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Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, D.C. 20057
Address all correspondence and requests for reprints to: Vassilios Papadopoulos, Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, 3900 Reservoir Road Northwest, Washington, D.C. 20057. E-mail: papdopv{at}georgetown.edu.
Cholesterol is a basic component of all membranes and is the precursor of steroid hormones, bile acids, and vitamin D. Cholesterol and cholesteryl esters are insoluble in water and are transported in the blood from the tissues of origin, mainly liver, to the tissue of storage. Reverse cholesterol transport describes the pathway for removal of excess cholesterol from peripheral tissues via the liver into bile, and its subsequent excretion (1, 2). Although it generally has been assumed that high-density lipoprotein is the obligate transport vehicle for reverse cholesterol transport, new protein members of the nuclear receptor subfamilies and ATP-binding cassette (ABC) transporter were found to regulate cholesterol fluxes (3, 4). Experiments with transgenic animals have indicated that disruption of steps involved in reverse cholesterol transport results in atherosclerosis, whereas overexpression of key components of reverse cholesterol transport exerts atheroprotective effects (4).
The liver X receptor (LXR) belongs to the nuclear receptor family recently shown to act a sensor of cholesterol metabolism and lipid biosynthesis (5). The LXR subfamily consists of two members, LXR
and LXRß. LXR is found mainly in liver, adipose tissue, small intestine, adrenal and macrophages, whereas LXRß is a ubiquitous protein. Both proteins are activated by oxysterols. After activation, LXRs heterodimerize with retinoid X receptors (RXR) and initiate the transcription of genes involved in cholesterol efflux, including ABC transporter A1 (ABCA1), sterol regulatory element binding protein, apolipoprotein E, and scavenger receptor class B, member I (5, 6). A physiological role for LXR in the maintenance of cholesterol homeostasis was indicated by the finding that LXR knockout mice, when fed a high-cholesterol diet, developed massive hepatic accumulation of cholesterol (7). Interestingly, LXR–/–, but not LXRß–/–, mice showed a significant increase in hepatic cholesterol content (8), and LXR–/–/LXRß–/– mice showed changes in blood lipid profiles (9).
In this issue of Endocrinology, Robertson et al. (10) report data demonstrating that LXRß plays a crucial role in maintaining cholesterol homeostasis in the testis. Importantly, detailed morphological analysis of the testis revealed that deletion of the LXRß gene, but not LXR, resulted in dramatic, time-dependent Sertoli cell cholesterol ester lipid accumulation and germ cell depletion that were correlated with infertility. The effects on germ cell loss were even more dramatic in LXR–/–ß–/– mice. In contrast to the effects seen in Sertoli cells, there was no lipid accumulation in Leydig cells in LXRß–/–or in LXR–/–ß–/– mice, although testosterone formation by these cells was reduced.
The Sertoli cell phagocytizes germ cells undergoing apoptosis and degrades residual bodies generated in the last steps of spermatogenesis (11, 12). This extensive phagocytotic activity would be expected to result in excess lipid accumulation in Sertoli cells, and an active lipid efflux process would be required to eliminate this material. Lipid accumulation in Sertoli cells was shown in this manuscript (10) to correlate with reduced numbers of germ cells and with infertility and has been shown in humans to correlate with azoospermia (13). Sertoli cell cholesterol could come from de novo synthesis, increased uptake of high-density lipoprotein cholesterol (14), or reduced efflux. Because hydroxymethylglutaryl-coenzyme A reductase or synthase, low-density lipoprotein (LDL) receptor and vLDL receptor gene expression were not affected by the deletion of LXRß, it can be concluded that the cholesterol efflux mechanism was impaired in LXRß null mice. Thus, the data presented in this paper suggest that a LXRß-target gene mediates cholesterol efflux in Sertoli cells. ABCA1 is a LXRß target gene. Indeed, recent data obtained in ABCA1–/– mice indicated a phenotype close to that seen in LXRß–/– mice, with increased lipid accumulation in Sertoli cells paralleling reduced fertility (15). In another recent paper, it was shown that ABCA1 levels were reduced in LXRß–/– mice, and that this led to Sertoli cell lipid accumulation (16). However, the authors failed to observe an effect on ABCA1 gene expression suggesting that other not-yet-identified LXR target genes might be involved in mediating cholesterol efflux in Sertoli cells.
Despite the dramatic effect of the deletion of LXR genes on Sertoli cell lipid accumulation, it is unlikely that this was the sole factor involved in the arrest of spermatogenesis, and thus, infertility. As noted earlier, LXR heterodimerizes with RXR to induce changes in gene transcription. It recently was shown that although RXRß–/– mice are sterile, RXRßaf20 males are fertile. RXRßaf20 mice express RXRß carrying a mutation of its activation function-2 core responsible for the transcriptional function of the protein (16). Interestingly, testes from both RXRß–/– and RXRßaf20 mice show increased lipid accumulation and same size lipid droplets in the Sertoli cells of the seminiferous epithelium.
The finding that Leydig cells in LXRß–/– and LXR–/– ß–/– mice produced less testosterone than the wild-type mice is of interest. Considering that LH levels have been reported to be unaffected or even increased in older animals, these results suggest the possibility of a direct effect of LXR deletion on Leydig cell function. There are other possibilities, however. For example, the observation that the lipid content of Leydig cells was not affected, whereas Sertoli cells were dramatically affected, led the authors to hypothesize that the effect on Leydig cells might be due to changes in paracrine regulation of Leydig cell androgen formation by Sertoli cell products (17). Indeed, data presented in this paper and by Mascrez et al. (16) suggest that Sertoli cell function is under the control of LXR, and there is solid evidence for paracrine regulation of Leydig cell function by the Sertoli cell (17). Another possibility is that reduced androgen formation might be due to the increased serum corticosterone levels seen in LXR–/–ß–/– compared with wild-type mice (18). Indeed, increased glucocorticoid levels have been show to inhibit in vitro and in vivo Leydig cell function (19, 20), and in men, stress-induced increase in glucocorticoid levels resulted in inhibition of androgen formation, low sperm counts, and infertility (21).
Changes in Sertoli cell function, coupled with reduced testosterone in LXRß null mice, might also result in reduced estrogen formation by the testis. The testis forms approximately 25% of circulating estrogens in rodents (22, 23). Recent data suggest that estradiol may be a critical factor for normal reproduction, but also for various physiopathological processes, such as atherosclerosis (24, 25, 26).
In conclusion, the study of Robertson et al. (10) identifies LXRß as the key regulator of cholesterol homeostasis in the Sertoli cells and confirms recent findings on the critical nature of cholesterol efflux by Sertoli cells in spermatogenesis and fertility in rodents and humans. Identification of the LXRß target genes mediating this effect of LXR on Sertoli cell cholesterol efflux would elucidate the mechanism of cholesterol efflux by these cells. Importantly, the data showing that LXR–/–ß–/– mice have impaired triglyceride metabolism and increased LDL (9), increased glucocorticoid (18), and reduced testosterone (10) levels, accumulated cholesterol in the arterial wall (9), and are infertile (10) could also be interpreted as an indication that LXR might be the link between risk factors (high cholesterol) for atherosclerosis and cardiovascular disease in general, the leading cause of global mortality (27), and reports of global decline in the numbers of spermatozoa produced by men (28, 29), an alarming prospect for the future of our species.
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Footnotes |
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Received March 17, 2005.
Accepted for publication March 24, 2005.
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References |
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 Top References |
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. Cell 93:693–704[CrossRef][Medline]
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