Grant: Discovery Grants Program - Individual

Lipogenesis is responsible for the synthesis of lipids from exogenous substrates such as sugar, other lipids and proteins. For a long time, lipogenesis has been considered as an accessory pathway only activated in presence of excessive substrate supply. However, recently, more and more evidences point for a key role of this pathway in lipid accumulation in various organs. At the difference of lipid provide by food, lipids synthesized from lipogenesis are preferentially stored in tissues such as adipose tissues, liver and muscle. In the present research program we aim to characterize the role of lipogenesis in lipid accumulation in liver and its importance for the maintenance of appropriate hepatic metabolism. As a first aim we propose to characterize the inhibitory role of hexanoate on lipogenesis and the link with hepatic lipid deposition. The effect of hexanoate on general hepatic metabolism will be also analysed. These studies will be performed in HepG2 cells cultured in presence of insulin and T3 to stimulate lipogenesis or in presence of oleate to induce fat accumulation. The effect of hexanoate will be also evaluated in rat fed with a high fat/high sugar diet to induce hepatic steatosis. The second aim of our study will be to evaluate the role of a lipogenic enzyme the stearoyl CoA desaturase 1 (SCD1) in the formation of lipid droplets in hepatocytes . Several studies point for an important role for SCD1 in the formation of lipid droplets (LD), the structures that store lipids in cells. Our specific goals will be to characterize the role of SCD1 on LD formation, morphology and composition and to precisely localize SCD1 on the LD or in its vicinity. The impact of SCD1 expression in association with fatty acid deposition will be also evaluated on hepatic metabolism. To perform these studies, we will use HepG2 cells over and under-expressing SCD1. Rats displaying hepatic steatosis will be used to evaluate the effect of a specific SCD1 inhibitor on metabolic responses. Understanding how lipids are stored in liver and how lipogenesis modulate this lipid infiltration are fundamental for our understanding of the maintenance of an appropriate lipid homeostasis in organisms.