Functional changes of the liver in the absence of growth hormone (GH) action – Proteomic and metabolomic insights from a GH receptor deficient pig model
Objective: The liver is a central target organ of growth hormone (GH), which stimulates the synthesis of insulin-like growth factor 1 (IGF1) and affects multiple biochemical pathways. A systematic multi-omics analysis of GH effects in the liver has not been performed. GH receptor (GHR) deficiency is...
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Elsevier
2020-06-01
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Series: | Molecular Metabolism |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820300521 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Evamaria O. Riedel Arne Hinrichs Elisabeth Kemter Maik Dahlhoff Mattias Backman Birgit Rathkolb Cornelia Prehn Jerzy Adamski Simone Renner Andreas Blutke Martin Hrabĕ de Angelis Martin Bidlingmaier Jochen Schopohl Georg J. Arnold Thomas Fröhlich Eckhard Wolf |
spellingShingle |
Evamaria O. Riedel Arne Hinrichs Elisabeth Kemter Maik Dahlhoff Mattias Backman Birgit Rathkolb Cornelia Prehn Jerzy Adamski Simone Renner Andreas Blutke Martin Hrabĕ de Angelis Martin Bidlingmaier Jochen Schopohl Georg J. Arnold Thomas Fröhlich Eckhard Wolf Functional changes of the liver in the absence of growth hormone (GH) action – Proteomic and metabolomic insights from a GH receptor deficient pig model Molecular Metabolism Liver Growth hormone Laron syndrome Pig model Proteomics Metabolomics |
author_facet |
Evamaria O. Riedel Arne Hinrichs Elisabeth Kemter Maik Dahlhoff Mattias Backman Birgit Rathkolb Cornelia Prehn Jerzy Adamski Simone Renner Andreas Blutke Martin Hrabĕ de Angelis Martin Bidlingmaier Jochen Schopohl Georg J. Arnold Thomas Fröhlich Eckhard Wolf |
author_sort |
Evamaria O. Riedel |
title |
Functional changes of the liver in the absence of growth hormone (GH) action – Proteomic and metabolomic insights from a GH receptor deficient pig model |
title_short |
Functional changes of the liver in the absence of growth hormone (GH) action – Proteomic and metabolomic insights from a GH receptor deficient pig model |
title_full |
Functional changes of the liver in the absence of growth hormone (GH) action – Proteomic and metabolomic insights from a GH receptor deficient pig model |
title_fullStr |
Functional changes of the liver in the absence of growth hormone (GH) action – Proteomic and metabolomic insights from a GH receptor deficient pig model |
title_full_unstemmed |
Functional changes of the liver in the absence of growth hormone (GH) action – Proteomic and metabolomic insights from a GH receptor deficient pig model |
title_sort |
functional changes of the liver in the absence of growth hormone (gh) action – proteomic and metabolomic insights from a gh receptor deficient pig model |
publisher |
Elsevier |
series |
Molecular Metabolism |
issn |
2212-8778 |
publishDate |
2020-06-01 |
description |
Objective: The liver is a central target organ of growth hormone (GH), which stimulates the synthesis of insulin-like growth factor 1 (IGF1) and affects multiple biochemical pathways. A systematic multi-omics analysis of GH effects in the liver has not been performed. GH receptor (GHR) deficiency is a unique model for studying the consequences of lacking GH action. In this study, we used molecular profiling techniques to capture a broad spectrum of these effects in the liver of a clinically relevant large animal model for Laron syndrome. Methods: We performed holistic proteome and targeted metabolome analyses of liver samples from 6-month-old GHR-deficient (GHR-KO) pigs and GHR-expressing controls (four males, four females per group). Results: GHR deficiency resulted in an increased abundance of enzymes involved in amino acid degradation, in the urea cycle, and in the tricarboxylic acid cycle. A decreased ratio of long-chain acylcarnitines to free carnitine suggested reduced activity of carnitine palmitoyltransferase 1A and thus reduced mitochondrial import of fatty acids for beta-oxidation. Increased levels of short-chain acylcarnitines in the liver and in the circulation of GHR-KO pigs may result from impaired beta-oxidation of short-chain fatty acids or from increased degradation of specific amino acids. The concentration of mono-unsaturated glycerophosphocholines was significantly increased in the liver of GHR-KO pigs without morphological signs of steatosis, although the abundances of several proteins functionally linked to non-alcoholic fatty liver disease (fetuin B, retinol binding protein 4, several mitochondrial proteins) were increased. Moreover, GHR-deficient liver samples revealed distinct changes in the methionine and glutathione metabolic pathways, in particular, a significantly increased level of glycine N-methyltransferase and increased levels of total and free glutathione. Several proteins revealed a sex-related abundance difference in the control group but not in the GHR-KO group. Conclusions: Our integrated proteomics/targeted metabolomics study of GHR-deficient and control liver samples from a clinically relevant large animal model identified a spectrum of biological pathways that are significantly altered in the absence of GH action. Moreover, new insights into the role of GH in the sex-related specification of liver functions were provided. |
