Universität zu Köln

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 ORCID: 0000-0003-2008-4582, 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:	Creators Email ORCID ORCID Put Code Hammerschmidt, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Ostkotte, Daniela UNSPECIFIED UNSPECIFIED UNSPECIFIED Nolte, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerl, Mathias J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jais, Alexander UNSPECIFIED orcid.org/0000-0002-9897-4983 UNSPECIFIED Brunner, Hanna L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sprenger, Hans-Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Awazawa, Motoharu UNSPECIFIED UNSPECIFIED UNSPECIFIED Nicholls, Hayley T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Turpin-Nolan, Sarah M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Krueger, Marcus UNSPECIFIED orcid.org/0000-0003-2008-4582 UNSPECIFIED Bruegger, Britta UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruening, Jens C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INDUCED INSULIN-RESISTANCE; CERAMIDE SYNTHESIS; FISSION; KINASE; RECRUITMENT; DYNAMICS; SCHLANK; DRP1; DEGRADATION; SENSITIVITY Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14774