Lipogenesis as a central player for fatty acids deposit

脂肪生成作用负责从糖、其他脂类和蛋白质等外源底物合成脂类。长期以来，脂肪生成一直被认为是只有在底物供应过多的情况下才被激活的一种辅助途径。然而，最近越来越多的证据表明，这一途径在不同器官中的脂质积累中起着关键作用。由于食物提供的脂肪的不同，脂肪合成的脂肪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，我们的目标是确定脂肪生成在肝脏脂肪堆积中的作用，以及它对维持适当的肝脏代谢的重要性。作为第一个目标，我们建议表征己酸对脂肪生成的抑制作用以及与肝脏脂肪沉积的联系。还将分析己酸对一般肝脏代谢的影响。这些研究将在存在胰岛素和T3的情况下培养的HepG2细胞中进行，以刺激脂肪生成或在油酸盐存在的情况下诱导脂肪积累。还将评估己酸对喂食高脂肪/高糖饮食的大鼠诱导肝脏脂肪变性的影响。我们研究的第二个目的是评估一种造脂酶，硬脂酰辅酶A脱饱和酶1(SCD1)在肝细胞中形成脂滴中的作用。一些研究指出，SCD1在脂滴(LD)的形成中起着重要作用，LD是一种在细胞中储存脂质的结构。我们的具体目标将是确定SCD1在LD的形成、形态和组成中的作用，并准确地定位SCD1在LD或其附近。SCD1的表达与脂肪酸沉积相关的影响也将被评估对肝脏代谢的影响。为了进行这些研究，我们将使用高表达和低表达SCD1的HepG2细胞。出现肝脏脂肪变性的大鼠将被用来评估一种特定的SCD1抑制剂对代谢反应的影响。了解脂肪是如何储存在肝脏中的，以及脂肪生成是如何调节这种脂质渗透的，这对于我们理解生物体中维持适当的脂平衡是基本的。

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.