Dataset Information

HELA cells Sphingolipid pulldown (Cers6 and Cers5)

ABSTRACT: Ectopic lipid deposition and altered mitochondrial dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between both processes remains unclear. Here we demonstrate that abrogation of ceramide synthase (CerS)6, which generates C16:0-sphingolipids, but not of the alternative C16:0-sphingolipid synthetizing CerS5 protects from obesity and insulin resistance, and both enzymes regulate C16:0-sphingolipid synthesis in distinct intracellular compartments. Moreover, we identify proteins, which specifically interact with C16:0-sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C16:0-sphingolipids bind the mitochondrial fission factor (Mff). CerS6- and Mff-deficiency protects from fatty acid-induced mitochondrial fragmentation in vitro, and both proteins genetically interact in vivo in obesity-induced mitochondrial fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid-signaling depending on specific synthetizing enzymes, provide a mechanistic link between lipid deposition and mitochondrial dynamics in obesity, and define the CerS6/sphingolid/Mff interaction as a therapeutic target for obesity and diabetes.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Hendrik Nolte

LAB HEAD: Marcus Krueger

PROVIDER: PXD007158 | Pride | 2019-05-20

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20151218_UC_ColID_50_Hammerschmidt_Bruening_1_1_1A_01.raw	Raw
	20151218_UC_ColID_50_Hammerschmidt_Bruening_1_1_1B_02.raw	Raw
	20151218_UC_ColID_50_Hammerschmidt_Bruening_1_1_1C_03.raw	Raw
	20151218_UC_ColID_50_Hammerschmidt_Bruening_1_1_1D_04.raw	Raw
	20151218_UC_ColID_50_Hammerschmidt_Bruening_1_1_1E_05.raw	Raw

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Publications

CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity.

Hammerschmidt Philipp P Ostkotte Daniela D Nolte Hendrik H Gerl Mathias J MJ Jais Alexander A Brunner Hanna L HL Sprenger Hans-Georg HG Awazawa Motoharu M Nicholls Hayley T HT Turpin-Nolan Sarah M SM Langer Thomas T Krüger Marcus M Brügger Britta B Brüning Jens C JC

Cell 20190501 6

Ectopic lipid deposition and altered mitochondrial 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<sub>16:0</sub> 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<sub>16:0</su ...[more]

PMID: 31150623

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