1. NaCT/SLC13A5 facilitates citrate import and metabolism under nutrient-limited conditions.
- Author
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Kumar A, Cordes T, Thalacker-Mercer AE, Pajor AM, Murphy AN, and Metallo CM
- Subjects
- Acetyl Coenzyme A metabolism, Adult, Animals, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Cell Hypoxia, Cell Line, Tumor, Cell Survival drug effects, Female, Gene Editing, Glutamine metabolism, Glutamine pharmacology, Humans, Lipogenesis, Liver Neoplasms metabolism, Liver Neoplasms pathology, Male, Neurons cytology, Neurons metabolism, Nutrients pharmacology, Rats, Symporters deficiency, Symporters genetics, Zinc pharmacology, Citrates metabolism, Nutrients metabolism, Symporters metabolism
- Abstract
Citrate lies at a critical node of metabolism, linking tricarboxylic acid metabolism and lipogenesis via acetyl-coenzyme A. Recent studies have observed that deficiency of the sodium-dependent citrate transporter (NaCT), encoded by SLC13A5, dysregulates hepatic metabolism and drives pediatric epilepsy. To examine how NaCT contributes to citrate metabolism in cells relevant to the pathophysiology of these diseases, we apply
13 C isotope tracing to SLC13A5-deficient hepatocellular carcinoma (HCC) cells and primary rat cortical neurons. Exogenous citrate appreciably contributes to intermediary metabolism only under hypoxic conditions. In the absence of glutamine, citrate supplementation increases de novo lipogenesis and growth of HCC cells. Knockout of SLC13A5 in Huh7 cells compromises citrate uptake and catabolism. Citrate supplementation rescues Huh7 cell viability in response to glutamine deprivation or Zn2+ treatment, and NaCT deficiency mitigates these effects. Collectively, these findings demonstrate that NaCT-mediated citrate uptake is metabolically important under nutrient-limited conditions and may facilitate resistance to metal toxicity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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