Regulation of liver subcellular architecture controls metabolic homeostasis

Güneş Parlakgül, Ana Paula Arruda, Song Pang, Erika Cagampan, Nina Min, Ekin Güney, Grace Yankun Lee, Karen Inouye, Harald F. Hess, C. Shan Xu and Gökhan S. Hotamışlıgil ()
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Güneş Parlakgül: Harvard T.H. Chan School of Public Health
Ana Paula Arruda: Harvard T.H. Chan School of Public Health
Song Pang: HHMI Janelia Research Campus
Erika Cagampan: Harvard T.H. Chan School of Public Health
Nina Min: Harvard T.H. Chan School of Public Health
Ekin Güney: Harvard T.H. Chan School of Public Health
Grace Yankun Lee: Harvard T.H. Chan School of Public Health
Karen Inouye: Harvard T.H. Chan School of Public Health
Harald F. Hess: HHMI Janelia Research Campus
C. Shan Xu: HHMI Janelia Research Campus
Gökhan S. Hotamışlıgil: Harvard T.H. Chan School of Public Health

Nature, 2022, vol. 603, issue 7902, 736-742

Abstract: Abstract Cells display complex intracellular organization by compartmentalization of metabolic processes into organelles, yet the resolution of these structures in the native tissue context and their functional consequences are not well understood. Here we resolved the three-dimensional structural organization of organelles in large (more than 2.8 × 105 µm3) volumes of intact liver tissue (15 partial or full hepatocytes per condition) at high resolution (8 nm isotropic pixel size) using enhanced focused ion beam scanning electron microscopy1,2 imaging followed by deep-learning-based automated image segmentation and 3D reconstruction. We also performed a comparative analysis of subcellular structures in liver tissue of lean and obese mice and found substantial alterations, particularly in hepatic endoplasmic reticulum (ER), which undergoes massive structural reorganization characterized by marked disorganization of stacks of ER sheets3 and predominance of ER tubules. Finally, we demonstrated the functional importance of these structural changes by monitoring the effects of experimental recovery of the subcellular organization on cellular and systemic metabolism. We conclude that the hepatic subcellular organization of the ER architecture are highly dynamic, integrated with the metabolic state and critical for adaptive homeostasis and tissue health.

Date: 2022
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DOI: 10.1038/s41586-022-04488-5

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