Bile acid composition regulates the manganese transporter Slc30a10 in intestine

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 (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.

Genetic and Microbial Associations to Plasma and Fecal Bile Acids in Obesity Relate to Plasma Lipids and Liver Fat Content

“…How these transporters might modulate plasma levels of secondary BAs is not known and requires functional follow-up. Interestingly, Ahmad et al (2020) recently reported that the non-12a hydroxylated secondary species LCA induces the expression of the ileal manganese efflux transporter SLC30A10 via activation of VDR, which supports the existence of a functional link between BA and manganese metabolism. Additionally, we found four zincfinger-protein-related genetic variants (ZFN569, ZFN250, ZFN706, and JAZF1) to associate with five fecal BA entities, including fecal DCA and CDCA contents.…”

Toward a Cell Culture Model of Portal Axis Lipid Handling

“…However, IBABP expression, like FGF19, was robustly induced by H10 and, to a lesser extent, by H90. As the commercial formulation appeared to yield results more consistent with published findings [15], we favored it to perform the experiments in 2D-hIO below.…”

“…Unconjugated bile acid mixes were prepared and dissolved in DMSO according to proportions we have published previously [15]. H10 (i.e., 10% 12-HBA, 90% non-12-HBA) consists, on a molar basis, of: 7% cholic acid (CA), 3% deoxycholic acid (DCA), 86.85% chenodeoxycholic acid (CDCA), 2.25% ursodeoxycholic acid (UDCA), and 0.90% lithocholic acid (LCA).…”

“…However, 12-HBA may also play a causal role in the development of IR [14], thereby potentially establishing a pathologic cycle. As 12-HBA and non-12-HBA differentially affect gene expression in enterocytes [15], a shift in their balance may contribute to dysregulated metabolic coordination between intestine and WAT, in turn setting the stage for the development of IR.…”

Alterations in Gene Pair Correlations as Potential Diagnostic Markers for Colon Cancer

“…The loss-of-function mutations of SLC30A10 are associated with adult-onset Parkinsonism. Expression of SLC30A10 and cellular Mn efflux are regulated by the composition of bile acids [ 67 ].…”