title: Expression of human hormone-sensitive lipase (HSL) in postmeiotic germ cells confers normal fertility to HSL-deficient mice.
abstract: Hormone-sensitive lipase (HSL, Lipe, E.C.3.1.1.3) is a multifunctional fatty acyl esterase that is essential for male fertility and spermatogenesis and that also plays important roles in the function of adipocytes, pancreatic beta-cells, and adrenal cortical cells. Gene-targeted HSL-deficient (HSL-/-) male mice are infertile, have a 2-fold reduction in testicular mass, a 2-fold elevation of the ratio of esterified to free cholesterol in testis, and unique morphological abnormalities in round and elongating spermatids. Postmeiotic germ cells in the testis express a specific HSL isoform. We created transgenic mice expressing a normal human testicular HSL cDNA from the mouse protamine-1 promoter, which mediates expression specifically in postmeiotic germ cells. Testicular cholesteryl esterase activity was undetectable in HSL-/- mice, but in HSL-/- males expressing the testicular transgene, activity was 2-fold greater than normal. HSL transgene mRNA became detectable in testes between 19 and 25 days of age, coinciding with the first wave of postmeiotic transcription in round spermatids. In contrast to nontransgenic HSL-/- mice, HSL-/- males expressing the testicular transgene were normal with respect to fertility, testicular mass, testicular esterified/free cholesterol ratio, and testicular histology. Their cauda epididymides contained abundant, normal-appearing spermatozoa. We conclude that human testicular HSL is functional in mouse testis and that the mechanism of infertility in HSL-deficient males is cell autonomous and resides in postmeiotic germ cells, because HSL expression in these cells is in itself sufficient to restore normal fertility.
authors.affiliation: Service of Medical Genetics, Hôpital Sainte-Justine, Montréal, Québec, Canada.
authors.forename: Shu Pei
authors.initials: SP
authors.lastname: Wang
authors.forename: Shari
authors.initials: S
authors.lastname: Chung
authors.forename: Krishnakant
authors.initials: K
authors.lastname: Soni
authors.forename: Hugo
authors.initials: H
authors.lastname: Bourdages
authors.forename: Louis
authors.initials: L
authors.lastname: Hermo
authors.forename: Jacquetta
authors.initials: J
authors.lastname: Trasler
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D018076:DNA, Complementary; D005260:Female; D006801:Humans; D007248:Infertility, Male / Q000503:physiopathology*; D008297:Male; D008540:Meiosis; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011479:Protamines / Q000235:genetics; D013087:Spermatids / Q000166:cytology / Q000502:physiology*; D002787:Sterol Esterase / Q000172:deficiency / Q000235:genetics*; D013737:Testis / Q000166:cytology / Q000502:physiology; D019076:Transgenes / Q000502:physiology
chemical_list: D018076:DNA, Complementary; C082073:PRM1 protein, human; C513176:Prm1 protein, mouse; D011479:Protamines; D002787:Sterol Esterase