NaCT/SLC13A5 facilitates citrate import and metabolism under nutrient-limited conditions

Cell Rep. 2021 Sep 14;36(11):109701. doi: 10.1016/j.celrep.2021.109701.

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 13C 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.

Keywords: NaCT; SLC13A5; citrate; hepatocellular carcinoma; lipogenesis; neurons; zinc.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl Coenzyme A / metabolism
  • Adult
  • Animals
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Citrates / metabolism*
  • Female
  • Gene Editing
  • Glutamine / metabolism
  • Glutamine / pharmacology
  • Humans
  • Lipogenesis
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Neurons / cytology
  • Neurons / metabolism
  • Nutrients / metabolism*
  • Nutrients / pharmacology
  • Rats
  • Symporters / deficiency
  • Symporters / genetics
  • Symporters / metabolism*
  • Zinc / pharmacology

Substances

  • Citrates
  • SLC13A5 protein, human
  • Symporters
  • Glutamine
  • Acetyl Coenzyme A
  • Zinc