Université de Poitiers, Institut de Physiologie et de Biologie Cellulaires, FRE CNRS 3511, Pôle Biologie-Santé, 1, Rue Georges BONNET, BP 633, 86022, Poitiers Cedex, France.
Traffic. 2013 Dec;14(12):1228-41. doi: 10.1111/tra.12117. Epub 2013 Oct 2.
Saturated fatty acids (SFA) have been reported to alter organelle integrity and function in many cell types, including muscle and pancreatic β-cells, adipocytes, hepatocytes and cardiomyocytes. SFA accumulation results in increased amounts of ceramides/sphingolipids and saturated phospholipids (PL). In this study, using a yeast-based model that recapitulates most of the trademarks of SFA-induced lipotoxicity in mammalian cells, we demonstrate that these lipid species act at different levels of the secretory pathway. Ceramides mostly appear to modulate the induction of the unfolded protein response and the transcription of nutrient transporters destined to the cell surface. On the other hand, saturated PL, by altering membrane properties, directly impact vesicular budding at later steps in the secretory pathway, i.e. at the trans-Golgi Network level. They appear to do so by increasing lipid order within intracellular membranes which, in turn, alters the recruitment of loose lipid packing-sensing proteins, required for optimal budding, to nascent vesicles. We propose that this latter general mechanism could account for the well-documented deleterious impacts of fatty acids on the last steps of the secretory pathway in several cell types.
饱和脂肪酸（SFA）已被报道在许多细胞类型中改变细胞器的完整性和功能，包括肌肉和胰腺β细胞、脂肪细胞、肝细胞和心肌细胞。SFA 的积累导致神经酰胺/鞘脂和饱和磷脂（PL）的含量增加。在这项研究中，我们使用基于酵母的模型，该模型重现了哺乳动物细胞中 SFA 诱导的脂毒性的大多数特征，证明这些脂质种类在分泌途径的不同水平上起作用。神经酰胺似乎主要调节未折叠蛋白反应的诱导和注定到达细胞表面的营养转运蛋白的转录。另一方面，饱和 PL 通过改变膜特性，直接影响分泌途径中较晚步骤的囊泡出芽，即在高尔基网络水平。它们似乎通过增加细胞内膜内的脂质有序性来实现这一点，这反过来又改变了对最佳出芽所必需的松散脂质包装感应蛋白向新生囊泡的募集。我们提出，这种后一种普遍机制可以解释脂肪酸对几种细胞类型的分泌途径最后步骤的记录在案的有害影响。
