Cooperative transcriptional activation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 genes by nuclear receptors including Liver-X-Receptor

Su Sun Back; Jinsu Kim; Daehyung Choi; Eui Sup Lee; Soo Young Choi; Kyuhyung Han

doi:10.5483/bmbrep.2013.46.6.246

Cooperative transcriptional activation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 genes by nuclear receptors including Liver-X-Receptor

BMB Rep. 2013 Jun;46(6):322-7. doi: 10.5483/bmbrep.2013.46.6.246.

Authors

Su Sun Back¹, Jinsu Kim, Daehyung Choi, Eui Sup Lee, Soo Young Choi, Kyuhyung Han

Affiliation

¹ Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702, Korea.

Abstract

The ATP-binding cassette transporters ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. To identify cis-regulatory elements of the two genes, we have cloned and analyzed twenty-three evolutionary conserved region (ECR) fragments using the CMV-luciferase reporter system in HepG2 cells. Two ECRs were found to be responsive to the Liver-X-Receptor (LXR). Through elaborate deletion studies, regions containing putative LXREs were identified and the binding of LXRα was demonstrated by EMSA and ChIP assay. When the LXREs were inserted upstream of the intergenic promoter, synergistic activation by LXRα/RXRα in combination with GATA4, HNF4α, and LRH-1, which had been shown to bind to the intergenic region, was observed. In conclusion, we have identified two LXREs in ABCG5/ABCG8 genes for the first time and propose that these LXREs, especially in the ECR20, play major roles in regulating these genes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 5
ATP Binding Cassette Transporter, Subfamily G, Member 8
ATP-Binding Cassette Transporters / genetics*
ATP-Binding Cassette Transporters / metabolism
Chromatin Immunoprecipitation
Electrophoretic Mobility Shift Assay
GATA4 Transcription Factor / genetics
GATA4 Transcription Factor / metabolism
Hep G2 Cells
Hepatocyte Nuclear Factor 4 / genetics
Hepatocyte Nuclear Factor 4 / metabolism
Humans
Lipoproteins / genetics*
Lipoproteins / metabolism
Liver X Receptors
Orphan Nuclear Receptors / genetics
Orphan Nuclear Receptors / metabolism*
Promoter Regions, Genetic
Protein Binding
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism
Regulatory Elements, Transcriptional / genetics
Response Elements / genetics
Transcriptional Activation

Substances

ABCG5 protein, human
ABCG8 protein, human
ATP Binding Cassette Transporter, Subfamily G, Member 5
ATP Binding Cassette Transporter, Subfamily G, Member 8
ATP-Binding Cassette Transporters
GATA4 Transcription Factor
GATA4 protein, human
HNF4A protein, human
Hepatocyte Nuclear Factor 4
Lipoproteins
Liver X Receptors
NR1H3 protein, human
NR5A2 protein, human
Orphan Nuclear Receptors
Receptors, Cytoplasmic and Nuclear