topic |
Liver Growth hormone Laron syndrome Pig model Proteomics Metabolomics |
url |
http://www.sciencedirect.com/science/article/pii/S2212877820300521 |
work_keys_str_mv |
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doaj-4c13755fb0f34d8a9cce6ab85f9e00612020-11-25T03:24:05ZengElsevierMolecular Metabolism2212-87782020-06-0136Functional changes of the liver in the absence of growth hormone (GH) action – Proteomic and metabolomic insights from a GH receptor deficient pig modelEvamaria O. Riedel0Arne Hinrichs1Elisabeth Kemter2Maik Dahlhoff3Mattias Backman4Birgit Rathkolb5Cornelia Prehn6Jerzy Adamski7Simone Renner8Andreas Blutke9Martin Hrabĕ de Angelis10Martin Bidlingmaier11Jochen Schopohl12Georg J. Arnold13Thomas Fröhlich14Eckhard Wolf15Laboratory for Functional Genome Analysis, (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, 80336 Munich, GermanyInstitute of Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, GermanyInstitute of Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, GermanyInstitute of Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, GermanyLaboratory for Functional Genome Analysis, (LAFUGA), Gene Center, LMU Munich, 81377 Munich, GermanyInstitute of Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; German Mouse Clinic (GMC), Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, GermanyResearch Unit Molecular Endocrinology and Metabolism (MEM), Helmholtz Zentrum München, 85764 Neuherberg, GermanyResearch Unit Molecular Endocrinology and Metabolism (MEM), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85354 Freising, Germany; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeInstitute of Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, GermanyResearch Unit Analytical Pathology, Helmholtz Zentrum München, 85764 Neuherberg, GermanyGerman Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; German Mouse Clinic (GMC), Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85354 Freising, GermanyMedizinische Klinik und Poliklinik IV, Klinikum der LMU München, 80336 Munich, GermanyMedizinische Klinik und Poliklinik IV, Klinikum der LMU München, 80336 Munich, GermanyLaboratory for Functional Genome Analysis, (LAFUGA), Gene Center, LMU Munich, 81377 Munich, GermanyLaboratory for Functional Genome Analysis, (LAFUGA), Gene Center, LMU Munich, 81377 Munich, GermanyLaboratory for Functional Genome Analysis, (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; Institute of Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Corresponding author. Gene Center, LMU Munich, Feodor-Lynen-Str. 25, 81377 Munich, Germany.Objective: The liver is a central target organ of growth hormone (GH), which stimulates the synthesis of insulin-like growth factor 1 (IGF1) and affects multiple biochemical pathways. A systematic multi-omics analysis of GH effects in the liver has not been performed. GH receptor (GHR) deficiency is a unique model for studying the consequences of lacking GH action. In this study, we used molecular profiling techniques to capture a broad spectrum of these effects in the liver of a clinically relevant large animal model for Laron syndrome. Methods: We performed holistic proteome and targeted metabolome analyses of liver samples from 6-month-old GHR-deficient (GHR-KO) pigs and GHR-expressing controls (four males, four females per group). Results: GHR deficiency resulted in an increased abundance of enzymes involved in amino acid degradation, in the urea cycle, and in the tricarboxylic acid cycle. A decreased ratio of long-chain acylcarnitines to free carnitine suggested reduced activity of carnitine palmitoyltransferase 1A and thus reduced mitochondrial import of fatty acids for beta-oxidation. Increased levels of short-chain acylcarnitines in the liver and in the circulation of GHR-KO pigs may result from impaired beta-oxidation of short-chain fatty acids or from increased degradation of specific amino acids. The concentration of mono-unsaturated glycerophosphocholines was significantly increased in the liver of GHR-KO pigs without morphological signs of steatosis, although the abundances of several proteins functionally linked to non-alcoholic fatty liver disease (fetuin B, retinol binding protein 4, several mitochondrial proteins) were increased. Moreover, GHR-deficient liver samples revealed distinct changes in the methionine and glutathione metabolic pathways, in particular, a significantly increased level of glycine N-methyltransferase and increased levels of total and free glutathione. Several proteins revealed a sex-related abundance difference in the control group but not in the GHR-KO group. Conclusions: Our integrated proteomics/targeted metabolomics study of GHR-deficient and control liver samples from a clinically relevant large animal model identified a spectrum of biological pathways that are significantly altered in the absence of GH action. Moreover, new insights into the role of GH in the sex-related specification of liver functions were provided.http://www.sciencedirect.com/science/article/pii/S2212877820300521LiverGrowth hormoneLaron syndromePig modelProteomicsMetabolomics |