Decreased lipid efflux and increased susceptibility to cholesterol-induced apoptosis in macrophages lacking phosphatidylcholine transfer protein.
Macrophages are the predominant cellular component of atherosclerotic lesions, where they scavenge oxidatively modified lipoproteins while defending themselves against cholesterol-induced cytotoxicity by adaptive mechanisms that depend in part on the synthesis, distribution and efflux of phosphatidylcholines. PC-TP (phosphatidylcholine transfer protein) is a START (steroidogenic acute regulatory protein-related lipid transfer) domain protein that catalyses the intermembrane transfer of phosphatidylcholines and promotes apolipoprotein AI-mediated lipid efflux when overexpressed in the cytosol of Chinese-hamster ovary cells. To explore a role for PC-TP in the adaptive responses of macrophages to cholesterol loading, we utilized peritoneal macrophages from mice with homozygous disruption of the gene encoding PC-TP (Pctp(-/-)) and wild-type littermate controls. PC-TP was abundantly expressed in macrophages from wild-type but not Pctp(-/-) mice. In cholesteryl ester-loaded macrophages from Pctp(-/-) mice, the apolipoprotein AI-mediated efflux of phospholipids and cholesterol was decreased. This could be attributed to proportional decreases in the expression levels of ATP-binding cassette A1. Also, in response to free cholesterol loading, the absence of PC-TP from macrophages was associated with marked increases in apoptotic cell death. These findings suggest that PC-TP in macrophages may serve an atheroprotective role by defending against cholesterol-induced cytotoxicity.
Baez
Juan M
JM
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Tabas
Ira
I
Cohen
David E
DE
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D049294:Phospholipid Transfer Proteins / Q000235:genetics* / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase