Liver lipid metabolism is altered by increased circulating estrogen to androgen ratio in male mouse

Anni P Vehmas; Marion Adam; Teemu D Laajala; Gabi Kastenmüller; Cornelia Prehn; Jan Rozman; Claes Ohlsson; Helmut Fuchs; Martin Hrabě de Angelis; Valérie Gailus-Durner; Laura L Elo; Tero Aittokallio; Jerzy Adamski; Garry Corthals; Matti Poutanen; Leena Strauss

doi:10.1016/j.jprot.2015.12.009

Liver lipid metabolism is altered by increased circulating estrogen to androgen ratio in male mouse

J Proteomics. 2016 Feb 5:133:66-75. doi: 10.1016/j.jprot.2015.12.009. Epub 2015 Dec 9.

Authors

Anni P Vehmas¹, Marion Adam², Teemu D Laajala³, Gabi Kastenmüller⁴, Cornelia Prehn⁵, Jan Rozman⁶, Claes Ohlsson⁷, Helmut Fuchs⁸, Martin Hrabě de Angelis⁹, Valérie Gailus-Durner⁸, Laura L Elo¹⁰, Tero Aittokallio¹¹, Jerzy Adamski¹², Garry Corthals¹³, Matti Poutanen¹⁴, Leena Strauss¹⁵

Affiliations

¹ Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
² Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Center for Disease Modeling, University of Turku, Turku, Finland.
³ Turku Center for Disease Modeling, University of Turku, Turku, Finland; Department of Mathematics and Statistics, University of Turku, Turku, Finland; Drug Research Doctoral Programme, University of Turku, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
⁴ Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
⁵ Genome Analysis Center, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁶ German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Molecular Nutritional Medicine, Else Kröner-Fresenius Center, Technische Universität München, Freising-Weihenstephan, Germany.
⁷ Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
⁸ German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁹ German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Neuherberg, Germany.
¹⁰ Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; Department of Mathematics and Statistics, University of Turku, Turku, Finland.
¹¹ Department of Mathematics and Statistics, University of Turku, Turku, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
¹² Genome Analysis Center, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Neuherberg, Germany.
¹³ Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, The Netherlands.
¹⁴ Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
¹⁵ Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Center for Disease Modeling, University of Turku, Turku, Finland. Electronic address: leesal@utu.fi.

PMID: 26691839
DOI: 10.1016/j.jprot.2015.12.009

Abstract

Estrogens are suggested to lower the risk of developing metabolic syndrome in both sexes. In this study, we investigated how the increased circulating estrogen-to-androgen ratio (E/A) alters liver lipid metabolism in males. The cytochrome P450 aromatase (P450arom) is an enzyme converting androgens to estrogens. Male mice overexpressing human aromatase enzyme (AROM+ mice), and thus have high circulating E/A, were used as a model in this study. Proteomics and gene expression analyses indicated an increase in the peroxisomal β-oxidation in the liver of AROM+ mice as compared with their wild type littermates. Correspondingly, metabolomic analysis revealed a decrease in the amount of phosphatidylcholines with long-chain fatty acids in the plasma. With interest we noted that the expression of Cyp4a12a enzyme, which specifically metabolizes arachidonic acid (AA) to 20-hydroxy AA, was dramatically decreased in the AROM+ liver. As a consequence, increased amounts of phospholipids having AA as a fatty acid tail were detected in the plasma of the AROM+ mice. Overall, these observations demonstrate that high circulating E/A in males is linked to indicators of higher peroxisomal β-oxidation and lower AA metabolism in the liver. Furthermore, the plasma phospholipid profile reflects the changes in the liver lipid metabolism.

Keywords: Aromatase; Label free quantitative proteomics; Liver; Male mouse; Metabolomics; Phospholipid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgens / blood*
Androgens / genetics
Animals
Aromatase / genetics
Aromatase / metabolism*
Estrogens / blood*
Estrogens / genetics
Humans
Lipid Metabolism*
Liver / metabolism*
Male
Mice
Mice, Transgenic
Peroxisomes / genetics
Peroxisomes / metabolism*
Phosphatidylcholines / biosynthesis
Phosphatidylcholines / genetics

Substances

Androgens
Estrogens
Phosphatidylcholines
Aromatase