In the present study, combined with RNA-seq data of Lrh1-knockout pancreas samples, FTF was the only TF of Lrh1 identified based on TRANSFAC database and may regulate cholesterol catabolism into bile acids by activation of the promoter-binding factor CYP7A. Many literatures have elucidated the function of Lrh1/Nr5a2/FTF/CYP7A via experimental studies [21–25].
FTF is highly expressed in the liver and intestine and is implicated in the regulation of cholesterol, bile acid and steroid hormone homeostasis . Nearly 50% of the body cholesterol is catabolized to bile acids via bile acid biosynthetic pathway, of which cholic acid (hydroxylated at position 12) and chenodeoxycholic acid are the major primary bile acids and play an important role in cholesterol homeostasis . Chenodeoxycholic acid can repress FTF expression and is a more potent suppressor of HMG-CoA reductase and cholesterol 7α-hydroxylase/CYP7A1 (7α-hydroxylase) than cholic acid . It has been proposed that Lrh1, also known as CYP7A promoter-binding factor, LRH1, or FTF, is required for the transcription of the 7α-hydroxylase gene [19, 28]. The small heterodimer partner 1 (SHP) of the nuclear bile acid receptor, FXR (farnesoid X receptor) can dimerize with FTF and diminish its activity on the 7α-hydroxylase promoter .
Although Lrh1 has been demonstrated the function in feedback regulation of CYP7A1 expression as part of the FXR-SHP-LRH-1 cascade, in which bile acids can inhibit their own synthesis, the mechanisms have not been well understood. Out C et al.  have suggested that CYP7A1 expression is increased rather than decreased under chow-fed conditions in Lrh1-knockdown mice that is coincided with a significant reduction in expression of intestinal Fgf15, a suppressor of CYP7A1. Besides, Noshiro M et al.  have suggested that the circadian rhythm of CYP7A is regulated by multiple transcription factors, including DBP, REV-ERBα/β, LXRα, HNF4α DEC2, E4BP4, and PPARα. Hepatocyte nuclear factor 4α (HNF4α) and FTF are two major TFs driving CYP7A1 promoter activity in lipid homeostasis. Bochkis IM et al.  have shown that prospero-related homeobox (Prox1) directly interacts with both HNF4α and FTF and potently co-represses CYP7A1 transcription.
In the present study, we annotated the SNPs of Lrh1 and its homologous genes, showing that the majority was located in intron and upstream. Quiles Romagosa MÁ  has reported that a functional SNP located in Lrh1 promoter is related to Body Mass Index (BMI) and these SNPs might play important roles in the obese phenotype. However, previous researches mostly focused on SNPs associated with pancreatic cancer cell growth and proliferation. For example, a previous genome-wide association study has identified five SNPs on 1q32.1 associated with pancreatic cancer that mapped to Lrh1 gene and its up-stream regulatory region .