Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis

• Published in: Nature communications Vol. 12; no. 1; pp. 290 - 12
• Main Authors: Kim, Jung-Hwan, Matsubara, Tsutomu, Lee, Jaekwon, Fenollar-Ferrer, Cristina, Han, Kyungreem, Kim, Donghwan, Jia, Shang, Chang, Christopher J., Yang, Heejung, Nagano, Tomokazu, Krausz, Kristopher W., Yim, Sun-Hee, Gonzalez, Frank J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/44; 14/28; 14/5; 140/58; 38/39; 38/5; 38/70; 38/77; 49/109; 49/61; 631/443/319; 631/80; 64/60; 692/4020/4021; 692/499; 82/51; 82/80; 96/109; Accumulation; Animals; Catabolism; Contaminants; Copper; Copper - metabolism; Copper Transport Proteins - genetics; Copper Transport Proteins - metabolism; Cytosol - drug effects; Cytosol - metabolism; Dioxins; Green Fluorescent Proteins - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - ultrastructure; High fat diet; Homeostasis; Homeostasis - drug effects; Humanities and Social Sciences; Ions; Lipid metabolism; Lipids; Liver; Liver - metabolism; Lysosomes - drug effects; Lysosomes - metabolism; Male; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Models, Biological; Morphology; multidisciplinary; Polychlorinated Dibenzodioxins - toxicity; Proton-Coupled Folate Transporter - genetics; Proton-Coupled Folate Transporter - metabolism; Receptors, Aryl Hydrocarbon - metabolism; Science; Science (multidisciplinary); Substrate Specificity - drug effects; Superoxide Dismutase - metabolism; TCDD; Toxicity; Triglycerides; Triglycerides - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20461-0

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. 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.