title: Imbalanced lipid homeostasis in the conditional Dicer1 knockout mouse epididymis causes instability of the sperm membrane.
abstract: During epididymal sperm maturation, the lipid content of the sperm membrane is modified, which facilitates sperm motility and fertility. However, little is known about the mechanisms regulating the maturation process. By generating a conditional knockout (cKO) of Dicer1 in the proximal part of the mouse epididymis, we studied the role of RNA interference in epididymal functions. The Dicer1 cKO epididymis displayed an altered lipid homeostasis associated with a 0.6-fold reduction in the expression of the gene elongation of very long chain fatty acids-like 2, an enzyme needed for production of long-chain polyunsaturated fatty acids (PUFAs). Furthermore, the expression of several factors involved in cholesterol synthesis was up-regulated. Accordingly, the Dicer1 cKO sperm membrane showed a 0.7-fold decrease in long-chain PUFAs, whereas the amount of cholesterol in acrosome-reacted sperm displayed a 1.7-fold increase. The increased cholesterol:PUFA ratio of the sperm membrane caused breakage of the neck and acrosome region and immotility of sperm. Dicer1 cKO mice sperm also displayed reduced ability to bind to and fertilize the oocyte in vitro. This study thus shows that Dicer1 is critical for lipid synthesis in the epididymis, which directly affects sperm membrane integrity and male fertility.
authors.affiliation: *Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Doctoral Programme of Biomedical Sciences, Turku, Finland; Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland; Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; **Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland; and Laboratory Animal Centre, University of Helsinki, Helsinki, Finland.
authors.forename: Ida
authors.initials: I
authors.lastname: Björkgren
authors.affiliation: *Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Doctoral Programme of Biomedical Sciences, Turku, Finland; Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland; Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; **Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland; and Laboratory Animal Centre, University of Helsinki, Helsinki, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Gylling
authors.affiliation: *Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Doctoral Programme of Biomedical Sciences, Turku, Finland; Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland; Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; **Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland; and Laboratory Animal Centre, University of Helsinki, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Turunen
authors.affiliation: *Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Doctoral Programme of Biomedical Sciences, Turku, Finland; Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland; Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; **Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland; and Laboratory Animal Centre, University of Helsinki, Helsinki, Finland.
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.affiliation: *Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Doctoral Programme of Biomedical Sciences, Turku, Finland; Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland; Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; **Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland; and Laboratory Animal Centre, University of Helsinki, Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Strauss
authors.affiliation: *Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Doctoral Programme of Biomedical Sciences, Turku, Finland; Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland; Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; **Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland; and Laboratory Animal Centre, University of Helsinki, Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
authors.affiliation: *Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Doctoral Programme of Biomedical Sciences, Turku, Finland; Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland; Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; **Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland; and Laboratory Animal Centre, University of Helsinki, Helsinki, Finland petra.sipila@helsinki.fi.
authors.forename: Petra
authors.initials: P
authors.lastname: Sipilä
mesh_terms: D020101:Acrosome Reaction; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004822:Epididymis / Q000378:metabolism / Q000503:physiopathology*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006706:Homeostasis; D050356:Lipid Metabolism; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D043244:Ribonuclease III / Q000235:genetics*; D013075:Sperm Capacitation; D013079:Sperm Maturation / Q000502:physiology; D013081:Sperm Motility; D013091:Spermatogenesis; D013094:Spermatozoa / Q000378:metabolism* / Q000473:pathology; D013109:Sphingomyelins / Q000378:metabolism; D013737:Testis / Q000473:pathology; D015044:Zona Pellucida / Q000378:metabolism
chemical_list: D005231:Fatty Acids, Unsaturated; D008563:Membrane Lipids; D013109:Sphingomyelins; D002784:Cholesterol; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: RNA interference; cholesterol; infertility; polyunsaturated fatty acids; sperm maturation