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

ACCESS DATA

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

Similar Datasets

Project description:ABSTRACT: Sphingolipid synthesis is initiated by condensation of serine with palmitoyl-CoA to produce 3-ketodihydrosphinganine (3-KDS), which is subsequently reduced by a 3-KDS reductase to dihydrosphinganine (DHS). Serine palmitoyltransferase was recently shown to be essential for plant viability, but the 3-KDS reductase step of sphingolipid synthesis has not been investigated in plants. Arabidopsis thaliana contains two genes (At3g06060/TSC10A and At5g19200/TSC10B) that encode proteins with significant homology to the yeast 3-KDS reductase, Tsc10p. Heterologous expression, in yeast, of either A. thaliana gene restored 3-KDS reductase activity to the yeast tsc10Δ mutant, thereby identifying both as bona fide 3-KDS reductase genes. Consistent with previous evidence that sphingolipids have essential functions in plants, double mutant progeny lacking both genes were not recovered. Although the 3-KDS reductase genes are functionally redundant and ubiquitously expressed in A. thaliana, 3-KDS reductase activity was reduced to approximately 10% of wild-type levels in the loss-of-function tsc10a mutant, leading to an altered sphingolipid profile compared to wild-type plants. Interestingly, this perturbation of sphingolipid biosynthesis in the A. thaliana tsc10a mutant leads to significant alterations in the leaf ionome, including increases in Na, K and Rb (a K analogue), and decreases in Mg, Ca, Fe, and Mo. Reciprocal grafting revealed that these changes in the leaf ionome are driven by the root, and are associated with both increases in root suberin, and elevation of expression in the root of genes involved in Fe homoeostasis, including the Fe-transporter IRT1. Keywords: genomic hybridization bulked segregant analysis Hybridizations from a set of Bulk Segregant analysis. An F2 population from 7113 in the col-0 background crossed to Ler-0 was analyzed. This series contains the 3 hybs from Ler used to identify Single Feature Polymorphisms, the 3 hybs of Col-0 they were compared to, and 1 hyb for each pool from the BSA mapping(low Ca/Mg Pool and wild type pools).

Dataset Information

HELA cells Sphingolipid pulldown (Cers6 and Cers5)

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure