Stearoyl-CoA desaturase inhibits ATP-binding cassette transporter A1-mediated cholesterol efflux and modulates membrane domain structure.
Liver X receptor/retinoid X receptor (LXR/RXR) transcription factors have been found to induce a number of genes involved in the regulation of cellular cholesterol efflux, including the ATP-binding cassette transporter A1 (ABCA1), which mediates the active efflux of cellular cholesterol and phospholipids to extracellular acceptors, such as apolipoprotein A-I (apoA-I). In a screen for macrophage LXR/RXR target genes, we identified stearoyl-CoA desaturases 1 and 2 (Scd1 and Scd2), and subsequently tested the hypothesis that SCD activity might modulate cellular cholesterol efflux. In HEK 293 cells co-transfection of ABCA1 with either SCD1 or SCD2 inhibited ABCA1-mediated cholesterol efflux but not phospholipid efflux. In Chinese hamster ovary (CHO) cells with moderate stable overexpression of SCD1, cholesterol efflux to apoA-I was inhibited by 73%, whereas phospholipid efflux and ABCA1 protein levels were unchanged. In contrast, cholesterol efflux to HDL(2), which is not dependent on ABCA1, was increased 2-fold in CHO-SCD1 cells. The effect of SCD on cholesterol efflux to apoA-I was independent of acyl-CoA:cholesterol acyltransferase (ACAT) activity. SCD activity led to an increased content of plasma membrane monounsaturated fatty acids (18:1) at the expense of saturated fatty acids (18:0). As shown by confocal microscopy, SCD overexpression led to a decrease of Triton X-100-resistant domains in the plasma membrane, indicating a decrease in membrane-ordered regions. The data suggest that SCD changes membrane organization and depletes a specific pool of membrane cholesterol supporting ABCA1-mediated efflux, whereas increasing availability of cholesterol for passive efflux by HDL(2). ABCA1-mediated cholesterol and phospholipid efflux may be uncoupled in pathological states associated with high SCD activity, as in hyperinsulinemic obese mice, or in animals treated with LXR activators.
Sun
Yu
Y
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
Hao
Mingming
M
Luo
Yi
Y
Liang
Chien-ping
CP
Silver
David L
DL
Cheng
Celina
C
Maxfield
Frederick R
FR
Tall
Alan R
AR
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000648:ultrastructure*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D005786:Gene Expression Regulation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D007527:Isoenzymes; D010743:Phospholipids; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002784:Cholesterol; D013230:Stearoyl-CoA Desaturase