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Transcriptional profile reveals altered hepatic lipid and cholesterol metabolism in hyposulfatemic NaS1 null mice

¹ School of Biomedical Sciences, University of Queensland, St. Lucia, Australia
² Institute for Molecular Bioscience, University of Queensland, St. Lucia, Australia

Sulfate plays an essential role in human growth and development, and its circulating levels are maintained by the renal Na⁺-SO₄^2– cotransporter, NaS1. We previously generated a NaS1 knockout (Nas1^–/–) mouse, an animal model for hyposulfatemia, that exhibits reduced growth and liver abnormalities including hepatomegaly. In this study, we investigated the hepatic gene expression profile of Nas1^–/– mice using oligonucleotide microarrays. The mRNA expression levels of 92 genes with known functional roles in metabolism, cell signaling, cell defense, immune response, cell structure, transcription, or protein synthesis were increased (n = 51) or decreased (n = 41) in Nas1^–/– mice when compared with Nas1^+/+ mice. The most upregulated transcript levels in Nas1^–/– mice were found for the sulfotransferase genes, Sult3a1 (500% increase) and Sult2a2 (100% increase), whereas the metallothionein-1 gene, Mt1, was among the most downregulated genes (70% decrease). Several genes involved in lipid and cholesterol metabolism, including Scd1, Acly, Gpam, Elov16, Acsl5, Mvd, Insig1, and Apoa4, were found to be upregulated (30% increase) in Nas1^–/– mice. In addition, Nas1^–/– mice exhibited increased levels of hepatic lipid (16% increase), serum cholesterol (20% increase), and low-density lipoprotein (100% increase) and reduced hepatic glycogen (50% decrease) levels. In conclusion, these data suggest an altered lipid and cholesterol metabolism in the hyposulfatemic Nas1^–/– mouse and provide new insights into the metabolic state of the liver in Nas1^–/– mice.

sulfate; gene expression; liver; transporter; slc13a1