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.

柠檬酸盐位于代谢的关键节点，通过乙酰辅酶 A 将三羧酸代谢和脂肪生成联系起来。最近的研究发现，由SLC13A5编码的钠依赖性柠檬酸盐转运蛋白 (NaCT) 的缺乏会导致肝脏代谢失调并导致小儿癫痫。为了检查 NaCT 如何促进与这些疾病的病理生理学相关的细胞中的柠檬酸盐代谢，我们将¹³ C同位素示踪应用于SLC13A5 缺陷型肝细胞癌 (HCC) 细胞和原代大鼠皮质神经元。外源性柠檬酸盐仅在缺氧条件下明显有助于中间代谢。在没有谷氨酰胺的情况下，补充柠檬酸盐会从头增加HCC细胞的脂肪生成和生长。Huh7 细胞中SLC13A5的敲除会损害柠檬酸盐的摄取和分解代谢。柠檬酸盐补充剂可挽救 Huh7 细胞对谷氨酰胺剥夺或 Zn ²⁺治疗的反应，而 NaCT 缺乏可减轻这些影响。总的来说，这些研究结果表明，NaCT 介导的柠檬酸盐摄取在营养有限的条件下具有重要的代谢作用，并且可能有助于抵抗金属毒性。