Abstract
This work shows that an overload of dietary cholesterol causes complete infertility in dyslipidemic male mice (the Liver X Receptor-deficient mouse model). Infertility resulted from post-testicular defects affecting the fertilizing potential of spermatozoa. Spermatozoa of cholesterol-fed lxr−/− animals were found to be dramatically less viable and motile, and highly susceptible to undergo a premature acrosome reaction. We also provide evidence, that this lipid-induced infertility is associated with the accelerated appearance of a highly regionalized epididymal phenotype in segments 1 and 2 of the caput epididymidis that was otherwise only observed in aged LXR-deficient males. The epididymal epithelial phenotype is characterized by peritubular accumulation of cholesteryl ester lipid droplets in smooth muscle cells lining the epididymal duct, leading to their transdifferentiation into foam cells that eventually migrate through the duct wall, a situation that resembles the inflammatory atherosclerotic process. These findings establish the high level of susceptibility of epididymal sperm maturation to dietary cholesterol overload and could partly explain reproductive failures encountered by young dyslipidemic men as well as ageing males wishing to reproduce.
Highlights
Cellular and plasma cholesterol levels are tightly controlled to prevent excessive accumulation of cholesterol in tissues [1]
Peritubular smooth muscle cells (SMC) of the epididymis transdifferentiate into foam cells Looking closer at the caput epididymidis phenotype, we observed in several locations peritubular cells involved in an infiltration-like process through the epididymal epithelium
Oil-red-O staining of cryosections from the same samples revealed that the peritubular accumulations of lipid droplets concerned SMC fusiform cells that were present in the infiltrations (Fig. 5B, arrowheads)
Summary
Cellular and plasma cholesterol levels are tightly controlled to prevent excessive accumulation of cholesterol in tissues [1]. Among transcription factors regulating cholesterol homeostasis, Liver X Receptors a (LXRa – Nr1h3) and b (LXRb – Nr1h2) play central roles in various cell types. Both are activated by metabolic derivatives or oxidized forms of cholesterol, and have been shown to control the expression of a wide spectrum of genes that determine lipid and metabolic homeostasis, energy utilization, differentiation, proliferation, inflammation, and reproduction [6,7,8,9]. Young LXR-deficient male mice are a good model to address the question of how an excess of dietary lipid affects reproductive functions in dyslipidemic animals
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