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

项目摘要 类胡萝卜素是一组不同的化合物，负责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以分为维生素A原类胡萝卜素，如β-胡萝卜素，和 非维生素原A类胡萝卜素如叶黄素。 虽然类胡萝卜素在促进人类健康和预防疾病中的作用是 显然，人们对控制这些物质分布和排泄的机制知之甚少 化合物.这种知识上的差距，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学类胡萝卜素积累。例如，酶 负责类胡萝卜素降解，这是存在于所有哺乳动物，是非常活跃的小鼠 但在人类中却没有，这导致了膳食类胡萝卜素在我们的组织中的积累，与之相反， 发生在老鼠身上的事情。克服这一技术局限性的唯一途径就是依靠敲除小鼠 β-胡萝卜素加氧酶1（BCO 1）和BCO 2的模型，BCO 1裂解β-胡萝卜素，BCO 2裂解叶黄素 和其他类胡萝卜素。 在我们的亲本R 01中，我们旨在确定β-胡萝卜素和维生素A在动脉粥样硬化中的作用， 为此，我们将缺乏BCO 1和低密度脂蛋白受体（LDLR）的小鼠结合起来。因此，在本发明中， 这些复合小鼠积累类胡萝卜素并由于缺乏BCO 1而发展为动脉粥样硬化， LDLR，分别。我们正在产生缺乏BCO 2和LDLR的复合突变体， 我们将能够研究LDLR在叶黄素积累中的作用。 通过使用这两个新的小鼠品系单独BCO 1和BCO 2，我们将研究LDLR在以下方面的作用： (1)类胡萝卜素的生物分布，和（2）肠道消除。使用最先进的方法， 定量组织、血浆和粪便中的这些化合物，我们将确定LDLR在 类胡萝卜素转运

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.