Cooperative interaction between hepatocyte nuclear factor 4α and GATA transcription factors regulates ATP-binding cassette sterol transporters ABCG5 and ABCG8

Koichi Sumi, Toshiya Tanaka, Aoi Uchida, Kenta Magoori, Yasuyo Urashima, Riuko Ohashi, Hiroto Ohguchi, Masashi Okamura, Hiromi Kudo, Kenji Daigo, Takashi Maejima, Noriaki Kojima, Iori Sakakibara, Shuying Jiang, Go Hasegawa, Insook Kim, Timothy F. Osborne, Makoto Naito, Frank J. Gonzalez, Takao HamakuboTatsuhiko Kodama, Juro Sakai

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)

Abstract

Cholesterol homeostasis is maintained by coordinate regulation of cholesterol synthesis and its conversion to bile acids in the liver. The excretion of cholesterol from liver and intestine is regulated by ATP-binding cassette half-transporters ABCG5 and ABCG8. The genes for these two proteins are closely linked and divergently transcribed from a common intergenic promoter region. Here, we identified a binding site for hepatocyte nuclear factor 4α (HNF4α) in the ABCG5/ABCG8 intergenic promoter, through which HNF4α strongly activated the expression of a reporter gene in both directions. The HNF4α-responsive element is flanked by two conserved GATA boxes that were also required for stimulation by HNF4α. GATA4 and GATA6 bind to the GATA boxes, coexpression of GATA4 and HNF4α leads to a striking synergistic activation of both the ABCG5 and the ABCG8 promoters, and binding sites for HNF4α and GATA were essential for maximal synergism. We also show that HNF4α, GATA4, and GATA6 colocalize in the nuclei of HepG2 cells and that a physical interaction between HNF4α and GATA4 is critical for the synergistic response. This is the first demonstration that HNF4α acts synergistically with GATA factors to activate gene expression in a bidirectional fashion.

Original languageEnglish
Pages (from-to)4248-4260
Number of pages13
JournalMolecular and cellular biology
Volume27
Issue number12
DOIs
Publication statusPublished - 2007 Jun

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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