Selva David M, Hirsch-Reinshagen Veronica, Burgess Braydon, Zhou Steven, Chan Jeniffer, McIsaac Sean, Hayden Michael R, Hammond Geoffrey L, Vogl A Wayne, Wellington Cheryl L
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
J Lipid Res. 2004 Jun;45(6):1040-50. doi: 10.1194/jlr.M400007-JLR200. Epub 2004 Mar 16.
The liver X receptor/retinoid X receptor (LXR/RXR)-regulated gene ABCA1 effluxes cellular cholesterol and phospholipid to apolipoprotein A1 (apoA1), which is the rate-limiting step in high-density lipoprotein synthesis. The RXR pathway plays a critical role in testicular lipid trafficking, and RXRbeta-deficient male mice are sterile and accumulate lipids in Sertoli cells. Here, we demonstrate that ABCA1 mRNA and protein are abundant in Sertoli cells, whereas germ cells express little ABCA1. LXR/RXR agonists stimulate ABCA1 expression in cultured Sertoli MSC1 and Leydig TM3 cell lines. However, Sertoli TM4 cells lack ABCA1, and TM4 cells or primary Sertoli cells cultured from ABCA1(-/-) mice both fail to efflux cholesterol to apoA1. Expression of exogenous ABCA1 restores apoA1-dependent cholesterol efflux in Sertoli TM4 cells. In vivo, ABCA1-deficient mice exhibit lipid accumulation in Sertoli cells and depletion of normal lipid droplets from Leydig cells by 2 months of age. By 6 months of age, intratesticular testosterone levels and sperm counts are significantly reduced in ABCA1(-/-) mice compared with wild-type (WT) controls. Finally, a 21% decrease (P = 0.01) in fertility was observed between ABCA1(-/-) males compared with WT controls across their reproductive lifespans. These results show that ABCA1 plays an important role in lipid transport in Sertoli cells and influences male fertility.
肝X受体/视黄醇X受体（LXR/RXR）调控的基因ABCA1将细胞内的胆固醇和磷脂转运至载脂蛋白A1（apoA1），这是高密度脂蛋白合成中的限速步骤。RXR信号通路在睾丸脂质转运中起关键作用，RXRβ基因敲除的雄性小鼠不育，支持细胞中脂质蓄积。在此，我们证明ABCA1的mRNA和蛋白在支持细胞中大量存在，而生殖细胞中ABCA1表达很少。LXR/RXR激动剂可刺激培养的支持细胞系MSC1和睾丸间质细胞系TM3中ABCA1的表达。然而，支持细胞系TM4缺乏ABCA1，来自ABCA1基因敲除小鼠的TM4细胞或原代支持细胞均无法将胆固醇转运至apoA1。外源性ABCA1的表达可恢复支持细胞系TM4中apoA1依赖的胆固醇转运。在体内，ABCA1基因敲除小鼠在2月龄时支持细胞中出现脂质蓄积，睾丸间质细胞中正常脂滴减少。到6月龄时，与野生型（WT）对照相比，ABCA1基因敲除小鼠的睾丸内睾酮水平和精子计数显著降低。最后，在整个生殖寿命期内，与WT对照相比，ABCA1基因敲除雄性小鼠的生育力下降了21%（P = 0.01）。这些结果表明，ABCA1在支持细胞的脂质转运中起重要作用，并影响雄性生育力。
