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Organellar Proteomics and Phospho-Proteomics Reveal Subcellular Reorganization in Diet-Induced Hepatic Steatosis

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Krahmer,  Natalie
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Schueder,  Florian
Jungmann, Ralf / Molecular Imaging and Bionanotechnology, Max Planck Institute of Biochemistry, Max Planck Society;

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Steger,  Martin
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Kasper,  Robert
MPI of Neurobiology, Max Planck Society;

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Salinas,  Favio
Cox, Jürgen / Computational Systems Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Cox,  Jürgen
Cox, Jürgen / Computational Systems Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons172959

Jungmann,  Ralf
Jungmann, Ralf / Molecular Imaging and Bionanotechnology, Max Planck Institute of Biochemistry, Max Planck Society;

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Borner,  Georg Heinz Helmut
Borner, Georg / Systems Biology of Membrane Trafficking, Max Planck Institute of Biochemistry, Max Planck Society;

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Mann,  Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Krahmer, N., Najafi, B., Schueder, F., Quagliarini, F., Steger, M., Seitz, S., et al. (2018). Organellar Proteomics and Phospho-Proteomics Reveal Subcellular Reorganization in Diet-Induced Hepatic Steatosis. Developmental Cell, 47(2), 205-221.e7. doi:10.1016/j.devcel.2018.09.017.


Cite as: http://hdl.handle.net/21.11116/0000-0002-F139-E
Abstract
Lipid metabolism is highly compartmentalized between cellular organelles that dynamically adapt their compositions and interactions in response to metabolic challenges. Here, we investigate how diet-induced hepatic lipid accumulation, observed in non-alcoholic fatty liver disease (NAFLD), affects protein localization, organelle organization, and protein phosphorylation in vivo. We develop a mass spectrometric workflow for protein and phosphopeptide correlation profiling to monitor levels and cellular distributions of similar to 6,000 liver proteins and similar to 16,000 phosphopeptides during development of steatosis. Several organelle contact site proteins are targeted to lipid droplets (LDs) in steatotic liver, tethering organelles orchestrating lipid metabolism. Proteins of the secretory pathway dramatically redistribute, including the mis-localization of the COPI complex and sequestration of the Golgi apparatus at LDs. This correlates with reduced hepatic protein secretion. Our systematic in vivo analysis of subcellular rearrangements and organelle-specific phosphorylation reveals how nutrient overload leads to organellar reorganization and cellular dysfunction.