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: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=594476
• 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.

脂肪生成是导致来自糖，其他脂质和蛋白质等外源底物的脂质的合成。长期以来，脂肪形成被认为是仅在过度底物供应的情况下激活的辅助途径。但是，最近，越来越多的证据指出了该途径在各种器官中脂质积累中的关键作用。在食物提供的脂质的差异下，从脂肪生成合成的脂质优先存储在脂肪组织，肝脏和肌肉等组织中。在本研究计划中，我们旨在表征脂肪生成在脂质积累中的作用，以及其对维持适当肝代谢的重要性。作为第一个目的，我们建议表征己酸盐对脂肪生成的抑制作用以及与肝脂质沉积的联系。还将分析己酸盐对一般肝代谢的影响。这些研究将在胰岛素和T3存在的HEPG2细胞中进行，以刺激脂肪生成或在存在的Oleate存在下诱导脂肪积累。还将在喂养高脂肪/高糖饮食的大鼠中评估己酸盐的作用，以诱导肝脂肪变性。我们研究的第二个目的是评估脂肪酶在肝细胞中脂质液滴形成中脂肪酰基COA去饱和酶1（SCD1）的作用。几项研究指出了SCD1在形成脂质液滴（LD）中的重要作用，这是将脂质储存在细胞中的结构。我们的具体目标是表征SCD1在LD形成，形态和组成中的作用，并精确地将SCD1定位在LD或其附近。 SCD1表达与脂肪酸沉积相关的影响还将在肝代谢上进行评估。为了进行这些研究，我们将在表达SCD1上使用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。了解脂质如何存储在肝脏中，以及脂肪形成如何调节这种脂质浸润对于我们理解生物体中适当的脂质稳态的维持至关重要。