NR2F1 disrupts synergistic activation of the MTTP gene transcription by HNF-4α and HNF-1α.

Regulation of microsomal triglyceride transfer protein (MTP) expression mainly occurs at the transcriptional level. We have previously shown that MTTP gene expression was repressed in nondifferentiated intestinal cells by nuclear receptor 2 family 1 (NR2F1). However, mechanisms involved in the repression of MTP by NR2F1 were not elucidated. Here, we show that MTP expression requires hepatic nuclear factor (HNF)-4α transcription factor. Different HNF-1 proteins synergistically enhance MTP promoter activity along with HNF-4α by binding to different cis elements. NR2F1 does not alter individual effects of HNF-4α and HNF-1 proteins on the MTTP gene promoter. However, NR2F1 suppresses synergistic activation of the MTP promoter by HNF-4α/HNF-1α by binding to a direct repeat 1 (DR1) element. This suppression is further enhanced in the presence of nuclear receptor corepressor 1. In short, these studies identified a novel mechanism of MTP repression that involves binding of NR2F1 to the DR1 element and recruitment of corepressors. In this mechanism, NR2F1 does not affect activities of individual transcription factors; instead, it abrogates synergistic activation by HNF-4α and HNF-1 proteins.