HNF1α and SREBP2 are important regulators of NPC1L1 in human liver

Niemann-Pick C1-like 1 (NPC1L1), a key regulator of intestinal cholesterol absorption, is highly expressed in human liver. Here, we aimed to gain more insight into mechanisms participating in its hepatic regulation in humans. Correlation analysis in livers from Chinese patients with and without gallstone disease revealed strong positive correlations between NPC1L1 and sterol regulatory element binding protein 2 (SREBP2) (r = 0.74, P < 0.05) and between NPC1L1 and hepatic nuclear factor α (HNF4α) (r = 0.53, P < 0.05) mRNA expression. HNF4α is an upstream regulator of HNF1α; thus, we also tested whether HNF1α participates in the regulation of NPC1L1. We showed a dose-dependent regulation by SREBP2 on the NPC1L1 promoter activity and mRNA expression in HuH7 cells. Chromatin immunoprecipitation assay confirmed the binding of SREBP2 to the promoter in vivo. Surprisingly, HNF4α slightly decreased the NPC1L1 promoter activity but had no effect on its gene expression. By contrast, HNF1α increased the promoter activity and the gene expression, and an important HNF1 binding site was identified within the human NPC1L1 promoter. ChIP assays confirmed that HNF1α can bind to the NPC1L1 promoter in vivo.