To study the role of the low-density lipoprotein receptor on carotenoid biodistribution and excretion

项目总结 类胡萝卜素是一组不同的化合物，导致水果和水果中的黄色到红色 蔬菜。这些化合物被广泛认为是最重要的生物活性物质之一。 我们食物中的化合物。类胡萝卜素可分为维生素A原类胡萝卜素，如β-胡萝卜素，以及 非维生素A原类胡萝卜素，如叶黄素。 而类胡萝卜素在促进人类健康和预防疾病方面的作用是 显然，人们对这些物质的分布和排泄的控制机制知之甚少 化合物。这种认识上的差距，至少部分是由于缺乏可靠的动物模型 研究模拟人类类胡萝卜素生理的类胡萝卜素积累。例如，酶 负责类胡萝卜素降解的物质，在所有哺乳动物中都存在，在小鼠中非常活跃 但在人类中不是，这导致饮食中的类胡萝卜素在我们的组织中积累，与此形成对比的是 在老鼠身上发生了什么。克服这一技术限制的唯一方法是依靠敲除鼠标 β-胡萝卜素加氧酶1(BCO_1)和β-胡萝卜素加氧酶1(BCO_2)的模型 和其他类胡萝卜素。 在我们的母公司R01中，我们的目标是确定β-胡萝卜素和维生素A在动脉粥样硬化中的作用，并 为此，我们将缺乏BCO1和低密度脂蛋白受体(LDLR)的小鼠结合在一起。结果, 这些复合小鼠由于缺乏BCO1和BCO1而积累类胡萝卜素并发展为动脉粥样硬化 LDLR分别为。我们正在产生缺乏BCO2和LDLR的复合突变体，在 我们将能够研究低密度脂蛋白受体在叶黄素积累中的作用。 通过将这两个新的小鼠品系与BCO1和BCO2单独作用，我们将研究LDLR在BCO1和BCO2中的作用 (1)类胡萝卜素的生物分布；(2)肠道排泄。使用最先进的方法来 对组织、血浆和粪便中的这些化合物进行量化，我们将确定LDLR在 类胡萝卜素的运输。

PROJECT SUMMARY Carotenoids are a diverse group of compounds responsible for the yellow-to-red colors in fruits and vegetables. These compounds are widely considered to be among the most important bioactive compounds in our food. Carotenoids can be divided in provitamin A carotenoids such as β-carotene, and non-provitamin A carotenoids such as lutein. While the role of carotenoids in the promotion of health and the prevention of disease in humans is clear, little is known about the mechanisms that control the distribution and excretion of these compounds. This gap in knowledge occurs, at least in part, due to the lack of reliable animal models to study carotenoid accumulation that mimic human carotenoid physiology. For instance, the enzymes responsible of carotenoid degradation, which are present in all mammals, are extremely active in mice but not in humans, which leads to the accumulation of dietary carotenoids in our tissues, in contrast to what occurs in mice. The only way to overcome this technical limitation is to rely on knockout mouse models for β-carotene oxygenase 1 (BCO1), which cleaves β-carotene, and BCO2, which cleaves lutein and other carotenoids. In our parent R01, we aim to determine the role of β-carotene and vitamin A on atherosclerosis, and to this end, we combined mice lacking BCO1 and the low-density lipoprotein receptor (LDLR). As a result, these compound mice accumulate carotenoids and develop atherosclerosis due to the lack of BCO1 and LDLR, respectively. We are in the process of generating compound mutants lacking BCO2 and LDLR, in which we will be able to study the role of LDLR in lutein accumulation. By using these two novel new mouse strains to single BCO1 and BCO2, we will study the role of LDLR in (1) carotenoid biodistribution, and (2) intestinal elimination. Using state of the art methodologies to quantify these compounds in tissues, plasma, and feces, we will establish the role of the LDLR in carotenoid transport.