Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis

Title
Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis
Authors
한경림김정환Tsutomu Matsubara이재권Cristina Fenollar-Ferrer김동환Shang JiaChristopher J. Chang양희정Tomokazu NaganoKristopher W. Krausz임선희Frank J. Gonzalez
Issue Date
2021-01
Publisher
Nature Communications
Citation
VOL 12, 290
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.
URI
http://pubs.kist.re.kr/handle/201004/73086
ISSN
2041-1723
Appears in Collections:
KIST Publication > Article
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