Lipogenesis as a central player for fatty acids deposit

脂肪生成负责从外源底物如糖、其他脂质和蛋白质合成脂质。长期以来，脂肪生成一直被认为是一种仅在过量底物供应存在下激活的辅助途径。然而，最近越来越多的证据表明，该途径在各种器官的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，由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。在本研究计划中，我们的目标是描述脂肪生成在肝脏脂质蓄积中的作用及其对维持适当肝脏代谢的重要性。作为第一个目标，我们提出的特点己酸对脂肪生成的抑制作用和与肝脏脂质沉积的联系。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以刺激脂肪生成或存在油酸以诱导脂肪蓄积的HepG2细胞中进行。还将在喂食高脂肪/高糖饲料以诱导肝脂肪变性的大鼠中评价己酸的作用。我们研究的第二个目的是评估脂肪生成酶硬脂酰辅酶A去饱和酶1（SCD 1）在肝细胞脂滴形成中的作用。几项研究指出，SCD 1在脂滴（LD）形成中起着重要作用，脂滴是细胞中储存脂质的结构。我们的具体目标将是描述SCD 1对LD形成，形态和组成的作用，并精确定位SCD 1在LD或其附近。还将评价与脂肪酸沉积相关的SCD 1表达对肝脏代谢的影响。为了进行这些研究，我们将使用过表达和低表达SCD 1的HepG2细胞。显示肝脂肪变性的大鼠将用于评价特异性SCD 1抑制剂对代谢反应的影响。了解脂质如何储存在肝脏中以及脂肪生成如何调节这种脂质渗透对于我们了解生物体中维持适当的脂质稳态至关重要。

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.