4.7 Article

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

Journal

DIABETES
Volume 67, Issue 7, Pages 1258-1271

Publisher

AMER DIABETES ASSOC
DOI: 10.2337/db17-0901

Keywords

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Funding

  1. INSERM
  2. Societe Francophone du Diabete
  3. Agence Nationale de la Recherche [ANR 11 BSV1 03101-Crisalis]
  4. Fondation pour la Recherche Medicale [FRM DEQ20140329504]
  5. Sorbonne Universite
  6. Piano di sostegno alla ricerca BIOMETRA-Linea B [15-6-3003005-9]

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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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