Phospholipid Transfer Protein and Atherosclerosis
Genetic studies in humans and mice show that two related plasma lipid transfer proteins (cholesteryl ester transfer protein [CETP] and phospholipid transfer protein [PLTP]) have distinct roles in lipoprotein metabolism, despite their homology.1 In human homozygous CETP deficiency, HDL levels are massively elevated, and LDL levels are moderately decreased.2 While a human PLTP deficiency state has not been described, PLTP-/- mice have ≈50% reductions in HDL levels, indicating the essential role of PLTP in transferring phospholipids from triglyceride-carrying lipoproteins into HDL.3 When crossed with apoE-/- mice, or apoB transgenic mice, PLTP deficiency results in reductions in apoB lipoproteins, revealing a role of intracellular PLTP in the hepatic secretion of apoB lipoproteins.4
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Crosses of PLTP deficient mice into apoB transgenic, apoE-/-, or LDL R-/- backgrounds resulted in diminished atherosclerosis in all three of these standard mouse atherosclerosis models.4 In part this was related to the reduction of levels of apoB containing lipoproteins seen in apoB transgenic and apoE-/- mice. However, an anti-atherogenic effect of PLTP deficiency was also seen in LDL R-/- mice, despite a lack of reduction in apoB lipoprotein levels. A possible clue to understanding this unexpected observation was the finding that PLTP could facilitate the in vitro transfer of vitamin E from triglyceride rich lipoproteins (TRL) into HDL.5 An analysis of vitamin E revealed a build-up of levels in VLDL and LDL of PLTP deficient mice, associated with a reduction in susceptibility of apoB lipoproteins to Cu-mediated oxidation in vitro. Moreover, there was a reduction in antibodies to oxidized LDL in plasma.5 There was a 5-fold increase in VLDL vitamin E levels in apoE-/- mice, a level that was previously associated with atheroprotection in vitamin E feeding studies.6 Thus, in addition to reducing levels of apoB lipoproteins, PLTP deficiency resulted in an increase in their content of vitamin E and resistance to oxidation.
Somewhat surprisingly, overexpression of PTLP also is associated with an increase in atherosclerosis. This has been shown both in a transgenic model on a LDL R+/- background,7 and also now by Jiang et al8 by adenovirus overexpression in apoE-/- mice. The magnitude of the effect of PLTP overexpression on atherogenesis was large7 and does not seem to be readily explained by the reductions in HDL levels, because major reductions in HDL in apoA-I–deficient mice have either no or only moderate effects on atherosclerosis.9 The new study by Jiang et al8 offers a potential further mechanism to explain the increase in atherosclerosis, because they show that vitamin E levels in VLDL and LDL are reduced, and lag time for Cu-mediated oxidation is decreased in mice with PLTP overexpression. However, these changes were moderate in magnitude, and one suspects that there could be additional underlying mechanisms. Relevance to human pathophysiology in these overexpression models is somewhat uncertain: PLTP+/- mice with ≈50% of normal activity have no lipoprotein phenotype, suggesting that small variations in PTLP activity around the normal level will not have much effect on lipoproteins. Increases in PLTP activity have been seen in humans with type I or type II diabetes and obesity,10,11⇓ but the magnitude of change is only an increase from 15% to 50%. Notably, a comparable 1.3-fold increase in PLTP activity in the study of Jiang et al8 was not associated with a lipoprotein phenotype, and there was no effect on atherosclerosis.
Nonetheless, these findings add to the growing body of evidence suggesting that PLTP inhibition could be a therapeutic strategy for atherosclerosis. Unlike MTP inhibition, which is in some ways conceptually similar, PLTP deficiency does not result in fatty liver, presumably because secretion of apoB lipoproteins is inhibited at a later stage. Direct inhibition of PLTP by small molecules that bind to the putative N-terminal lipid binding pocket may be effective. Another approach could be to exploit the transcriptional regulation of PTLP expression. FXR activates PLTP expression,12 so FXR antagonists could reduce PLTP expression, in addition to reducing levels of TRL and possibly increasing HDL levels. Both PLTP13 and CETP14 are LXR targets, and presumably induction of both of these lipid transfer proteins would represent an adverse effect of LXR activators.
