G·A·B·B·A

The nuclear receptor Liver Receptor Homolog-1 (LRH-1; NR5A2), an established regulator of cholesterol and bile acid homeostasis, has recently emerged as a critical component in the control of hepatic intermediary metabolism by coordinating glucose-6-phospate availability and de novo lipogenesis. Although this function points to a regulatory role of LRH-1 in anabolic metabolism, several preliminary data from our laboratory indicate that loss-of-LRH-1 function in hepatocytes also greatly interferes with mitochondrial fatty acid degradation. More importantly, markers of the mitochondrial unfolded protein response (UPRmt) seem to be induced in mouse hepatoma cells in which the receptor has been silenced. Based on these preliminary findings, we postulate that LRH-1 may govern several basic aspects of mitochondrial function. The aim of this project is therefore to better investigate the exact function of LRH-1 in mitochondrial energy homeostasis and biology. To address this hypothesis at the molecular mechanistic level, by using in vitro cell based studies complemented with whole animal studies, we aim to: i) evaluate the regulation of mitochondrial functions by LRH-1; ii) analyse the intervention of LRH-1 in the mitochondrial-specific stress response - UPRmt; iii) perform the molecular mapping of the connection between LRH-1 and UPRmt. The insight gained by this work could validate LRH-1 as a potential therapeutic target to treat pathologies induced by mitochondrial dysfunction.