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

HNF1α and SREBP2 are important regulators of NPC1L1 in human liver

^*Division of Clinical Chemistry, Department of Endocrinology, Metabolism and Diabetes, and Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden
^†Department of Laboratory Medicine, and Molecular Nutrition Unit, Department of Endocrinology, Metabolism and Diabetes, and Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden
^§Department of Biosciences and Nutrition, Centre for Nutrition and Toxicology, NOVUM, and Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes, and Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden
^**Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine
^††Department of Surgery, Shanghai Oriental Hospital, Shanghai, 200120, China

1To whom correspondence should be addressed. e-mail: paolo.parini{at}cnt.ki.se

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 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.

Footnotes

Abbreviations:

ChIP

chromatin immunoprecipitation

GS

gallstone disease

GSF

gallstone-free

HNF

hepatic nuclear factor

NPC1

Niemann-Pick C1

NPC1L1

Niemann-Pick C1-like 1

SRE

sterol regulatory element

SREBP

sterol regulatory element binding protein
This work was supported by the Swedish Research Council, by the Stockholm County Council (ALF), by the Swedish Medical Association, by the Swedish Heart-Lung Foundation, by the Karolinska Institutet, and by the National Natural Science Foundation of China (No. 30672042 and No. 30700310). P.P. is a recipient of grants from AstraZeneca, Sweden.