TY - JOUR
T1 - Organellar Proteomics and Phospho-Proteomics Reveal Subcellular Reorganization in Diet-Induced Hepatic Steatosis
AU - Krahmer, Natalie
AU - Najafi, Bahar
AU - Schueder, Florian
AU - Quagliarini, Fabiana
AU - Steger, Martin
AU - Seitz, Susanne
AU - Kasper, Robert
AU - Salinas, Favio
AU - Cox, Jürgen
AU - Uhlenhaut, Nina Henriette
AU - Walther, Tobias Christian
AU - Jungmann, Ralf
AU - Zeigerer, Anja
AU - Borner, Georg Heinz Helmut
AU - Mann, Matthias
N1 - Copyright © 2018 Elsevier Inc. All rights reserved.
PY - 2018/10/22
Y1 - 2018/10/22
N2 - 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. The systematic proteomic in vivo analysis of subcellular rearrangements and organelle-specific phosphorylation by Krahmer et al. reveals how nutrient overload leads to organellar reorganization and cellular dysfunction in NAFLD. Lipid accumulation changes organelle contacts and leads to a dramatic redistribution of secretory pathway proteins, thereby affecting hepatic secretion.
AB - 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. The systematic proteomic in vivo analysis of subcellular rearrangements and organelle-specific phosphorylation by Krahmer et al. reveals how nutrient overload leads to organellar reorganization and cellular dysfunction in NAFLD. Lipid accumulation changes organelle contacts and leads to a dramatic redistribution of secretory pathway proteins, thereby affecting hepatic secretion.
U2 - 10.1016/j.devcel.2018.09.017
DO - 10.1016/j.devcel.2018.09.017
M3 - Journal article
C2 - 30352176
SN - 1534-5807
VL - 47
SP - 205-221.E7
JO - Developmental Cell
JF - Developmental Cell
IS - 2
ER -