Nikolaus Berndt1, Erik Kolbe2, Robert Gajowski3,4, Johannes Eckstein5, Fritzi Ott2, David Meierhofer3, Hermann-Georg Holzhütter5, Madlen Matz-Soja2,6. 1. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Berlin, Germany. 2. Rudolf-Schönheimer-Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany. 3. Max Planck Institute for Molecular Genetics, Berlin, Germany. 4. Department of Biology, Chemistry, Pharmacy, Freie Universität, Berlin, Germany. 5. Charité -Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biochemistry, Berlin, Germany. 6. Division of Hepatology, Department of Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases, Leipzig University Medical Center, Leipzig, Germany.
Abstract
BACKGROUND AND AIMS: Zone-dependent differences in expression of metabolic enzymes along the portocentral axis of the acinus are a long-known feature of liver metabolism. A prominent example is the preferential localization of the enzyme, glutamine synthetase, in pericentral hepatocytes, where it converts potentially toxic ammonia to the valuable amino acid, glutamine. However, with the exception of a few key regulatory enzymes, a comprehensive and quantitative assessment of zonal differences in the abundance of metabolic enzymes and, much more important, an estimation of the associated functional differences between portal and central hepatocytes is missing thus far. APPROACH AND RESULTS: We addressed this problem by establishing a method for the separation of periportal and pericentral hepatocytes that yields sufficiently pure fractions of both cell populations. Quantitative shotgun proteomics identified hundreds of differentially expressed enzymes in the two cell populations. We used zone-specific proteomics data for scaling of the maximal activities to generate portal and central instantiations of a comprehensive kinetic model of central hepatic metabolism (Hepatokin1). CONCLUSIONS: The model simulations revealed significant portal-to-central differences in almost all metabolic pathways involving carbohydrates, fatty acids, amino acids, and detoxification.
BACKGROUND AND AIMS: Zone-dependent differences in expression of metabolic enzymes along the portocentral axis of the acinus are a long-known feature of liver metabolism. A prominent example is the preferential localization of the enzyme, glutamine synthetase, in pericentral hepatocytes, where it converts potentially toxic ammonia to the valuable amino acid, glutamine. However, with the exception of a few key regulatory enzymes, a comprehensive and quantitative assessment of zonal differences in the abundance of metabolic enzymes and, much more important, an estimation of the associated functional differences between portal and central hepatocytes is missing thus far. APPROACH AND RESULTS: We addressed this problem by establishing a method for the separation of periportal and pericentral hepatocytes that yields sufficiently pure fractions of both cell populations. Quantitative shotgun proteomics identified hundreds of differentially expressed enzymes in the two cell populations. We used zone-specific proteomics data for scaling of the maximal activities to generate portal and central instantiations of a comprehensive kinetic model of central hepatic metabolism (Hepatokin1). CONCLUSIONS: The model simulations revealed significant portal-to-central differences in almost all metabolic pathways involving carbohydrates, fatty acids, amino acids, and detoxification.
Authors: Stefanie Schreyer; Nikolaus Berndt; Johannes Eckstein; Michael Mülleder; Shabnam Hemmati-Sadeghi; Charlotte Klein; Basim Abuelnor; Alina Panzel; David Meierhofer; Joachim Spranger; Barbara Steiner; Sebastian Brachs Journal: Aging (Albany NY) Date: 2021-04-16 Impact factor: 5.682
Authors: Sami Saarenpää; Ludvig Larsson; Noémi Van Hul; Franziska Hildebrandt; Alma Andersson; Sachie Kanatani; Jan Masek; Ewa Ellis; Antonio Barragan; Annelie Mollbrink; Emma R Andersson; Joakim Lundeberg; Johan Ankarklev Journal: Nat Commun Date: 2021-12-02 Impact factor: 14.919