FIT2在饱和脂肪酸诱导的β细胞脂毒性中的作用及机制研究

脂毒性诱导的胰岛β细胞功能障碍和凋亡是2型糖尿病（T2DM）最重要的发病原因之一，然而脂肪酸对β细胞造成损伤的机制尚未完全阐明。我们的前期结果表明饱和脂肪酸（SFA），而非不饱和脂肪酸，特异地下调β细胞脂肪储存诱导跨膜蛋白（FIT2）表达,从而抑制胞内脂滴形成,并引起内质网应激。S-脂酰化和内质网相关降解（ERAD）通路是调控SFA介导FIT2蛋白缺失的两种潜在机制。基于FIT2对调控脂滴形成的关键作用，以及脂滴在维持β细胞功能和存活的最新研究进展，我们提出假说：SFA通过诱导FIT2蛋白S-脂酰化，促使其通过ERAD通路降解，以阻止脂滴的形成，进而降低细胞分割和储存脂质的能力，最终导致β细胞功能障碍和凋亡。本项目将分别从细胞水平、小鼠胰岛水平及人类胰岛水平，探究FIT2在SFA诱导的β细胞脂毒性中的重要作用。本项目的实施将揭示β细胞脂毒性的新机制，并为防治T2DM提供潜在的干预靶点。

Lipotoxicity-induced pancreatic β-cell dysfunction and loss are one of the most important causes of type 2 diabetes (T2DM). However, the mechanism by which fatty acids（FA）play the deleterious roles on β-cells has not been fully elucidated. Our preliminary results show that saturated fatty acids (SFA)，but not unsaturated fatty acids (USFA), specifically down-regulate the expression of fat storage-inducing transmembrane protein (FIT2), disable intracellular lipid droplet (LD) formation, and induce endoplasmic reticulum stress in β-cells. S-acylation and endoplasmic reticulum-associated degradation (ERAD) pathways are two potential mechanisms involved in SFA-mediated FIT2 loss. Given the critical role of FIT2 in LD formation, as well as the recent research progress on the role of LD in maintaining β-cell function and survival, we hypothesize that SFA could disable LD formation by inducing S-acylation of FIT2 and subsequently promoting FIT2 degradation via ERAD pathways, which may in turn reduce the capacity of cells to sequester and store lipids, leading to β-cell dysfunction and death. In this project, we will investigate the role of FIT2 in SFA-induced β-cell lipotoxicity at the level of cells, mouse islets or human islets. The implementation of this project will reveal a novel molecular mechanism of β-cell lipotoxicity and provide the potential intervention targets for the prevention and treatment of T2DM.