HNF1α and SREBP2 are important regulators of NPC1L1 in human liver

Camilla Pramfalk,Zhao-Yan Jiang,Qu Cai,Hai Hu,Sheng-Dao Zhang,Tian-Quan Han,Mats Eriksson,Paolo Parini

doi:10.1194/jlr.m900274-jlr200

Abstract

HNF1α and SREBP2 are important regulators of NPC1L1 in human liver

Highlights

Niemann-Pick C1-like 1 (NPC1L1), a key regulator of intestinal cholesterol absorption, is highly expressed in human liver
As we recently reported [18], no significant differences were observed in NPC1L1, sterol regulatory element binding protein 2 (SREBP2), and HNF1␣ mRNA expression between gallstone disease (GS) and gallstone-free patients (GSF) patients, though GS patients had 43% (P < 0.05) higher HNF4␣ mRNA expression compared with GSF patients
The IgG antibody was used as a baseline control and used to compare the relative fold enrichment of the NPC1L1 promoter by the specific DNA fragments

Summary

Introduction

Niemann-Pick C1-like 1 (NPC1L1), a key regulator of intestinal cholesterol absorption, is highly expressed in human liver. 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 ␣ (HNF4␣) (r = 0.53, P < 0.05) mRNA expression. 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. HNF4␣ slightly decreased the NPC1L1 promoter activity but had no effect on its gene expression. HNF1␣ 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 HNF1␣ can bind to the NPC1L1 promoter in vivo.—Pramfalk, C., Z-Y. HNF1␣ and SREBP2 are important regulators of NPC1L1 in human liver.

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