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 - (LXRa and LXR), 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 LXR 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.
The liver X receptors (LXRa and LXR) play important roles in regulating cholesterol efflux, cholesterol transport, and lipogenesis, and have been implicated in the pathology of several diseases including diabetes, obesity, atherosclerosis, and inflammation. While LXRs physiology has been extensively studied, development of clinically effective LXR-target drugs has not yet been developed due to the complexity of LXR-regulated gene networks. We have identified a novel synthetic liver- specific LXR ligand that acts as inverse agonist and reduces hepatic lipids in a diet-induced obese mouse model. We predict that our proposed studies may provide the basis for novel therapeutics targeting LXR for the treatment of fatty liver diseases.
| Griffett, Kristine; Burris, Thomas P (2016) Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease. Biochem Biophys Res Commun 479:424-428 |
| Griffett, Kristine; Welch, Ryan D; Flaveny, Colin A et al. (2015) The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis. Mol Metab 4:353-7 |
