| Summary: | Liver X Receptors (LXRα and β) are members of the nuclear receptor superfamily of ligand-activated transcription factors. LXRs are activated by oxidised metabolites of cholesterol and several synthetic ligands, play a crucial role in the regulation of cholesterol and fatty acid homeostasis, and act as strong modulators of inflammation and immunity. This has positioned them as targets for the treatment of several pathologies, including atherosclerosis and obesity. Besides ligand binding, LXR activity can be modulated by post-translational modifications, and previous work has shown that phosphorylation of LXRα alters its transcriptional activity in a gene-specific manner in a macrophage cell line. This thesis has focused on better understanding the regulation of LXRα phosphorylation and investigating how changes in the receptor’s phosphorylation status modulate its activity in vivo; more specifically, in relation to its effects on hepatic lipid metabolism, and the development of inflammation and fibrosis. To do so, I have used a novel mouse model that expresses a whole-body non-phosphorylatable mutant version of LXRα (S196A) and have assessed its responses to a High Fat and High Cholesterol diet, as a dietary model of Non-Alcoholic Fatty Liver Disease (NAFLD). Furthermore, I have studied how the transcriptional capacity of the mutant receptor is modulated, assessing its differential binding to DNA and to other proteins. In order to evaluate the relevance of my findings in the context of human disease, I have also examined LXR activity on the activation of human hepatic stellate cells, key players in the development of liver fibrosis. Lastly, I have sought to examine new stimulants capable of inducing LXRα phosphorylation in vitro, and how this phenomenon can be pharmacologically impaired by using already-available kinase inhibitors. Overall, the work described in this thesis shows that LXRα phosphorylation critically acts as a novel nutritional sensor that promotes a unique diet-induced transcriptome and modulates metabolic, inflammatory and fibrotic responses that are key in NAFLD progression This novel work significantly contributes to our understanding of LXRα activity in liver disease in a pre-clinical setup, and places the modulation of LXRα phosphorylation as a potential anti-inflammatory/anti-fibrotic therapeutic target.
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