Investigating Synthetic Ligands for the Treatment of NASH

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 DESCRIPTION (provided by applicant): Metabolic diseases, associated with abnormal processing of proteins, carbohydrates, and lipids, are the cause of significant morbidity and mortality. The nuclear receptors, liver X receptor a, and -ß (LXRa and LXRß), 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 LXRß play important roles in cholesterol physiology and lipid metabolism, and have been implicated in the pathology of several diseases, including athereosclerosis, cancer, and obesity. Detailed examination of mice deficient in LXRa have revealed a significant amount of information regarding its role in regulating metabolic pathways, including lipid metabolism. Potential pharmacological roles of LXR in metabolism have been identified using synthetic agonists, however our focus for this study is the use of inverse agonists in the treatment of fatty liver diseases. We have identified a novel synthetic LXR inverse agonist that displays the ability to specifically suppress LXR target gene expression specifically in the liver, thus having the potential to suppress steatohepatitis. The long-term objective is to use these compounds as tools to study the effects of synthetic LXR ligands on diseases of the liver. We hypothesize that LXR inverse agonists can suppress the effects Fatty Liver Diseases in mouse models. Our hypothesis will be tested in the following specific aims: Specific Aim 1 will examine the mechanism(s) by which SR9238 effects LXR-mediated lipogenesis, inflammation, and cholesterol regulation; Specific Aim 2 will evaluate the potential for SR9238 as a therapeutic in Non- Alcoholic Steatohepatitis (NASH) in mouse models of the disease. Ligand-regulated nuclear hormone receptors have been definitively shown to be effective targets for the development of pharmaceuticals. We predict that these studies will provide the basis for novel therapeutics targeting LXR for the treatment of fatty live diseases and potentially other metabolic disorders.