The mammalian nuclear receptor superfamily of evolutionarily related DNA-binding transcription factors consists of approximately 50 members, many of which mediate gene expression in a ligand-dependent manner. From their functional similarities, nuclear receptors are divided into A-F regions that include the N-terminal A/B region, the highly conserved DNA-binding domain (DBD; C region), the C-terminal ligand-binding domain (LBD; E/F region), and the D region, which serves as a hinge between the C and the E/F regions. The A/B and the E/F regions contain ligand-independent activation function (AF-1) and ligand-dependent activation function (AF-2), respectively. 1-3) Nuclear receptors regulate gene expression through interactions with coregulator complexes along with the general transcriptional machinery. 4,5) The coregulators associating with the C-terminal region that mediate AF-2 are well documented, whereas the proteins interacting with the N-terminal region that mediate AF-1 and the mechanism involved are not well defined. 6)Liver receptor homolog-1 (LRH-1; NR5A2), part of the nuclear receptor family, is a monomeric orphan receptor initially identified as mammalian homolog of Drosophila Fushi tarazu factor 1 (NR5A3).7-10) The closest mammalian homolog of LRH-1 is steroidogenic factor-1 (SF-1; NR5A1), which is essential for the development and differentiation of steroidgenic tissues and sexual differentiation.11,12) LRH-1 is highly expressed in the liver and intestine involved in enterohepatic circulation, and the ovary. 7,9,13,14) LRH-1 is also expressed in the pancreas, placenta, and pre-adipocyte. 7,15,16) To date, four isoforms of LRH-1, referred to as LRH-1 v1 (NM_205860), 10) LRH-1 (NM_003822), 9,10) fetoprotein transcription factor (FTF; U93553), 17) and LRH-1 v2 (35-323 aa, AF049102), 17) have been reported. The most abundant isoform in liver is LRH-1 (NM_003822) which lacks 46 amino acid residues corresponding to exon 2. 9) LRH-1 v2 is a truncated version of LRH-1 with a deletion in the D region that corresponds to exon5, and does not possess transactivation activity.7) FTF, the N-terminally truncated isoform, is identical to LRH-1 except for a deletion in the A/B region of LRH-1 v1.LRH-1 plays an important role in the homeostasis of bile acids and cholesterol, controlling the expression of a number of genes, including small heterodimer partner (SHP; NR0B2) 18,19) and enzymes for the conversion of cholesterol to bile acids (CYP7A1 and CYP8B1) 10,20) and for high density lipoprotein-remodeling.21) In addition, LRH-1 contributes to development and ovulation.14,22,23) Unlike most nuclear receptors, LRH-1 binds to the LRH-1 response element (LRHRE) (5Ј-YCAAGGYCR-3Ј, Y; pyrimidine, R; purine), three base-pairs longer than the consensus nuclear receptor half-site, as a monomer. 7)Nuclear receptors typically regulate transcription in a ligand-dependent fashion. The binding of a ligand causes the repositioning of helix 12 within the LBD resulting in interaction with the coactivators.1-3) However, the mechanisms...

LRH-1 (liver receptor homologue-1), a transcription factor and member of the nuclear receptor superfamily, regulates the expression of its target genes, which are involved in bile acid and cholesterol homoeostasis. However, the molecular mechanisms of transcriptional control by LRH-1 are not completely understood. Previously, we identified Ku80 and Ku70 as LRH-1-binding proteins and reported that they function as co-repressors. In the present study, we identified an additional LRH-1-binding protein, ILF3 (interleukin enhancer-binding factor 3). ILF3 formed a complex with LRH-1 and the other two nuclear receptor co-activators PRMT1 (protein arginine methyltransferase 1) and PGC-1α (peroxisome proliferator-activated receptor γ co-activator-1α). We demonstrated that ILF3, PRMT1 and PGC-1α were recruited to the promoter region of the LRH-1-regulated SHP (small heterodimer partner) gene, encoding one of the nuclear receptors. ILF3 enhanced SHP gene expression in co-operation with PRMT1 and PGC-1α through the C-terminal region of ILF3. In addition, we found that the small interfering RNA-mediated down-regulation of ILF3 expression led to a reduction in the occupancy of PGC-1α at the SHP promoter and SHP expression. Taken together, our results suggest that ILF3 functions as a novel LRH-1 co-activator by acting synergistically with PRMT1 and PGC-1α, thereby promoting LRH-1-dependent gene expression.