CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondria! Fragmentation in Obesity

被引：203

作者：

Hammerschmidt, Philipp ^{[1
,2
,3
,4
]}

Ostkotte, Daniela ^{[5
]}

Nolte, Hendrik ^{[3
,4
,6
]}

Gerl, Mathias J. ^{[5
,7
]}

Jais, Alexander ^{[1
,2
,3
,4
]}

Brunner, Hanna L. ^{[5
]}

Sprenger, Hans-Georg ^{[3
,4
,6
]}

Awazawa, Motoharu ^{[1
,2
,3
,4
]}

Nicholls, Hayley T. ^{[1
,2
,3
,4
]}

Turpin-Nolan, Sarah M. ^{[1
,2
,3
,4
]}

Langer, Thomas ^{[3
,4
,6
]}

Krueger, Marcus ^{[3
,4
]}

Bruegger, Britta ^{[5
]}

Bruening, Jens C. ^{[1
,2
,3
,4
,8
]}

机构：

[1] Max Planck Inst Metab Res, Dept Neuronal Control Metab, Gleueler Str 50, D-50931 Cologne, Germany

[2] Univ Hosp Cologne, Ctr Endocrinol Diabet & Prevent Med CEDP, Kerpener Str 26, D-50924 Cologne, Germany

[3] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany

[4] Univ Cologne, CMMC, Cologne, Germany

[5] Heidelberg Univ, Biochem Ctr, Neuenheimer Feld 328, D-69120 Heidelberg, Germany

[6] Max Planck Inst Biol Ageing, Joseph Stelzmann Str 9B, D-50931 Cologne, Germany

[7] Lipotype GmbH, Tatzberg 47, D-01307 Dresden, Germany

[8] Natl Ctr Diabet Res DZD, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany

来源：

CELL | 2019年 / 177卷 / 06期

关键词：

INDUCED INSULIN-RESISTANCE; CERAMIDE SYNTHESIS; FISSION; KINASE; RECRUITMENT; DYNAMICS; SCHLANK; DRP1; DEGRADATION; SENSITIVITY;

D O I：

10.1016/j.cell.2019.05.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1536 / +

页数：40

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