HNF1  and SREBP2 are important regulators of NPC1L1 in human liver

Abstract

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 alpha (HNF4alpha) (r = 0.53, P < 0.05) mRNA expression. HNF4alpha is an upstream regulator of HNF1alpha; thus, we also tested whether HNF1alpha 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, HNF4alpha slightly decreased the NPC1L1 promoter activity but had no effect on its gene expression. By contrast, HNF1alpha 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 HNF1alpha can bind to the NPC1L1 promoter in vivo.