whereby saturated fatty acid promotes atherosclerosis without altering plasma cholesterol. The preliminary data suggest that a novel signaling mechanism exists for saturated fatty acids that involve SR-BI, caveolin, AMP kinase, and eNOS which subsequently results in the generation of the pro- atherogenic compound, peroxynitrite. Three specific aims are proposed. Aim 1: To determine the domains within SR-BI that interact with saturated fatty acids and caveolin and to determine the domain within caveolin that interacts with SR-BI. Aim 2: To elucidate the residue(s) in caveolin that are phosphorylated and the domains within caveolin and AMP kinase that interact. Aim 3: To determine if an endothelial-specific caveolin null mouse is protected from saturated fatty acid-induced peroxynitrite production and subsequently atherosclerosis.