Abstract
Citrate is a crucial energy sensor that plays a central role in cellular metabolic homeostasis. The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter highly expressed in the mammalian liver with relatively low levels in the testis and brain, imports citrate from extracellular spaces into the cells. The perturbation of SLC13A5 expression and/or activity is associated with non-alcoholic fatty liver disease, obesity, insulin resistance, cell proliferation, and early infantile epileptic encephalopathy. SLC13A5 has been proposed as a promising therapeutic target for the treatment of these metabolic disorders. In the liver, the inductive expression of SLC13A5 has been linked to several xenobiotic receptors such as the pregnane X receptor and the aryl hydrocarbon receptor as well as certain hormonal and nutritional stimuli. Nevertheless, in comparison to the heightened interest in understanding the biological function and clinical relevance of SLC13A5, studies focusing on the regulatory mechanisms of SLC13A5 expression are relatively limited. In this review, we discuss the current advances in our understanding of the molecular mechanisms by which the expression of SLC13A5 is regulated. We expect this review will provide greater insights into the regulation of the SLC13A5 gene transcription and the signaling pathways involved therein.
Highlights
The solute carrier family 13 member 5 (SLC13A5), known as the Na+/citrate cotransporter (NaCT), is a member of the sodium dicarboxylate/sulfate cotransporter family
Mitochondrial citrate generated from the tricarboxylic acid (TCA) cycle is transported outside the mitochondria by the citrate carrier (CIC), which is encoded by the SLC25A1 gene [5]
Cytosolic citrate can be imported from extracellular spaces via SLC13A5/NaCT expressed on the cell plasma membrane [6]
Summary
The solute carrier family 13 member 5 (SLC13A5), known as the Na+/citrate cotransporter (NaCT), is a member of the sodium dicarboxylate/sulfate cotransporter family It recognizes and transports various dicarboxylate and tricarboxylate intermediates of the tricarboxylic acid (TCA) cycle with citrate as the preferred substrate [1,2]. Mitochondrial citrate generated from the TCA cycle is transported outside the mitochondria by the citrate carrier (CIC), which is encoded by the SLC25A1 gene [5]. Cytosolic citrate can be imported from extracellular spaces via SLC13A5/NaCT expressed on the cell plasma membrane [6]. SLC13A5, being the primary uptake transporter of citrate, may play a key physiologic role in the generation of metabolic energy by facilitating the utilization of the circulating citrate. The purpose of this review is to highlight the recent progress in our understanding of the molecular mechanisms underlying the genetic and epigenetic regulation of the SLC13A5 gene expression in a tissue-specific manner, with a specific focus centering on the hepatic regulation of the SLC13A5 transcription
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