Lipogenesis as a central player for fatty acids deposit

脂肪生成是脂肪酸沉积的核心参与者

• 批准号: 251066-2013
• 负责人: Mounier, Catherine
• 金额: $ 3.13万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=525080
• 关键词: Lipogenesis; central; player; fatty; acids

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.

脂肪生成负责从外源底物（例如糖、其他脂质和蛋白质）合成脂质。长期以来，脂肪生成被认为是仅在底物供应过量的情况下才被激活的辅助途径。然而，最近，越来越多的证据表明该途径在各个器官的脂质积累中发挥着关键作用。与食物提供的脂质不同，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，我们的目标是表征脂肪生成在肝脏脂质积累中的作用及其对于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 的情况下培养的 HepG2 细胞中进行，以刺激脂肪生成，或在存在油酸盐的情况下诱导脂肪积累。还将在喂食高脂肪/高糖饮食的大鼠中评估己酸对诱导肝脂肪变性的影响。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 (SCD1) 在肝细胞脂滴形成中的作用。多项研究指出 SCD1 在脂滴 (LD)（细胞中储存脂质的结构）的形成中发挥着重要作用。我们的具体目标是表征 SCD1 对 LD 形成、形态和组成的作用，并精确定位 SCD1 在 LD 上或其附近。还将评估 SCD1 表达与脂肪酸沉积相关的对肝脏代谢的影响。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。表现出肝脂肪变性的大鼠将用于评估特定 SCD1 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理解维持生物体中适当的脂质稳态至关重要。