Physiological Significance of Conjugated Double Bonds in Membrane Lipids

描述(申请人提供)：虽然人造反式不饱和脂肪通常对人体健康有害，但一种新的天然存在的反式脂肪酸，称为共轭亚油酸(CLA)，存在于乳制品和肉类中，已被证明对健康有几个好处。膳食中的CLA由许多异构体组成，据报道，它对包括癌症、肥胖症、心脏病、炎症和糖尿病在内的几种疾病具有保护作用。然而，这些结果是有争议的，除了有益的效果外，也有许多不良影响的报道，包括脂肪肝、脂肪营养不良和胰岛素抵抗。CLA的广泛作用机制尚不清楚，但饮食中的两种主要异构体，即顺9反11(C9t11)和反式10顺12(T10c12)共轭亚油酸具有明显不同的生物学效应，前者与抗癌作用有关，后者与减肥作用有关。尽管共轭亚油酸异构体对特定基因表达的不同影响可能解释了一些结果，但既没有统一的假说来解释共轭亚油酸的大量看似无关的效应，也没有一个物理化学基础来解释它们的异构体特异性效应。为了解决这些问题，我们提出了两个新的假设。在具体目标1中，我们将使用培养的肝细胞和脂肪细胞来检验这一假说，即CLA的长期作用是改变膜筏的组成和功能的结果，膜筏在许多细胞功能中发挥着关键作用。在具体目标2中，我们将解决这样的假设，即脂肪链第9位的顺式双键在决定膜的物理化学性质(包括流动性、胆固醇结合和通透性)方面起着关键作用，这是c9t11和t10c12CLA异构体不同生物效应的原因。除了对合成的磷脂进行物理化学研究外，我们还将利用分子动力学模拟来研究共轭亚油酸与其他膜组分的原子水平相互作用，以验证这一假说。公共卫生相关性：共轭亚油酸(CLA)是广受欢迎的营养补充剂，据报道，它可以预防多种疾病，包括癌症、肥胖症、心脏病和炎症，因此被消费。这些研究的结果不仅使我们能够了解共轭亚油酸的作用机制，而且还可以修改它们的结构，以获得最佳的有益效果，而不会出现胰岛素抵抗等不良副作用。

DESCRIPTION (provided by applicant): Although the man-made trans-unsaturated fats are generally detrimental to human health, a new class of naturally occurring trans fatty acids, called conjugated linoleic acids (CLA), which are found in dairy products and meat, have been shown to have several health benefits. The dietary CLA, which are composed of many isomers, have been reported to be protective against several diseases including cancer, obesity, heart disease, inflammation and diabetes. However, these results are controversial, and in addition to the beneficial effects, many undesirable effects, including fatty liver, lipodystrophy, and insulin resistance have also been reported. The mechanisms underlying the wide range of CLA effects are unknown, but the two major isomers in the diet, namely cis 9 trans 11 (c9t11), and trans 10 cis 12 (t10c12) CLA have markedly different biological effects, with the former being associated with the anti-cancer effects, and the latter with the anti-obesity effects. Although the differential effects of CLA isomers on expression of specific genes may explain some of the results, there is neither an unifying hypothesis to explain the vast number of seemingly unrelated effects of CLA, nor a physicochemical basis for their isomer-specific effects. To address these issues, we propose two novel hypotheses. In Specific Aim 1, we will use cultured hepatocytes and adipocytes to test the hypothesis that the long term effects of CLA are the result of modification of the composition and function of membrane rafts, which play critical roles in numerous cellular functions. In Specific Aim 2, we will address the hypothesis that the cis double bond at position 9 of the fatty acid chain plays a critical role in determining the physicochemical properties of the membranes, including fluidity, cholesterol-binding, and permeability, and that this is responsible for the differential biological effects of the c9t11 and t10c12 CLA isomers. In addition to the physicochemical studies with the synthetic phospholipids, we will employ molecular dynamics simulation to study the atomic level interaction of CLA with other membrane components, to test this hypothesis. PUBLIC HEALTH RELEVANCE: Conjugated linoleic acids (CLA) are popular nutritional supplements, which are consumed because of their reported protection against several diseases including cancer, obesity, heart disease and inflammation. The results obtained from these studies should enable us not only to understand the mechanism of action of CLA, but also to modify their structures for optimum beneficial effects without the undesirable side effects such as insulin resistance.