The ATP-binding cassette transporter 1 mediates lipid efflux from Sertoli cells and influences male fertility.
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.
Selva
David M
DM
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
Hirsch-Reinshagen
Veronica
V
Burgess
Braydon
B
Zhou
Steven
S
Chan
Jeniffer
J
McIsaac
Sean
S
Hayden
Michael R
MR
Hammond
Geoffrey L
GL
Vogl
A Wayne
AW
Wellington
Cheryl L
CL
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000502:physiology; D000818:Animals; D002460:Cell Line; D005298:Fertility / Q000502:physiology*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005854:Germ Cells / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D012708:Sertoli Cells / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger