Hammerschmidt, Philipp, Ostkotte, Daniela, Nolte, Hendrik, Gerl, Mathias J., Jais, Alexander ORCID: 0000-0002-9897-4983, Brunner, Hanna L., Sprenger, Hans-Georg, Awazawa, Motoharu, Nicholls, Hayley T., Turpin-Nolan, Sarah M., Langer, Thomas, Krueger, Marcus, Bruegger, Britta and Bruening, Jens C. (2019). CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondria! Fragmentation in Obesity. Cell, 177 (6). S. 1536 - 1576. CAMBRIDGE: CELL PRESS. ISSN 1097-4172

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Abstract

Ectopic lipid deposition and altered mitochondria! dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between these processes remained unclear. Here we demonstrate that the C-16:0 sphingolipid synthesizing ceramide synthases, CerS5 and CerS6, affect distinct sphingolipid pools and that abrogation of CerS6 but not of CerS5 protects from obesity and insulin resistance. We identify proteins that specifically interact with C-16:0 sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C-16:0 sphingolipids bind the mitochondrial fission factor (Mff). CerS6 and Mff deficiency protect from fatty acid-induced mitochondria' fragmentation in vitro, and the two proteins genetically interact in vivo in obesity-induced mitochondria! fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid signaling depending on specific synthesizing enzymes, provide a mechanistic link between hepatic lipid deposition and mitochondrial fragmentation in obesity, and define the CerS6-derived sphingolipid/Mff interaction as a therapeutic target for metabolic diseases.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hammerschmidt, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ostkotte, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nolte, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerl, Mathias J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jais, AlexanderUNSPECIFIEDorcid.org/0000-0002-9897-4983UNSPECIFIED
Brunner, Hanna L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sprenger, Hans-GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Awazawa, MotoharuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nicholls, Hayley T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Turpin-Nolan, Sarah M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruegger, BrittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruening, Jens C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-147740
DOI: 10.1016/j.cell.2019.05.008
Journal or Publication Title: Cell
Volume: 177
Number: 6
Page Range: S. 1536 - 1576
Date: 2019
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4172
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INDUCED INSULIN-RESISTANCE; CERAMIDE SYNTHESIS; FISSION; KINASE; RECRUITMENT; DYNAMICS; SCHLANK; DRP1; DEGRADATION; SENSITIVITYMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14774

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