서영아 (University of Michigan)

한빛사논문

조회359

University of Michigan

CV File 778 kb

Nat. Commun., Jun 05 2024, 15 (1) | https://doi.org/10.1038/s41467-024-49049-8 The manganese transporter SLC39A8 links alkaline ceramidase 1 to inflammatory bowel disease

Eun-Kyung Choi ¹, Thekkelnaycke M. Rajendiran ^2,3, Tanu Soni ³, Jin-Ho Park ¹, Luisa Aring ¹, Chithra K. Muraleedharan ², Vicky Garcia-Hernandez ², Nobuhiko Kamada ^2,4, Linda C. Samuelson ^4,5, Asma Nusrat², Shigeki Iwase ⁶ & Young Ah Seo ^1,*

¹Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
²Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
³Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁶Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.

^*Corresponding author: correspondence to Young Ah Seo

Abstract

The metal ion transporter SLC39A8 is associated with physiological traits and diseases, including blood manganese (Mn) levels and inflammatory bowel diseases (IBD). The mechanisms by which SLC39A8 controls Mn homeostasis and epithelial integrity remain elusive. Here, we generate Slc39a8 intestinal epithelial cell-specific-knockout (Slc39a8-IEC KO) mice, which display markedly decreased Mn levels in blood and most organs. Radiotracer studies reveal impaired intestinal absorption of dietary Mn in Slc39a8-IEC KO mice. SLC39A8 is localized to the apical membrane and mediates ⁵⁴Mn uptake in intestinal organoid monolayer cultures. Unbiased transcriptomic analysis identifies alkaline ceramidase 1 (ACER1), a key enzyme in sphingolipid metabolism, as a potential therapeutic target for SLC39A8-associated IBDs. Importantly, treatment with an ACER1 inhibitor attenuates colitis in Slc39a8-IEC KO mice by remedying barrier dysfunction. Our results highlight the essential roles of SLC39A8 in intestinal Mn absorption and epithelial integrity and offer a therapeutic target for IBD associated with impaired Mn homeostasis.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-12)
연구진국외 연구진
분야 생명과학 > 생리학

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