Lipogenesis as a central player for fatty acids deposit

脂质生成是指由糖、其他脂质和蛋白质等外源性底物合成脂质。长期以来，脂肪生成一直被认为是一种辅助途径，只有在存在过量底物供应时才被激活。然而，近年来越来越多的证据表明该途径在各器官脂质积累中起着关键作用。在食物提供的脂质不同的情况下，脂肪生成合成的脂质优先储存在脂肪组织、肝脏和肌肉等组织中。在目前的研究计划中，我们的目的是表征脂肪生成在肝脏脂质积累中的作用及其对维持适当的肝脏代谢的重要性。作为第一个目的，我们提出表征己酸酯对脂肪生成的抑制作用及其与肝脏脂质沉积的联系。还将分析己酸酯对一般肝脏代谢的影响。这些研究将在HepG2细胞中进行，在胰岛素和T3刺激脂肪生成或油酸诱导脂肪积累的情况下培养。我们还将在喂食高脂/高糖饮食的大鼠中评估己酸酯诱导肝脂肪变性的效果。我们研究的第二个目的是评估脂质生成酶硬脂酰辅酶a去饱和酶1 （SCD1）在肝细胞脂滴形成中的作用。一些研究指出SCD1在脂滴（LD）的形成中起重要作用，脂滴是在细胞中储存脂质的结构。我们的具体目标将是表征SCD1在LD形成，形态和组成中的作用，并精确定位SCD1在LD或其附近的位置。与脂肪酸沉积相关的SCD1表达对肝脏代谢的影响也将被评估。为了进行这些研究，我们将使用表达过和过低表达SCD1的HepG2细胞。显示肝脂肪变性的大鼠将被用来评估特定SCD1抑制剂对代谢反应的影响。了解脂质如何在肝脏中储存，以及脂质生成如何调节这种脂质浸润，是我们理解维持生物体内适当的脂质稳态的基础。

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.