Physiological Significance of Conjugated Double Bonds in Membrane Lipids

描述（由申请人提供）：虽然人造反式不饱和脂肪通常对人体健康有害，但在乳制品和肉类中发现的一类新的天然反式脂肪酸，称为共轭亚油酸（CLA），已被证明具有多种健康益处。膳食中的CLA由许多异构体组成，据报道可以预防多种疾病，包括癌症、肥胖症、心脏病、炎症和糖尿病。然而，这些结果是有争议的，除了有益的效果，许多不良反应，包括脂肪肝，脂肪代谢障碍，胰岛素抵抗也被报道。CLA的广泛作用机制尚不清楚，但饮食中的两种主要异构体，即顺式9反式11（c9t11）和反式10顺式12（t10c12）CLA具有明显不同的生物学作用，前者与抗癌作用有关，后者与抗肥胖作用有关。尽管CLA异构体对特定基因表达的差异影响可以解释一些结果，但既没有统一的假设来解释CLA的大量看似不相关的影响，也没有其异构体特异性影响的物理化学基础。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设，即CLA的长期作用是膜筏的组成和功能改变的结果，膜筏在许多细胞功能中起着关键作用。在具体目标2中，我们将解决的假设，顺式双键在位置9的脂肪酸链起着决定膜的物理化学性质，包括流动性，胆固醇结合，和渗透性，这是负责的差异生物效应的c9t11和t10c12共轭亚油酸异构体。除了合成磷脂的物理化学研究外，我们还将采用分子动力学模拟来研究CLA与其他膜组分的原子水平相互作用，以验证这一假设。公共卫生相关性：共轭亚油酸（CLA）是一种受欢迎的营养补充剂，据报道，共轭亚油酸可以预防多种疾病，包括癌症、肥胖、心脏病和炎症。从这些研究中获得的结果应该使我们不仅能够了解CLA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，而不会产生不良的副作用，如胰岛素抵抗。

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.