<em>ATP8B1</em> Gene Expression Is Driven by a Housekeeping-Like Promoter Independent of Bile Acids and Farnesoid X Receptor

<div><h3>Background</h3><p>Mutations in <em>ATP8B1</em> gene were identified as a cause of low γ-glutamyltranspeptidase cholestasis with variable phenotype, ranging from Progressive Familial Intrahepatic Cholestasis to Benign Recurrent Intrahepatic Cholestasis. However, only the coding region of <em>ATP8B1</em> has been described. The aim of this research was to explore the regulatory regions, promoter and 5′untranslated region, of the <em>ATP8B1</em> gene.</p> <h3>Methodology/Principal Findings</h3><p>5′Rapid Amplification of cDNA Ends using human liver and intestinal tissue was performed to identify the presence of 5′ untranslated exons. Expression levels of <em>ATP8B1</em> transcripts were determined by quantitative reverse-transcription PCR and compared with the non-variable part of <em>ATP8B1</em>. Three putative promoters were examined <em>in vitro</em> using a reporter gene assay and the main promoter was stimulated with chenodeoxycholic acid. Four novel untranslated exons located up to 71 kb upstream of the previously published exon 1 and twelve different splicing variants were found both in the liver and the intestine. Multiple transcription start sites were identified within exon −3 and the proximal promoter upstream of this transcription start site cluster was proven to be an essential regulatory element responsible for 70% of total <em>ATP8B1</em> transcriptional activity. <em>In vitro</em> analysis demonstrated that the main promoter drives constitutive <em>ATP8B1</em> gene expression independent of bile acids.</p> <h3>Conclusions/Significance</h3><p>The structure of the <em>ATP8B1</em> gene is complex and the previously published transcription start site is not significant. The basal expression of <em>ATP8B1</em> is driven by a housekeeping-like promoter located 71 kb upstream of the first protein coding exon.</p>