title: The catalytic function of hormone-sensitive lipase is essential for fertility in male mice.
abstract: In male mice, deficiency of hormone sensitive lipase (HSL, Lipe gene, E.C.3.1.1.3) causes deficient spermatogenesis, azoospermia, and infertility. Postmeiotic germ cells express a specific HSL isoform that includes a 313 amino acid N-terminus encoded by a testis-specific exon (exon T1). The remainder of testicular HSL is identical to adipocyte HSL. The amino acid sequence of the testis-specific exon is poorly conserved, showing only a 46% amino acid identity with orthologous human and rat sequences, compared with 87% over the remainder of the HSL coding sequence, providing no evidence in favor of a vital functional role for the testis-specific N-terminus of HSL. However, exon T1 is important for Lipe transcription; in mouse testicular mRNA, we identified 3 major Lipe transcription start sites, finding numerous testicular transcription factor binding motifs upstream of the transcription start site. We directly explored two possible mechanisms for the infertility of HSL-deficient mice, using mice that expressed mutant HSL transgenes only in postmeiotic germ cells on a HSL-deficient background. One transgene expressed human HSL lacking enzyme activity but containing the testis-specific N-terminus (HSL-/-muttg mice). The other transgene expressed catalytically inactive HSL with the testis-specific N-terminal peptide (HSL-/-atg mice). HSL-/-muttg mice were infertile, with abnormal histology of the seminiferous epithelium and absence of spermatozoa in the epididymal lumen. In contrast, HSL-/-atg mice had normal fertility and normal testicular morphology. In conclusion, whereas the catalytic function of HSL is necessary for spermatogenesis in mice, the presence of the N-terminal testis-specific fragment is not essential.
authors.affiliation: Divisions of Medical Genetics (S.P.W., J.W.W., H.B., S.C., G.A.M.) and Hematology (J.F.L., D.L.), Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada, H3T 1C5; Valeant Cosméderme (H.B.), Laval, Québec, Canada, H7V 0A3; Centre for Molecular Medicine and Therapeutics (B.R.L.), Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada, V5Z 4H4; Department of Pediatrics (J.T.), Human Genetics and Pharmacology and Therapeutics, McGill University and Research Institute of the McGill University Health Centre at the Montreal Children's Hospital, Montréal, Québec, Canada, H3H 1P3; and Department of Anatomy and Cell Biology (C.E.S., L.H.), McGill University, Montréal, Québec, Canada, H3A 2B2.
authors.forename: Shu Pei
authors.initials: SP
authors.lastname: Wang
authors.forename: Jiang Wei
authors.initials: JW
authors.lastname: Wu
authors.forename: Hugo
authors.initials: H
authors.lastname: Bourdages
authors.forename: Jean François
authors.initials: JF
authors.lastname: Lefebvre
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Casavant
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: Damian
authors.initials: D
authors.lastname: Labuda
authors.forename: Jacquetta
authors.initials: J
authors.lastname: Trasler
authors.forename: Charles E
authors.initials: CE
authors.lastname: Smith
authors.forename: Louis
authors.initials: L
authors.lastname: Hermo
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D005298:Fertility; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D002787:Sterol Esterase / Q000378:metabolism*; D013737:Testis / Q000033:anatomy & histology / Q000502:physiology*
chemical_list: D010446:Peptide Fragments; D002787:Sterol Esterase