The nuclear receptors, liver X receptor-alpha and -beta (LXRa and LXRb), were originally identified as orphan members of the nuclear receptor (NR) superfamily that function as heterodimers with the retinoid X receptor (RXR). Both LXRa and LXRb play important roles in cholesterol homeostasis and lipid metabolism and have been implicated in the pathology of several diseases including atherosclerosis, cancer, and obesity. Detailed examination of mice deficient in LXRa have revealed significant information regarding its role in regulating lipid metabolism while pharmacological roles of LXR in metabolism and inflammation have been identified using synthetic agonists. We have identified novel synthetic LXR Inverse Agonists that display the ability to suppress lipogenesis and significantly improve the phenotype of fatty liver diseases in several mouse models. During our previous investigation of LXR inverse agonists and fatty liver, we observed a substantial decrease in LDL and total cholesterol, as well as a significant decrease in soat2 gene expression. Recent basic and clinical studies indicate that soat2 may be a potential therapeutic target for cholesterol regulation and atherosclerosis treatment. Based on our observations, we investigated the effects of tissue-selective LXR inverse agonists on cholesterol regulation with greater intensity. We hypothesized that soat2 may be a novel target of LXR and that selectively suppressing LXR in the liver and/or intestine may lead to lowered cholesterol levels in hyperlipidemic models (n = 12). While our research is currently ongoing, we have validated soat2 as a potential LXR target gene by ChIP in hepatocytes, RNA-Seq experiments, fecal cholesterol excretion experiments, as well as expression assays in LXRa/b double knockout mouse tissues (n = 3). Additional studies in LDLr KO mice indicate that selectively targeting LXR in the gut with inverse agonists significantly decrease total and LDL cholesterol (n=12). We believe that this is an innovative method of targeting hypercholesterolemia and may lead to a new class of atherosclerosis therapeutics.