CETP inhibitors that recapitulate many of the features of the human deficiency state are now in advanced clinical trials, awaiting demonstration of efficacy on atherosclerosis.15 It is interesting to speculate on the phenotype that would result from combined inhibition of CETP and PLTP in humans. Since inhibition of CETP reduces apoB lipoproteins by increasing clearance,16,17⇓ while PLTP affects synthesis,4 combined inhibition of PLTP and CETP could result in additive, substantial lowering of apoB-lipoproteins in humans. Moreover, there might be enrichment of the natural antioxidant, vitamin E. Although vitamin E supplementation trials in humans have been disappointing, a strategy that specifically increases vitamin E in apoB lipoproteins could be more effective. While PLTP inhibition would reduce HDL, this would be countered by the effects of CETP inhibition. In a future of combined drug therapies in the treatment of atherosclerosis, a combination inhibition of CETP and PLTP is not out of the question.
- ↵Jiang XC, Tall AR, Qin S, Lin M, Schneider M, Lalanne F, Deckert V, Desrumaux C, Athias A, Witztum JL, Lagrost L. Phospholipid transfer protein deficiency protects circulating lipoproteins from oxidation due to the enhanced accumulation of vitamin E. J Biol Chem. 2002; 277: 31850–31856.
- ↵Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, Stocker R. Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol. 2001; 21: 585–593.
- ↵van Haperen R, van Tol A, van Gent T, Scheek L, Visser P, van der Kamp A, Grosveld F, de Crom R. Increased risk of atherosclerosis by elevated plasma levels of phospholipid transfer protein. J Biol Chem. 2002; 277: 48938–48943.
- ↵Yang XP, Yan D, Qiao C, Liu RJ, Chen J-G, Li J, Schneider M, Lagrost L, Xiao X, Jiang X-C. Increased atherosclerotic lesions in apoE mice with plasma phospholipid transfer protein expression. Arterioscler Thromb Vasc Biol. 2003; 23: 1601–1607.
- ↵Li H, Reddick RL, Maeda N. Lack of apoA-I is not associated with increased susceptibility to atherosclerosis in mice. Arterioscler Thromb. 1993; 13: 1814–1821.
- ↵Colhoun HM, Taskinen MR, Otvos JD, Van Den Berg P, O’Connor J, Van Tol A. Relationship of phospholipid transfer protein activity to HDL and apolipoprotein B-containing lipoproteins in subjects with and without type 1 diabetes. Diabetes. 2002; 51: 3300–3305.
- ↵Urizar NL, Dowhan DH, Moore DD. The farnesoid X-activated receptor mediates bile acid activation of phospholipid transfer protein gene expression. J Biol Chem. 2000; 275: 39313–39317.
- ↵Cao G, Beyer TP, Yang XP, Schmidt RJ, Zhang Y, Bensch WR, Kauffman RF, Gao H, Ryan TP, Liang Y, Eacho PI, Jiang XC. Phospholipid transfer protein is regulated by liver X receptors in vivo. J Biol Chem. 2002; 277: 39561–39565.
- ↵Ikewaki K, Nishiwaki M, Sakamoto T, Ishikawa T, Fairwell T, Zech LA, Nagano M, Nakamura H, Brewer HB Jr, Rader DJ. Increased catabolic rate of low-density lipoproteins in humans with cholesteryl ester transfer protein deficiency. J Clin Invest. 1995; 96: 1573–1581.
- ↵Jiang XC, Masucci-Magoulas L, Mar J, Lin M, Walsh A, Breslow JL, Tall A. Down-regulation of mRNA for the low density lipoprotein receptor in transgenic mice containing the gene for human cholesteryl ester transfer protein: mechanism to explain accumulation of lipoprotein B particles. J Biol Chem. 1993; 268: 27406–27412.