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Bile acid composition regulates the manganese transporter Slc30a10 in intestine

Tiara R. Ahmad, Sei Higuchi, Enrico Bertaggia, Allison Hung, Niroshan Shanmugarajah, Nicole C. Guilz, Jennifer R. Gamarra, Rebecca A. Haeusler
doi: https://doi.org/10.1101/2020.02.11.944124
Tiara R. Ahmad
1Department of Pathology and Cell Biology, Columbia University, New York NY 10032
2Naomi Berrie Diabetes Center, Columbia University, New York NY 10032
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Sei Higuchi
1Department of Pathology and Cell Biology, Columbia University, New York NY 10032
2Naomi Berrie Diabetes Center, Columbia University, New York NY 10032
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Enrico Bertaggia
1Department of Pathology and Cell Biology, Columbia University, New York NY 10032
2Naomi Berrie Diabetes Center, Columbia University, New York NY 10032
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Allison Hung
2Naomi Berrie Diabetes Center, Columbia University, New York NY 10032
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Niroshan Shanmugarajah
1Department of Pathology and Cell Biology, Columbia University, New York NY 10032
2Naomi Berrie Diabetes Center, Columbia University, New York NY 10032
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Nicole C. Guilz
2Naomi Berrie Diabetes Center, Columbia University, New York NY 10032
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Jennifer R. Gamarra
2Naomi Berrie Diabetes Center, Columbia University, New York NY 10032
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Rebecca A. Haeusler
1Department of Pathology and Cell Biology, Columbia University, New York NY 10032
2Naomi Berrie Diabetes Center, Columbia University, New York NY 10032
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  • For correspondence: rah2130@columbia.edu
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ABSTRACT

Bile acids (BAs) comprise heterogenous amphipathic cholesterol-derived molecules that carry out physicochemical and signaling functions. A major site of BA action is the terminal ileum, where enterocytes actively reuptake BAs and express high levels of BA-sensitive nuclear receptors. BA pool size and composition are affected by changes in metabolic health, and vice versa. One of several factors that differentiate BAs is the presence of a hydroxyl group on C12 of the steroid ring. 12a-hydroxylated BAs (12HBAs) are altered in multiple disease settings, but the consequences of 12HBA abundance are incompletely understood. We employed mouse primary ileum organoids to investigate the transcriptional effects of varying 12HBA abundance in BA pools. We identified Slc30a10 as one of the top genes differentially induced by BA pools with varying 12HBA abundance. SLC30A10 is a manganese (Mn) efflux transporter critical for whole-body manganese excretion. We found that BA pools, especially those low in 12HBAs, induce cellular manganese efflux, and that Slc30a10 induction by BA pools is driven primarily by lithocholic acid signaling via the vitamin D receptor. Administration of lithocholic acid or a vitamin D receptor agonist resulted in increased Slc30a10 expression in mouse ileum epithelia. These data demonstrate a previously unknown role for BAs in intestinal control of Mn homeostasis.

  • Abbreviations

    12-HBA
    12α-hydroxylated bile acid;
    α-MCA
    α-muricholic acid;
    β-MCA
    β-muricholic acid;
    BA(s)
    bile acid(s);
    CA
    cholic acid;
    CDCA
    chenodeoxycholic acid;
    DCA
    deoxycholic acid;
    FXR
    farnesoid X receptor;
    LCA
    lithocholic acid;
    UDCA
    ursodeoxycholic acid;
    VDR
    vitamin D receptor
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    Posted February 12, 2020.
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    Bile acid composition regulates the manganese transporter Slc30a10 in intestine
    Tiara R. Ahmad, Sei Higuchi, Enrico Bertaggia, Allison Hung, Niroshan Shanmugarajah, Nicole C. Guilz, Jennifer R. Gamarra, Rebecca A. Haeusler
    bioRxiv 2020.02.11.944124; doi: https://doi.org/10.1101/2020.02.11.944124
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    Bile acid composition regulates the manganese transporter Slc30a10 in intestine
    Tiara R. Ahmad, Sei Higuchi, Enrico Bertaggia, Allison Hung, Niroshan Shanmugarajah, Nicole C. Guilz, Jennifer R. Gamarra, Rebecca A. Haeusler
    bioRxiv 2020.02.11.944124; doi: https://doi.org/10.1101/2020.02.11.944124

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