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

Diabetes
Cécile L BandetEric Hajduch

Abstract

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 i...Continue Reading

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Citations

Jan 27, 2019·International Journal of Molecular Sciences·Cécile L BandetEric Hajduch
Jan 5, 2020·Journal of Lipid Research·Bryon F TuthillLaura Palanker Musselman
Aug 28, 2020·Frontiers in Endocrinology·Sophie Tan-ChenEric Hajduch
Sep 6, 2020·International Journal of Molecular Sciences·Benjamin LairCedric Moro
Feb 19, 2021·Alzheimer's Research & Therapy·Simone M CrivelliPilar Martinez-Martinez
Mar 7, 2021·Journal of Clinical Medicine·Eric HajduchFabienne Foufelle
Apr 6, 2021·Frontiers in Endocrinology·Kamila Roszczyc-Owsiejczuk, Piotr Zabielski
Jun 1, 2021·Frontiers in Endocrinology·Ilona JuchnickaJacek Szamatowicz
Jul 8, 2021·Cell Metabolism·Christopher D GreenSarah Spiegel
Jul 18, 2021·Molecular Metabolism·Christophe Magnan, Hervé Le Stunff
Aug 28, 2021·International Journal of Molecular Sciences·Mariyam KhalidAbdu Adem

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