Graduate Thesis Or Dissertation

 

SLC23A1, the gene encoding sodium-dependent vitamin C transport protein 1 (SVCT1) : regulation of transcription and its functional consequences 公开 Deposited

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  • Vitamin C is an essential component of the human diet. Uptake of vitamin C in the cell is regulated by the function of sodium-dependent vitamin C transporters (SVCTs). SVCT1 (encoded by the SLC23A1 gene) is expressed in the colon, liver and kidney, where it plays a vital role in determining vitamin C levels in the body. Despite the importance of SVCT1 in vitamin C homeostasis, little is known about its genetic regulation. We isolated a 1239-base-pair fragment of the SLC23A1 5'-flanking sequence from HepG2 cells for the construction of a reporter gene assay. Deletion analysis attributed all promoter activity in this sequence to a small 135-bp region of the SLC23A1 promoter, where basal transcription of SLC23A1 required the binding of Hepatic Nuclear Factor 1 (HNF-1). We then sought to determine if regulation of SLC23A1 could occur through HNF-1 dependent pathways. Results showed that neither oxidants nor thiols appreciably altered gene expression. Only insulin and the dithiol compound, (R)-α-Lipoic Acid (LA), significantly elevated reporter gene expression over controls. LA did not elicit its effects by acting as a redox modulator, but through signaling pathways associated with the insulin signaling pathway. These results suggest a critical role for insulin-mediated signal transduction pathways in SLC23A1/SVCT1 regulation. To determine if a loss of SLC23A1 transcription results in changes of vitamin C homeostasis, we looked at vitamin C transport in an aging model. Ascorbic acid concentrations in hepatocytes from old Fischer 344 rats were 68% lower than cells from young animals. This was associated with a 45% decline in SVCT1 mRNA with age, with no significant changes in SVCT2 mRNA levels. This loss in SVCT1 transcription corresponded to a functional decline in sodium-dependent vitamin C uptake in older animals. LA treatment reversed some of the changes in the SLC23A1 transcription, suggesting that this would be an effective therapy for increasing vitamin C uptake in old animals. Thus, the data outlined in this dissertation suggests that vitamin C transport via SVCT1 gene transcription is primarily governed by the induction of HNF-1 and insulin signaling, which may have dramatic effects on vitamin C transport in aging.
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