Examining the role of LDLR in the biodistribution of carotenoids

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PROJECT SUMMARY The low-density lipoprotein receptor (LDLR) is a widely expressed protein known mostly for its role in hepatic uptake and clearance of LDL cholesterol. Like cholesterol, carotenoids such as β-carotene and lutein are transported in LDL particles due to their hydrophobic nature. There remains, however, unknowns about the metabolic fate of carotenoids found in lipoproteins, as well as the function of LDLR in these processes. In particular, LDLR is known to mediate transintestinal cholesterol excretion, which is known to account for up to 35% of cholesterol excretion in humans. Whether carotenoids are also eliminated through this process is unknown. Carotenoids are primarily stored in the liver, but surprisingly, several knowledge gaps exist in the hepatic metabolism of carotenoids, including if LDLR mediates the hepatic uptake of carotenoids, or if carotenoids, like cholesterol, modify the characteristics of secreted in VLDL particles. Therefore, the overarching objective of this proposal is to characterize the role of LDLR in carotenoid excretion and hepatic uptake, as well as examine the incorporation of carotenoids into VLDL particles and how VLDL characteristics are consequently altered. We hypothesize that LDLR mediates transintestinal carotenoid excretion and contributes to hepatic carotenoid uptake. We also hypothesize that hepatic carotenoids are incorporated into newly-synthesized VLDL and modify their size and lipid content. To test these hypotheses, we propose three objectives that will characterize the involvement of LDLR in carotenoid uptake and excretion, as well as hepatic participation in carotenoid distribution. These studies have the potential to reveal critical pathways in carotenoid transport and elimination in humans.