High resolution 3D imaging of liver reveals a central role for subcellular architectural organization in metabolism

Abstract

Cells display complex intracellular organization through compartmentalization of metabolic processes into organelles, yet neither the resolution of these structures in the native tissue context nor its functional consequences are well understood. Here, we resolved the 3-dimensional organelle structural organization in large (>2.8x105m3) volumes of intact liver tissue (15 partial or full hepatocytes per condition) in high resolution (8nm isotropic pixel size) by utilizing enhanced Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) imaging, followed by deep-learning-based image segmentation and 3D reconstruction. We also performed a comparative analysis of subcellular structures in liver tissue of lean and obese animals and found marked alterations particularly in hepatic endoplasmic reticulum (ER), which undergoes massive structural re-organization in obesity characterized by marked disorganization of stacks of ER sheets and predominance of ER tubules. Finally, we demonstrated the functional importance of these structural changes upon experimental recovery of the subcellular organization and its marked impact on cellular and systemic metabolism. We conclude that hepatic subcellular organization and ERs architecture is highly dynamic, integrated with the metabolic state, and critical for adaptive homeostasis and tissue health.