In vivo modulation of HDL phospholipid has opposing effects on SR-BI- and ABCA1-mediated cholesterol efflux

Abstract

The effects of in vivo modulation of HDL phospholipid (PL) on scavenger receptor class BI (SR-BI)-and ATP binding cassette transporter 1 (ABCA1)-mediated efflux were examined by overexpressing either endothelial lipase (EL) or phosphatidylserine phospholipase (PS-PLA 1 ) in human apolipoprotein A-I (apoA-I) transgenic mice. Overexpression of EL led to large reductions in the serum PL/apoA-I ratio ( ؊ 60%), total cholesterol (TC; ؊ 89%), and HDL cholesterol ( ؊ 91%). Relative to the serum before overexpression of EL, the efflux potential of the serum via SR-BI decreased by 90% and ABCA1-mediated efflux increased by 63%. In contrast to overexpression of EL, overexpression of PS-PLA 1 led to increases in the PL/apoA-I ratio (88%), TC (78%), HDL cholesterol (57%), and HDL size. The efflux potential of the serum increased by 60% via SR-BI and decreased by 57% via ABCA1. There were significant positive correlations between SR-BI-mediated efflux and a number of serum parameters, including PL/apoA-I ratio, PL, TC, free cholesterol (FC), and HDL cholesterol. In striking contrast, the same correlations were seen with ABCA1-mediated efflux, but the relationships were inverse. In summary, in vivo modulation of HDL PL content affects ABCA1-and SR-BI-mediated efflux in a reciprocal manner. These findings indicate that the type of lipase acting on HDL in vivo will determine which FC efflux pathway the HDL serves. Additionally, the extent of lipolysis will determine the efficiency of FC removal via this pathway. HDL cholesterol levels are inversely correlated with the incidence of coronary artery disease (1-4). One mechanism by which HDL is thought to protect against atherosclerosis is by the removal of excess free cholesterol (FC) from peripheral cells and subsequent delivery to the liver for excretion (5-7). There are three known mechanisms by which HDL and/or its apolipoproteins can remove FC from cells. Aqueous diffusion is a relatively inefficient efflux mechanism that occurs with all cell types (8). In recent years, two proteins have been discovered that mediate efficient cholesterol efflux. The scavenger receptor class BI (SR-BI) facilitates the bidirectional flux of FC between cells and HDL (9, 10), and the ATP binding cassette transporter 1 (ABCA1) (11-13) mediates the unidirectional efflux of cellular FC and phospholipid (PL) to lipid-poor apolipoprotein A-I (apoA-I) and other exchangeable apolipoproteins. A number of studies suggest that both mechanisms of efflux may operate in atherosclerotic lesions (14-16).The goal of the present study was to determine the effects of in vivo modulation of HDL PL on both ABCA1-and SR-BI-mediated FC efflux. The importance of studying the role of HDL PL in the flux of FC between cells and HDL is supported by a number of previous observations. The efflux of cholesterol from cells to serum is correlated with HDL PL content (17, 18). Importantly, it has been demonstrated that patients with coronary artery disease have low HDL PL levels (19). Past studies have used in vitro mani...

A novel model of cholesterol efflux from lipid-loaded cells

“…When the content of cholesterol in the plasma membrane exceeds 20%, SR-B1-dependent cholesterol efflux is blocked; when the ABC-A1 level decreases by 80%, ABC-A1-dependent cholesterol efflux is blocked [110] . Yancey et al [104] reported that when endothelial lipase was overexpressed in apo-A1 transgenic mice, the phospholipid/apo-A1 ratio, total cholesterol and HDL in the serum decreased by 60%, 89%, and 91%, respectively. In addition, ABC-A1-mediated cholesterol efflux increased by 63%, and SR-B1-induced cholesterol efflux decreased by 90%.…”

“…However, ABC-A1 mainly transfers cholesterol uni-directionally outside of cells using the energy provided by ATP. ABC-A1 is upregulated by PPAR/RXR, LXR/RXR, cAMP, and HDL and downregu- [38,63,104,109] . In general, there is a one-way and a two-way transmembrane transport system in almost all cells, but the components of the systems differ in different cells.…”

“…cAMP, PKC and PKA are also involved in regulating the extroversive transport of cholesterol mediated by the ABC-A1 signaling pathway [103,104] . We have found that eicosapentaenoic acid reduces ABC-A1 serine phosphorylation through the cAMP/PKA signaling pathway [37] .…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…92 The same investigators subsequently showed that enhanced in vivo hydrolysis of HDL phospholipids by overexpression of endothelial lipase in human apoA-I transgenic mice caused pronounced reductions in the serum phospholipid/apoA-I ratio and attenuated the capacity of serum to mediate cholesterol efflux via SR-BI by 90%, whereas the ABCA1-dependent efflux potential increased by 63%. 93 The opposite was observed in mice injected with an adenovirus expressing a phosphatidylserine-specific phospholipase. 93 Moreover, the cholesterol efflux capacity of rHDL differed with the phospholipid acyl chain length and the degree of unsaturation.…”

“…93 The opposite was observed in mice injected with an adenovirus expressing a phosphatidylserine-specific phospholipase. 93 Moreover, the cholesterol efflux capacity of rHDL differed with the phospholipid acyl chain length and the degree of unsaturation. 94 Also, the magnitude of inhibition of VCAM-1 expression in activated human umbilical vein endothelial cells varied markedly between discoidal rHDL composed of different phospholipid species.…”