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

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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.