Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis

Authors

Jung-Hwan Kim, Gyeongsang National University
Tsutomu Matsubara, National Institute of Health
Jaekwom Lee, University of Nebraska-LincolnFollow
Cristina Fenollar-Ferrer, National Institutes of Health
Kyungreem Han, National Institutes of Health
Donghwan Kim, National Institutes of Health
Shang Jia, University of California, Berkeley
Christopher J. Chang, University of California, Berkeley
Heejung Yang, National Institutes of Health
Tomokazu Nagano, National Institutes of Health
Kristopher W. Krausz, National Institutes of Health
Sun Hee Yim, National Institutes of Health
Frank J. Gonzalez, National Institutes of Health

ORCID IDs

Jung-Wan Kim

Tsutomu Matsubara

Christopher J. Chang

Heejung Yang

Frank J. Gonzalez

Document Type

Article

Date of this Version

2021

Citation

Kim, JH., Matsubara, T., Lee, J. et al. Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis. Nat Commun 12, 290 (2021). https://doi.org/10.1038/s41467-020-20461-0

Comments

CC-BY

Abstract

The 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.