Absence of endogenous phospholipid transfer protein impairs ABCA1-dependent efflux of cholesterol from macrophage foam cells

Cholesterol carried on HDL (HDL-C) has long been believed to be cardioprotective, based on consistent epidemiologic fi ndings of an inverse relationship between incident CVD and HDL-C levels in subjects healthy at baseline ( 1, 2 ). Estimates from the Framingham Heart Study found that risk of myocardial infarction (MI) increased by 25% for each 5 mg/dl decrease in HDL-C below median values of HDL-C for both healthy men and women ( 2 ). Similar fi ndings of the cardioprotective effects of HDL-C have also been reported in subjects with CVD at baseline ( 3 ).In confl ict with these epidemiologic fi ndings, recent attempts to establish a causal relationship between HDL-C Abstract Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a casecontrol study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A fi nal stepwise regression considering both nongenetic and genetic variables identifi ed the combination of covariates that explained maximal PLTPa variance. PLTPa was signifi cantly associated with CAAD (7.90 × 10 ؊ 9 ), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels ( P = 0.0042), diabetes ( P = 7.28 × 10 ؊ 5 ), paraoxonase 1 (PON1) activity ( P = 0.019), statin use ( P = 0.026), PLTP SNP rs4810479 ( P = 6.38 × 10 ؊ 7 ), and PCIF1 SNP rs181914932 ( P = 0.041) were all signifi cantly associated with PLTPa. PLTPa is signifi cantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of

Section: Discussionmentioning

confidence: 99%

PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

Kim

Burt

Ranchalis

et al. 2015

“…In addition, PLTP has been reported to cause proteolytic cleavage of apoA-I (33). We A plasma pool isolated from a group of 12 hPLTPtg/hApoAItg mice was subjected to FPLC and divided into three pools: very large HDL (fractions 6-9), large HDL (fractions [10][11][12][13][14], and total HDL (fractions 6-14). B: The ability of the three HDL pools to induce cholesterol efflux from labeled AcLDL-loaded peritoneal macrophages was determined (see Materials and Methods).…”

Section: Discussionmentioning

confidence: 99%

“…The latter HDL subfraction is a very efficient acceptor of cellular cholesterol. In this way, PLTP plays an important role in the early steps of reverse cholesterol transport (10)(11)(12).…”

mentioning

confidence: 99%

Atherogenic, enlarged, and dysfunctional HDL in human PLTP/apoA-I double transgenic mice

Moerland

Samyn

Gent

et al. 2007

Self Cite

In low density lipoprotein receptor (LDLR)-deficient mice, overexpression of human plasma phospholipid transfer protein (PLTP) results in increased atherosclerosis. PLTP strongly decreases HDL levels and might alter the antiatherogenic properties of HDL particles. To study the potential interaction between human PLTP and apolipoprotein A-I (apoA-I), double transgenic animals (hPLTPtg/ hApoAItg) were compared with hApoAItg mice. PLTP activity was increased 4.5-fold. Plasma total cholesterol and phospholipid were decreased. Average HDL size (analyzed by gel filtration) increased strongly, hPLTPtg/hApoAItg mice having very large, LDL-sized, HDL particles. Also, after density gradient ultracentrifugation, a substantial part of the apoA-I-containing lipoproteins in hPLTPtg/hApoAItg mice was found in the LDL density range. In cholesterol efflux studies from macrophages, HDL isolated from hPLTPtg/ hApoAItg mice was less efficient than HDL isolated from hApoAItg mice. Furthermore, it was found that the largest subfraction of the HDL particles present in hPLTPtg/hApoAItg mice was markedly inferior as a cholesterol acceptor, as no labeled cholesterol was transferred to this fraction. In an LDLR-deficient background, the human PLTP-expressing mouse line showed a 2.2-fold increased atherosclerotic lesion area. These data demonstrate that the action of human PLTP in the presence of human apoA-I results in the formation of a dysfunctional HDL subfraction, which is less efficient in the uptake of cholesterol from cholesterol-laden macrophages.-Moerland, M., H. Samyn, T. van Gent, M. Jauhiainen, J. Metso, R. The incidence of coronary heart disease shows a strong inverse relationship with the concentration of plasma HDL (1). Therefore, HDL is believed to have antiatherogenic properties, which are attributed to its effects on endothelial cells, its antioxidant activity, and its role in reverse cholesterol transport, a pathway in which peripheral cellular cholesterol is transported to the liver (2-4). One important determinant of the plasma HDL concentration is phospholipid transfer protein (PLTP) activity. During lipolysis, PLTP transfers phospholipids from apolipoprotein Bcontaining lipoproteins to HDL (5). Furthermore, PLTP acts as an HDL conversion factor by remodeling HDL to produce large particles and small lipid-poor particles, known as preb-HDL (6-9). The latter HDL subfraction is a very efficient acceptor of cellular cholesterol. In this way, PLTP plays an important role in the early steps of reverse cholesterol transport (10-12).Although the involvement of PLTP in the cellular efflux of cholesterol and phospholipids is potentially antiatherogenic, different in vivo studies showed that an increase in plasma PLTP activity is associated with decreased HDL cholesterol levels (9, 13, 14) and increased atherosclerotic lesion development (15-17). The PLTP-dependent decrease in HDL levels was explained by an accelerated HDL catabolism (13). In addition to its effect on HDL cholesterol levels, PLTP may alter the antiathe...

