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.
Highlights
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans
TCDD toxicity is due to its ability to activate the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that is activated by xenobiotics including dioxins and polycyclic aromatic hydrocarbons[6]
Slc46a3 mRNA was induced by TCDD in the mouse liver while no induction was found in kidney or different regions of the small intestine and the colon, where constitutive Slc46a3 mRNA was detected, indicating liver-specific induction by the AhR (Fig. 1a)
Summary
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. 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. The TCDD-induced hepatic triglyceride accumulation was significantly decreased in Slc46a3−/− mice and was more pronounced when these mice were fed a highfat 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, linking copper status to mitochondrial function, lipid metabolism and TCDD-induced liver toxicity. Accidental exposure to dioxins induces tissue-specific toxicity with decreased immune function, increased hepatic drug metabolizing-enzyme induction, teratogenesis, thymic degeneration, cirrhosis, endocrine disruption, infertility, liver toxicity associated with increased lipid accumulation, and cancer[4,5]. Induction of lysosomal SLC46A3 by TCDD induces intracellular copper deficiency, which results in mitochondrial dysfunction resulting in lower lipid catabolism and hepatic lipid accumulation
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