TY - JOUR T1 - SLC13A5 is A Novel Transcriptional Target of the Pregnane X Receptor and Sensitizes Drug-Induced Steatosis in Human Liver JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.097287 SP - mol.114.097287 AU - Linhao Li AU - Haishan Li AU - Brandy Garzel AU - Hui Yang AU - Tatsuya Sueyoshi AU - Qing Li AU - Yan Shu AU - Junran Zhang AU - Bingfang Hu AU - Scott Heyward AU - Timothy Moeller AU - Wen Xie AU - Masahiko Negishi AU - Hongbing Wang Y1 - 2015/01/27 UR - http://molpharm.aspetjournals.org/content/early/2015/01/27/mol.114.097287.abstract N2 - The solute carrier family 13 member 5 (SLC13A5) is a sodium-coupled transporter that mediates cellular uptake of citrate, which plays important roles in the synthesis of fatty acids and cholesterol. Recently, the pregnane X receptor (PXR, NR1I2) initially characterized as a xenobiotic sensor, has been functionally linked to the regulation of various physiological processes that are associated with lipid metabolism and energy homeostasis. Here, we show that the SLC13A5 gene is a novel transcriptional target of PXR and altered expression of SLC13A5 affects lipid accumulation in human liver cells. The prototypical PXR activator rifampicin markedly induced the mRNA and protein expression of SLC13A5 in human primary hepatocytes. Utilizing cell-based luciferase reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays, we identified and functionally characterized two enhancer modules located upstream of the SLC13A5 gene transcription start site, that are associated with regulation of PXR-mediated SLC13A5 induction. Functional analysis further revealed that rifampicin can enhance lipid accumulation in human primary hepatocytes; and knockdown of SLC13A5 expression alone leads to significant decrease of the lipid content in HepG2 cells. Overall, our results uncover SLC13A5 as a novel target gene of PXR and may contribute to drug-induced steatosis and metabolic disorders in humans. ER -