Decreased lipid efflux and increased susceptibility to cholesterol-induced apoptosis in macrophages lacking phosphatidylcholine transfer protein

Abstract

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.

Les protéines à domaine START, des trafiquants intracellulaires de lipides

“…L'analyse phylogénétique montre que les protéines à domaine START se distinguent plus par leur spécificité vis-à-vis du STARD2 est une protéine cytoplasmique qui promeut l'échange rapide de la phosphatidylcholine (PC) supposément de son lieu de synthèse vers la face interne de la membrane plasmique et/ou la membrane externe de la mitochondrie. STARD2 serait responsable du remplissage de la membrane plasmique par de la PC en réponse à l'efflux de phospholipides vers les lipoprotéines plasmatiques de type HDL (high density lipoproteins) au cours du transport des HDL entre les tissus [17,18]. In vitro, STARD10 permet l'échange membranaire de PC et PE [14].…”

Homozygous disruption of Pctp modulates atherosclerosis in apolipoprotein E-deficient mice

“…In a study of mouse peritoneal macrophages from Pctp 2/2 and wild-type mice, we observed that the absence of PC-TP expression increased the susceptibility of macrophages to apoptotic, but not necrotic, cell death in response to loading with unesterified cholesterol (6). The influence of macrophage apoptosis on atherosclerosis is dependent on a balance of apoptosis and phagocytosis (22,23).…”

“…PC-TP (also known as StarD2) is a member of the steroidogenic acute regulatory-related lipid transfer (START) domain protein superfamily (3). It is expressed in a variety of tissues and is enriched in liver (1,4,5) and macrophages (6). Although PC-TP promotes the exchange of phosphatidylcholine between membranes in vitro (1), its biological function remains elusive.…”

Targeted disruption of steroidogenic acute regulatory protein D4 leads to modest weight reduction and minor alterations in lipid metabolism

“…Other LysM-cre specifi c crosses were done for the PCTP (StARD2) protein, whose initial lipid phenotype was unclear. In this case, macrophage specifi c deletion of PCTP resulted in decreased cholesterol effl ux to ApoA-I particles ( 34 ). It is possible that StARD4 might play an important role in the development of atherosclerosis by infl uencing macrophage cholesterol effl ux.…”