Timely regulation of cholesterol and cholesterol metabolites is critical for the maintenance of cell and organismal homeostasis. The study of cholesterol metabolism is especially relevant to human health in light of the high incidence of cardiovascular disease worldwide and its correlation to serum cholesterol levels. Liver X Receptors (LXRs) act as 'cholesterol sensors,'lowering cellular cholesterol levels via induction of genes involved in cholesterol efflux and the inhibition of cholesterol uptake. Abrogation of LXR expression in murine models results in cholesterol accumulation and accelerated atherosclerosis. Conversely, activation of LXR via synthetic agonist confers protection against an atherosclerotic phenotype. Furthermore, LXRs attenuate the expression of pro-inflammatory molecules, suggesting that the anti-inflammatory effects of LXRs also contribute to atheroprotection. Here we seek to further elucidate the functions of LXR in the control of metabolism and cardiovascular vascular biology through characterization of novel LXR-regulated E3 ubiquitin ligases. Ubiquitin ligases are important regulators of protein stability, causing targeted degradation of specific proteins via the proteasome. We have identified a putative ubiquitin ligase that is transcriptionally upregulated upon treatment of hepatocytes with LXR-agonist. We will determine if this gene is a direct transcriptional target of LXR using in vitr biochemical and cell culture techniques. We will identify the localization and potential ubiquitination targets of this protein in relevant tissues using in vitro cell culture and murine model systems. We will also examine the impact of gain or loss of function of this gene, both in cultured tissues and in mouse models, in order to examine the physiological role for this novel ligase. Our goals are to determine the relevance of this new LXR target to cholesterol metabolism and, ultimately, human disease.
The proposed research will help us understand the function of Liver X Receptors (LXRs), which are key regulators of major metabolic pathways including cholesterol homeostasis, lipogenesis, and inflammation. These pathways play a major role in some of the most prevalent diseases in Western society, including obesity, diabetes, and cardiovascular disease.