“…Because cholesterol loading in macrophages via the formation of oxysterols upregulates these receptors, it also leads to increased secretion of CETP, a response that has been considered to prevent the accumulation of cellular cholesterol (13). The concomitant secretion of CETP and PLTP by macrophage foam cells (10,14) raises the question of whether CETP may assist PLTP in facilitating cellular choles-terol efflux to HDL (15,16). Because CETP mass was found to be abundant in the macrophage foam cells of human atherosclerotic lesions and CETP transfection in COS cells increased cholesterol efflux, a direct antiatherogenic role of CETP in the removal of cholesterol from foam cells has been suggested (17).…”

mentioning

confidence: 99%

Association of cholesteryl ester transfer protein with HDL particles reduces its proteolytic inactivation by mast cell chymase

Lee-Rueckert

Vikstedt

Metso

et al. 2008

Self Cite

Human atherosclerotic intima contains mast cells that secrete the neutral protease chymase into the intimal fluid, which also contains HDL-modifying proteins, such as cholesteryl ester transfer protein (CETP), in addition to abundant amounts of nascent discoidal HDL particles. Here, we studied chymase-dependent degradation of a) CETP isolated from human plasma and b) CETP-HDL complexes as well as the functional consequences of such degradations. Incubation with chymase caused a rapid cleavage of CETP, yielding a specific proteolytic pattern with a concomitant reduction in its cholesteryl ester transfer activity. These chymase-dependent effects were attenuated after CETP was complexed with HDL. This attenuation was more effective when CETP was complexed with HDL 3 and HDL 2 than with discoidal reconstituted high density lipoprotein (rHDL). Conversely, rHDL, but not spherical HDLs, was protected in such CETP complexes against functional inactivation by chymase. Thus, in contrast to the complexes of CETP with spherical HDLs, the ability of the CETP-rHDL complexes to promote cholesterol efflux from macrophage foam cells remained unchanged, despite treatment with chymase. In summary, complexation of CETP and HDL modifies their resistance to proteolytic inactivation: spherical HDLs protect CETP, and CETP protects discoidal HDL. These results suggest that in inflamed atherosclerotic intima, CETP, via its complexation with HDL, has a novel protective role in early steps of reverse cholesterol transport.-LeeRueckert, M., R. Vikstedt, J. Metso, M. Jauhiainen, and P. T. Kovanen. Association of cholesteryl ester transfer protein with HDL particles reduces its proteolytic inactivation by mast cell chymase. J. Lipid Res. 2008. 49: 358-368.