Infertility and testicular defects in hormone-sensitive lipase-deficient mice

The 84-kDa hormone-sensitive lipase (gene designation Lipe; EC 3.1.1.3) is a cholesterol esterase and triglyceride hydrolase that functions in the rel ease of fatty acids from adipocytes. The role of hormone-sensitive lipase i n other tissues such as the testis, where a specific 120-kDa testis-specifi c isoform is expressed, is unknown. To study this, we examined the fertilit y and testicular histology of gene-targeted hormone-sensitive lipase-defici ent mice. Homozygous hormone-sensitive lipase-deficient male mice are infer tile and have decreased testis weights; female homozygotes are fertile. Tes ticular abnormalities, detected at the fight and electron microscopic level s, included the presence of multinucleated round and elongating spermatids, vacuolization of the seminiferous epithelium, asynchronization of the sper matogenic cycle, sloughing of postmeiotic germ cells from the seminiferous epithelium into the lumen, and a marked reduction in the numbers of late sp ermatids. Extensive nuclear head deformation was noted in late spermatids a s well as the sharing of a common acrosome in multinucleated cells. In some multinucleated cells, nuclei were separated from their acrosomes, with the acrosomes remaining attached to areas of ectoplasmic specializations, sugg esting defects in intercellular cytoplasmic bridge integrity. Although the lumen of the epididymis was essentially devoid of spermatozoa and filled in stead with spherical degenerating cells, the epididymal epithelial cells ap peared normal. The few late spermatids present in the epididymis were abnor mal. There was no morphological evidence, as judged by the absence of lipid droplets of triacylglycerol or cholesteryl ester accumulation in the testi s. Together, the data suggest that hormone-sensitive lipase deficiency resu lts in abnormalities in spermiogenesis that are incompatible with normal fe rtility. We speculate that a metabolite downstream from the hormone sensiti ve lipase reaction may be essential for membrane stabilization and integrit y in the seminiferous epithelium and, in particular, may play an important role in the maintenance of intercellular cytoplasmic bridges between postme iotic germ cells.