These results indicate that activation of FXR could induce Sr-bi transcription by directly binding to multiple IR1s located in Sr-bi gene. However, a recent study showed that FXR up-regulated Sr-bi in mouse hepatocytes through a FXR-pJNK-hepatocyte nuclear factor 4 a SR-BI pathway, which indicates FXR may regulate SR-BI in both direct and indirect manners. In addition to FXR, another nuclear receptor, peroxisome proliferator-activated receptor a, can also increase Sr-bi Anemarsaponin-BIII expression in liver of rats. PPARa has also been shown to be activated by FXR in HepG2 cells, which may represent another indirect mechanism of FXR in induction of Sr-bi expression in human. However, activation of PPARa in mouse livers by fibrates decreased hepatic Sr-bi protein expression without changing Sr-bi mRNA levels. The posttranscriptional regulatory effect of fibrates on murine hepatic Sr-bi protein levels was further demonstrated PPARa dependent using PPARa deficient mice. These controversial results on Sr-bi regulation by activation of PPARa may due to species-specific differences. Even though no IR1 was found in the human SR-BI gene compared to the mouse gene, our results still showed that activating FXR increased SR-BI expression in primary human hepatocytes and a human hepatoma cell line. One recent study demonstrated that FXR directly activates SR-BI gene transcription by binding to a DR8 motif in the promoter region of the human SR-BI gene, which may help in understanding the underlying molecular mechanisms of FXR in regulating human SR-BI expression. Increasing studies also have shown that a variety of nuclear receptors, including liver X receptors, LRH-1, peroxisome proliferator-activated receptor c, and HNF4a can stimulate hepatic SR-BI gene expression in humans. Thus, FXR may also modulate SR-BI expression through regulating or interacting with these nuclear receptors or signaling pathways. These data suggest that activation of FXR could up-regulate hepatic SR-BI transcription either directly or through coordinating the activity of other nuclear receptors in both mouse and human livers. Hepatic SR-BI has been shown to serve as a key mediator of RCT by taking of HDL cholesterol to the liver. A series of studies using transgenic or recombinant adenovirus-mediated mice showed that hepatic over-expression of SR-BI markedly reduces atherosclerosis. Furthermore, SR-BI KO mice have higher HDL cholesterol in the circulation and enhanced atherosclerosis Hexamethonium Bromide development. These results suggest that hepatic SR-BI is critical in protecting against atherosclerosis development. Our studies showed that, compared to WT mice, FXR-KO mice had more serum total and HDL cholesterol.