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Characterization of hepatic zonation in mice by mass-spectrometric and antibody-based proteomics approaches

Authors
  • Kling, Simon1
  • Lang, Benedikt1
  • Hammer, Helen S.1, 2
  • Naboulsi, Wael2
  • Sprenger, Heike3
  • Frenzel, Falko3
  • Pötz, Oliver2
  • Schwarz, Michael4
  • Braeuning, Albert3
  • Templin, Markus F.1
  • 1 Natural and Medical Sciences Institute, University of Tübingen, Markwiesenstr. 55, D-72770 , (Germany)
  • 2 Signatope, Markwiesenstr. 55, D-72770 , (Germany)
  • 3 German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, D-10589 , (Germany)
  • 4 Institute of Experimental and Clinical Pharmacology and Toxicology, Wilhelmstr. 56, D-72074 , (Germany)
Type
Published Article
Journal
Biological Chemistry
Publisher
Walter de Gruyter GmbH
Publication Date
Oct 04, 2021
Volume
403
Issue
3
Pages
331–343
Identifiers
DOI: 10.1515/hsz-2021-0314
Source
De Gruyter
Keywords
License
Yellow

Abstract

Periportal and perivenous hepatocytes show zonal heterogeneity in metabolism and signaling. Here, hepatic zonation in mouse liver was analyzed by non-targeted mass spectrometry (MS) and by the antibody-based DigiWest technique, yielding a comprehensive overview of protein expression in periportal and perivenous hepatocytes. Targeted immunoaffinity-based proteomics were used to substantiate findings related to drug metabolism. 165 (MS) and 82 (DigiWest) zonated proteins were identified based on the selected criteria for statistical significance, including 7 (MS) and 43 (DigiWest) proteins not identified as zonated before. New zonated proteins especially comprised kinases and phosphatases related to growth factor-dependent signaling, with mainly periportal localization. Moreover, the mainly perivenous zonation of a large panel of cytochrome P450 enzymes was characterized. DigiWest data were shown to complement the MS results, substantially improving possibilities to bioinformatically identify zonated biological processes. Data mining revealed key regulators and pathways preferentially active in either periportal or perivenous hepatocytes, with β-catenin signaling and nuclear xeno-sensing receptors as the most prominent perivenous regulators, and several kinase- and G-protein-dependent signaling cascades active mainly in periportal hepatocytes. In summary, the present data substantially broaden our knowledge of hepatic zonation in mouse liver at the protein level.

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