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Journal of Lipid Research, Vol. 45, 1040-1050, June 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

The ATP-binding cassette transporter 1 mediates lipid efflux from Sertoli cells and influences male fertility

David M. Selva^*, Veronica Hirsch-Reinshagen, Braydon Burgess, Steven Zhou, Jeniffer Chan, Sean McIsaac, Michael R. Hayden, Geoffrey L. Hammond^*, A. Wayne Vogl^** and Cheryl L. Wellington^1,

^* Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
British Columbia Research Institute for Children's and Women's Health, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada
^** British Columbia Research Institute for Children's and Women's Health, and Department of Anatomy and Cell Biology, University of British Columbia, Vancouver, BC, Canada

¹ To whom correspondence should be addressed. e-mail: cheryl{at}cmmt.ubc.ca

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 RXRß-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.

Abbreviations: apoA1, apolipoprotein A1; HDL-C, HDL cholesterol; LXR, liver X receptor; RXR, retinoid X receptor; TD, Tangier disease; WT, wild-type; SR-BI, scavenger receptor class B type I

Supplementary key words cholesterol efflux • liver X receptor • testes

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