神经酰胺
脂毒性
细胞生物学
胰岛素
鞘脂
胰岛素受体
内质网
脂质信号
高尔基体
生物
化学
内科学
信号转导
内分泌学
胰岛素抵抗
细胞凋亡
生物化学
受体
医学
作者
Cécile L. Bandet,Rana Mahfouz,Julien Véret,Athanassia Sotiropoulos,Maxime Poirier,Paola Giussani,Mélanie Campana,Erwann Philippe,Agnieszka Błachnio‐Zabielska,Raphaëlle Ballaire,Xavier Le Lièpvre,Olivier Bourron,Dušan Berkeš,J Górski,Pascal Ferré,Hervé Le Stunff,Fabienne Foufelle,Éric Hajduch
出处
期刊:Diabetes
[American Diabetes Association]
日期:2018-05-14
卷期号:67 (7): 1258-1271
被引量:39
摘要
One main mechanism of insulin resistance (IR), a key feature of type 2 diabetes, is the accumulation of saturated fatty acids (FAs) in the muscles of obese patients with type 2 diabetes. Understanding the mechanism that underlies lipid-induced IR is an important challenge. Saturated FAs are metabolized into lipid derivatives called ceramides, and their accumulation plays a central role in the development of muscle IR. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi apparatus through a transporter called CERT, where they are converted into various sphingolipid species. We show that CERT protein expression is reduced in all IR models studied because of a caspase-dependent cleavage. Inhibiting CERT activity in vitro potentiates the deleterious action of lipotoxicity on insulin signaling, whereas overexpression of CERT in vitro or in vivo decreases muscle ceramide content and improves insulin signaling. In addition, inhibition of caspase activity prevents ceramide-induced insulin signaling defects in C2C12 muscle cells. Altogether, these results demonstrate the importance of physiological ER-to-Golgi ceramide traffic to preserve muscle cell insulin signaling and identify CERT as a major actor in this process.
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