Ballaire, Raphaelle

Bandet, Cécile,

Berkeš, Dušan

Blachnio-Zabielska, Agnieszka

Bourron, Olivier

Campana, Mélanie

Ferré, Pascal

Foufelle, Fabienne

Giussani, Paola

Gorski, Jan

Hajduch, Eric

Le Liepvre, Xavier

Le Stunff, Hervé

Mahfouz, Rana

Philippe, Erwann

Poirier, Maxime

Sotiropoulos, Athanassia

Véret, Julien

Diabetes

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.</jats:p

Cécile L. Bandet

Rana Mahfouz

Julien Véret

Athanassia Sotiropoulos

Maxime Poirier

Paola Giussani

Mélanie Campana

Erwann Philippe

Agnieszka Blachnio-Zabielska

Raphaëlle Ballaire

Xavier Le Liepvre

Olivier Bourron

Dušan Berkeš

Jan Górski

Pascal Ferré

Hervé Le Stunff

Fabienne Foufelle

Eric Hajduch

Crossref

Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions

Hal-Diderot

International audienceOne 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

Bandet, Cécile, L

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Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions

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Hal-Diderot

HAL-Inserm

Archive Ouverte en Sciences de l'Information et de la Communication

HAL Descartes