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Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions
- Source :
- Diabetes, Diabetes, American Diabetes Association, 2018, 67 (7), pp.1258-1271. ⟨10.2337/db17-0901⟩, Diabetes, 2018, 67 (7), pp.1258-1271. ⟨10.2337/db17-0901⟩
- Publication Year :
- 2018
- Publisher :
- HAL CCSD, 2018.
-
Abstract
- International audience; 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.
- Subjects :
- 0301 basic medicine
Adult
Male
Ceramide
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Golgi Apparatus
Mice, Transgenic
[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
Protein Serine-Threonine Kinases
Ceramides
Endoplasmic Reticulum
03 medical and health sciences
chemistry.chemical_compound
Mice
Insulin resistance
Internal Medicine
medicine
[SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
Myocyte
Animals
Humans
Insulin
Cells, Cultured
ComputingMilieux_MISCELLANEOUS
biology
Muscles
Fatty Acids
medicine.disease
Sphingolipid
Cell biology
Mice, Inbred C57BL
Insulin receptor
030104 developmental biology
chemistry
Lipotoxicity
biology.protein
Signal transduction
Insulin Resistance
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 00121797 and 1939327X
- Database :
- OpenAIRE
- Journal :
- Diabetes, Diabetes, American Diabetes Association, 2018, 67 (7), pp.1258-1271. ⟨10.2337/db17-0901⟩, Diabetes, 2018, 67 (7), pp.1258-1271. ⟨10.2337/db17-0901⟩
- Accession number :
- edsair.doi.dedup.....4c98612fe781a2776f3e46af4629e39a