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This Article Full Text Full Text (PDF) Supplemental Figures and Tables All Versions of this Article: 297/5/C1220    most recent 00348.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Michels, A. J. Articles by Hagen, T. M. PubMed PubMed Citation Articles by Michels, A. J. Articles by Hagen, T. M.

Membrane Transporters, Ion Channels, and Pumps

Hepatocyte nuclear factor 1 is essential for transcription of sodium-dependent vitamin C transporter protein 1

Linus Pauling Institute and the Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon

Submitted 3 August 2009 ; accepted in final form 8 September 2009

Transport and distribution of vitamin C is primarily regulated by the function of sodium-dependent vitamin C transporters (SVCTs). SVCT1 is expressed in the small intestine, liver, and kidney, organs that play a vital role in whole body vitamin C homeostasis. Despite the importance of this protein, little is known about regulation of the gene encoding SVCT1, Slc23a1. In this study, we present the first investigation of the transcriptional regulation of human Slc23a1, identifying transcription factors that may influence its expression. A 1,239-bp genomic DNA fragment corresponding to the 5'-flanking region of Slc23a1 was isolated from a human hepatocarcinoma cell line (HepG2) and sequenced. When cloned into a reporter gene construct, robust transcriptional activity was seen in this sequence, nearly 25-fold above the control vector. Deletion analysis of the SVCT1 reporter gene vector defined the minimal active promoter as a small 135-bp region upstream of the transcriptional start site. While several transcription factor binding sites were identified within this sequence, reporter constructs showed that basal transcription required the binding of hepatic nuclear factor 1 (HNF-1) to its cognate sequence. Furthermore, mutation of this HNF-1 binding site resulted in complete loss of luciferase expression, even in the context of the whole promoter. Additionally, small interfering RNA knockdown of both members of the HNF-1 family, HNF-1 and HNF-1β, resulted in a significant decline in SVCT1 transcription. Together, these data suggest that HNF-1 and/or HNF-1β binding is required for SVCT1 expression and may be involved in the coordinate regulation of whole body vitamin C status.

vitamin C transport; ascorbate; hepatic nuclear factors