An Essential Role for Liver ERα in Coupling Hepatic Metabolism to the Reproductive Cycle
Sara Della Torre,
Nico Mitro,
Roberta Fontana,
Monica Gomaraschi,
Elda Favari,
Camilla Recordati,
Federica Lolli,
Fabiana Quagliarini,
Clara Meda,
Claes Ohlsson,
Maurizio Crestani,
Nina Henriette Uhlenhaut,
Laura Calabresi,
Adriana Maggi
Affiliations
Sara Della Torre
Center of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy
Nico Mitro
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy
Roberta Fontana
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy
Monica Gomaraschi
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy
Elda Favari
Department of Pharmacy, University of Parma, 43121 Parma, Italy
Camilla Recordati
Mouse and Animal Pathology Laboratory, Fondazione Filarete, 20139 Milan, Italy
Federica Lolli
Center of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy
Fabiana Quagliarini
Helmholtz Diabetes Center (HDC) and German Center for Diabetes Research (DZD), Helmholtz Zentrum Muenchen, 85764 Munich-Neuherberg, Germany
Clara Meda
Center of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy
Claes Ohlsson
Centre for Bone and Arthritis Research and Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
Maurizio Crestani
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy
Nina Henriette Uhlenhaut
Helmholtz Diabetes Center (HDC) and German Center for Diabetes Research (DZD), Helmholtz Zentrum Muenchen, 85764 Munich-Neuherberg, Germany
Laura Calabresi
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy
Adriana Maggi
Center of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy
Lipoprotein synthesis is controlled by estrogens, but the exact mechanisms underpinning this regulation and the role of the hepatic estrogen receptor α (ERα) in cholesterol physiology are unclear. Utilizing a mouse model involving selective ablation of ERα in the liver, we demonstrate that hepatic ERα couples lipid metabolism to the reproductive cycle. We show that this receptor regulates the synthesis of cholesterol transport proteins, enzymes for lipoprotein remodeling, and receptors for cholesterol uptake. Additionally, ERα is indispensable during proestrus for the generation of high-density lipoproteins efficient in eliciting cholesterol efflux from macrophages. We propose that a specific interaction with liver X receptor α (LXRα) mediates the broad effects of ERα on the hepatic lipid metabolism.
