The outcomes implicated that FXR antagonism probably has a somewhat increased capacity to export bile chemicals out from the hepatocyte back into the circulation and capability to excrete cholesterol into bile. Also, FXR deficiency in Ldlr /mice resulted in a reduction in size of atherosclerotic lesions in the aorta, generally with a decreased level of plasma LDL cholesterol, and a decrease of Hedgehog agonist the accumulation of neutral lipid in peritoneal macrophages. There have been several conflicting results, depending on the experimental animal model in research areas associated with atherosclerosis, that might originate from various mechanisms of cholesterol metabolism between species. It has been reported that rodents have a very hydrophilic bile acid pool, which will be less efficient in service of FXR, hence, the LXRfificould be a crucial regulator of CYP7A1 in mice. In contrast, CYP7A1 expression was down-regulated with a large cholesterol diet in African green monkeys and in rabbits, because the inhibitory effect of FXR may override the stimulatory effect of LXRfi. There are still another regulator of bile acid synthesis, named steroid and xenobiotic receptor pregnane X receptor, which represses CYP7A1 in bile acid synthesis in the liver and causes human cytochrome P4503A4 in drug k-calorie burning. PXR is activated with a large numbers of endogenous and exogenous chemicals including naturally occurring Organism, antibiotics, antimycotics, bile acids, steroids and the herbal anti-depressant St. Johns wort. It’s possible that various steroids released from acLDL may possibly stimulate PXR, which downregulated CYP proteins in HepG2 cells. These results led us to propose that the disappointing results of ACAT inhibitors, avasimibe and pactimibe found in several clinical studies may result from activation of FXR, because of the elevated pool of ligand for FXR, as outcome, cholesterol could not be excreted from the body. In this study, we discovered that BC secreted from acLDL loaded macrophages during ACAT inhibition behaved as an FXR activator and Ubiquitin ligase inhibitor regulated the expression of apoE, CYP7A1, and CYP7B1, and that these results were abolished by the FXR antagonist, GS. Therefore, it is possible that ACAT inhibition promotes release of BC from macrophages but represses bile acid synthesis in hepatocytes via the activation of FXR as presented in Figure 7. Nishimaki Mogami et al. shown that some BC, which can be metabolized beyond 27 hydroxylation in the classic pathway of bile acid synthesis, exhibited activity for FXR similar to that of CDCA, conversely, early intermediates in the bile acid synthesis pathway, such as 7fi hydroxycholesterol and 27 hydroxycholesterol, showed no activity. Hence, we could consider that cholesterol was metabolized at least beyond 27 hydroxylation in macrophages during ACAT inhibition, which is why the little change of absolute values of BC in the TMCM could activate the FXR pathway of HepG2 cells considerably.