Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis

dc.creatorKim, Jung-Hwan
dc.creatorMatsubara, Tsutomu
dc.creatorLee, Jaekwon
dc.creatorFenollar-Ferrar, Cristina
dc.creatorHan, Kyungreem
dc.creatorKim, Donghwan
dc.creatorJia, Shang
dc.creatorChang, Christopher J.
dc.creatorYang, Heejung
dc.creatorNagano, Tomokazu
dc.creatorKrausz, Kristopher W.
dc.creatorYim, Sun-Hee
dc.creatorGonzalez, Frank J.
dc.date.accessioned2021-09-21T18:05:08Z
dc.date.available2021-09-21T18:05:08Z
dc.date.issued2021
dc.descriptionThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.en_US
dc.description.abstractThe environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function. SLC46A3 was localized to the lysosome where it modulated intracellular copper levels. Forced expression of hepatic SLC46A3 resulted in decreased mitochondrial membrane potential and abnormal mitochondria morphology consistent with lower copper levels. SLC46A3 expression increased hepatic lipid accumulation similar to the known effects of TCDD exposure in mice and humans. The TCDD-induced hepatic triglyceride accumulation was significantly decreased in Slc46a3−/− mice and was more pronounced when these mice were fed a high-fat diet, as compared to wild-type mice. These data are consistent with a model where lysosomal SLC46A3 induction by TCDD leads to cytosolic copper deficiency resulting in mitochondrial dysfunction leading to lower lipid catabolism, thus linking copper status to mitochondrial function, lipid metabolism and TCDD-induced liver toxicity.en_US
dc.identifier.citationKim, JH., Matsubara, T., Lee, J. et al. Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis. Nat Commun 12, 290 (2021). https://doi.org/10.1038/s41467-020-20461-0en_US
dc.identifier.urihttps://doi.org/10.1038/s41467-020-20461-0
dc.identifier.urihttps://hdl.handle.net/2346/87950
dc.language.isoengen_US
dc.subjectCell Biologyen_US
dc.subjectHepatologyen_US
dc.subjectMetabolismen_US
dc.subjectRisk Factorsen_US
dc.titleLysosomal SLC46A3 modulates hepatic cytosolic copper homeostasisen_US
dc.typeArticleen_US
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