{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC13A5 encodes a sodium‐coupled citrate transporter (often referred to as NaCT) that is expressed in key tissues such as the liver, brain, and testis. Functionally, it mediates the Na⁺‐dependent uptake of extracellular citrate—a critical intermediate involved in energy production, lipogenesis, and neurotransmitter synthesis. Detailed biochemical and structural studies have demonstrated that human NaCT is electrogenic, exhibits a distinct Na⁺/citrate stoichiometry, and differs from rodent orthologues by having a lower affinity yet a higher capacity for citrate transport. In addition, dynamic structural models of the slc13 transporter family have shed light on key sodium‐binding and conformational elements that underlie its transport mechanism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn hepatocytes, SLC13A5 plays a critical role in importing circulating citrate to support metabolic pathways such as fatty acid and cholesterol synthesis, gluconeogenesis, and energy production. The transporter’s activity is subject to regulation by various factors including lithium, which can enhance citrate uptake, and nuclear receptors such as the pregnane X receptor that modulate its expression. Its functional inhibition by small molecules or dietary polyphenols (e.g., curcumin) has been shown to reduce hepatic lipid accumulation and is being explored as a therapeutic avenue in metabolic disorders and liver cancer. Importantly, species-specific differences in transporter capacity may explain why SLC13A5 deficiency protects against metabolic syndrome in rodents while in humans its loss leads to detrimental metabolic as well as systemic alterations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPerturbations in SLC13A5 function due to various loss‐of‐function mutations have been directly linked to severe neurological disorders. In particular, biallelic or compound heterozygous mutations disrupt NaCT activity in neurons, which appear to depend on extracellular citrate uptake for maintaining energy homeostasis and neurotransmitter production. These genetic alterations manifest clinically as early‐onset epileptic encephalopathy, developmental delay, and dental abnormalities, with comprehensive genotype–phenotype analyses and structural insights providing explanations for the transporter’s impaired function. Such findings underscore the central importance of citrate metabolism in neurodevelopment and the distinct clinical consequences of SLC13A5 deficiency in humans compared to animal models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Katsuhisa Inoue, Lina Zhuang, Vadivel Ganapathy "}, {"type": "b", "children": [{"type": "t", "text": "Human Na+ -coupled citrate transporter: primary structure, genomic organization, and transport function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0006-291x(02)02669-4"}], "href": "https://doi.org/10.1016/s0006-291x(02"}, {"type": "t", "text": "02669-4) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12445824"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12445824"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Katsuhisa Inoue, Lina Zhuang, Dennis M Maddox, et al. 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