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

View ORCID ProfileGüneş Parlakgül, View ORCID ProfileAna Paula Arruda, Erika Cagampan, Song Pang, View ORCID ProfileEkin Güney, Yankun Lee, View ORCID ProfileHarald F. Hess, View ORCID ProfileC. Shan Xu, View ORCID ProfileGökhan S Hotamışlıgil
doi: https://doi.org/10.1101/2020.11.18.387803
Güneş Parlakgül
1Sabri Ülker Center of Metabolic Research and Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
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  • ORCID record for Güneş Parlakgül
Ana Paula Arruda
1Sabri Ülker Center of Metabolic Research and Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
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Erika Cagampan
1Sabri Ülker Center of Metabolic Research and Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
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Song Pang
3HHMI Janelia Research Campus, Ashburn, VA 20147, USA
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Ekin Güney
1Sabri Ülker Center of Metabolic Research and Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
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Yankun Lee
1Sabri Ülker Center of Metabolic Research and Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
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Harald F. Hess
3HHMI Janelia Research Campus, Ashburn, VA 20147, USA
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C. Shan Xu
3HHMI Janelia Research Campus, Ashburn, VA 20147, USA
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Gökhan S Hotamışlıgil
1Sabri Ülker Center of Metabolic Research and Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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  • For correspondence: ghotamis@hsph.harvard.edu
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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 (>2.8×105μm3) 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 ER’s architecture is highly dynamic, integrated with the metabolic state, and critical for adaptive homeostasis and tissue health.

Competing Interest Statement

C.S.X and H.F.H are the inventors of a US patent assigned to HHMI for the enhanced FIB-SEM systems used in this work: Xu, C.S., Hayworth K.J., Hess H.F. (2020) Enhanced FIB-SEM systems for large-volume 3D imaging. US Patent 10,600,615, 24 Mar 2020.

Footnotes

  • Updated the manuscript and figures

  • https://www.youtube.com/playlist?list=PLpzquMkvsJ9XZvqAKyHcz62iDQkoKxmpx

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 30, 2020.
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High resolution 3D imaging of liver reveals a central role for subcellular architectural organization in metabolism
Güneş Parlakgül, Ana Paula Arruda, Erika Cagampan, Song Pang, Ekin Güney, Yankun Lee, Harald F. Hess, C. Shan Xu, Gökhan S Hotamışlıgil
bioRxiv 2020.11.18.387803; doi: https://doi.org/10.1101/2020.11.18.387803
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High resolution 3D imaging of liver reveals a central role for subcellular architectural organization in metabolism
Güneş Parlakgül, Ana Paula Arruda, Erika Cagampan, Song Pang, Ekin Güney, Yankun Lee, Harald F. Hess, C. Shan Xu, Gökhan S Hotamışlıgil
bioRxiv 2020.11.18.387803; doi: https://doi.org/10.1101/2020.11.18.387803

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