Graphical AbstractHighlights d Protein localization and organelle-specific phosphosites upon hepatic LD accumulation d HFD induces contacts between organelles, orchestrating lipid metabolism d LDs sequester compartment-specific proteins upon steatosis d The secretory apparatus redistributes, reducing protein secretion SUMMARY 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.

Highlights d Proteomics define the NSC niche-specific extracellular matrix d Detergent-solubility profiling reveals extracellular matrix architecture d Transglutaminase 2 regulates neurogenesis d Stiffness is increased in the neurogenic niches of the brain

No abstract

No abstract