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. 12α-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 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 manganese homeostasis.
Highlights
Bile acids (BAs) are cholesterol catabolites that regulate many biological functions, including multiple aspects of macronutrient metabolism
The differences between the pools were due to two key features: (i) the proportion of 12a-hydroxylated bile acid (12HBA), either 10% or 90%, and (ii) the BA pool of the species we modeled, either human or mouse (Table 1 and Fig. 1B)
Consistent with this, removing T-chenodeoxycholic acid (CDCA) from mouse low (10%) 12HBA (M10) and mouse high (90%) 12HBA (M90) pools resulted in blunted Fgf15 and Fabp6 induction (Fig. 3F). These findings indicate that lithocholic acid (LCA), but not CDCA, is the BA primarily responsible for the differential expression of Slc30a10 between low- versus high-12HBA pools
Summary
Bile acids (BAs) are cholesterol catabolites that regulate many biological functions, including multiple aspects of macronutrient metabolism. Among the genes identified to be differentially expressed between BA pools with varying 12HBA abundance, one of the most robust was Slc30a10 (Fig. 1D). Low-12HBA pools were superior to high12HBA pools in inducing Slc30a10 (Fig. 2, A and B).
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