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Mammalian Carotenoid Metabolism

Palczewski, Grzegorz
http://rave.ohiolink.edu/etdc/view?acc_num=case1467993233

Abstract Details

2016, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
Carotenoids are involved in a rich variety of physiological functions in nature and are essential as retinoid precursors. While the knowledge about retinoid homeostasis has increased over the past, the metabolism of carotenoids, the parent precursors of retinoids, is less well described. Retinoids, such as vitamin A, are produced from dietary carotenoids such as ß-carotene by centric cleavage via the enzyme BCO1. While BCO1 cleaves provitamin A carotenoids, a second enzyme, BCO2, is more promiscuous and metabolizes a veritable host of carotenoids, including nonprovitamin A carotenoids such as zeaxanthin into short and long chain apocarotenoids. We demonstrated in cell lines that human BCO2 is associated with the inner mitochondrial membrane. Different human BCO2 isoforms possess cleavable N-terminal leader sequences critical for mitochondrial import. Subfractionation of murine hepatic mitochondria confirmed the localization of the murine homolog to the inner mitochondrial membrane. Studies in knockout mice revealed that zeaxanthin accumulates in the inner mitochondrial membrane; in contrast, ß-carotene is retained predominantly in the cytoplasm. With the use of a mouse model lacking both BCO1 and BCO2 and applying a genome wide microarray analysis we assessed the effects of supplemented carotenoids on the liver transcriptome and documented changes in pathways for liver lipid metabolism and mitochondrial respiration. By genetically dissecting carotenoid and apocartenoid functions, we observed that ß-carotene accumulation resulted in an elevation of liver triglycerides and liver cholesterol, while zeaxanthin accumulation increased serum cholesterol levels. We further showed that carotenoids were predominantly transported within HDL particles in the serum of mice. Thus our findings were twofold; first we provided evidence for a compartmentalization of carotenoid metabolism which prevents competition between BCO1 and BCO2 for the precious ß-carotene and the production of non-canonical ß-apocarotenoid metabolites. Second we observed that accumulation of parent carotenoids interacts with lipid metabolism and that structurally related carotenoids displayed distinct biological functions in mammals.
Johannes von Lintig (Advisor)
Martin Snider (Committee Chair)
Charles Hoppel (Committee Member)
Jason Mears (Committee Member)
John Mieyal (Committee Member)
David Samols (Committee Member)
145 p.
Biochemistry
BCO1; BCO2; beta-carotene; zeaxanthin; carotenoids

Recommended Citations

Citations

  • Palczewski, G. (2016). Mammalian Carotenoid Metabolism [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1467993233

    APA Style (7th edition)

  • Palczewski, Grzegorz. Mammalian Carotenoid Metabolism. 2016. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1467993233.

    MLA Style (8th edition)

  • Palczewski, Grzegorz. "Mammalian Carotenoid Metabolism." Doctoral dissertation, Case Western Reserve University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1467993233

    Chicago Manual of Style (17th edition)

case1467993233
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© 2016, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.