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Dev Cell. 2018 Oct 22;47(2):205-221.e7. doi: 10.1016/j.devcel.2018.09.017.

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

Author information

1
Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried 82152, Germany.
2
Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg 85764, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany.
3
Department of Physics and Center for Nanoscience, Ludwig Maximilian University, Munich, Germany; Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
4
Helmholtz Diabetes Center (HMGU) and German Center for Diabetes Research (DZD), IDO, Garching, Munich 85748, Germany.
5
Max Planck Institute of Neurobiology, Imaging facility, Martinsried 82152, Germany.
6
Computational Systems Biochemistry, Max-Planck Institute of Biochemistry, Martinsried 82152, Germany.
7
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA.
8
Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried 82152, Germany; Faculty of Health Sciences, NNF Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: mmann@biochem.mpg.de.

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 ∼6,000 liver proteins and ∼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.

KEYWORDS:

COPI; Golgi apparatus; contact sites; correlation profiling; hepatic steatosis; high-fat diet; lipid droplet; organelle phosphoproteome; organelle proteome; secretion defect

PMID:
30352176
DOI:
10.1016/j.devcel.2018.09.017
[Indexed for MEDLINE]

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