Phospholipid Transfer Protein

Phospholipid transfer protein (PLTP) transfers phospholipids, diacylglycerol (Rao et al. 1997), free cholesterol (Nishida and Nishida 1997), R-tocopherol (vitamin E) (Kostner et al. 1995), and lipopolysaccharide among lipoproteins and between lipoproteins and cells (Hailman et al. 1996; Levels et al. 2005) (Fig. 8c). In vitro studies have identified a number of functions for PLTP in HDL metabolism (Albers and Cheung 2004; Siggins et al. 2007). PLTP displays two major functions in circulation: (1) it transforms HDL particles in a conversion or fusion process whereby small HDL3 particles are fused leading to the generation of large fused HDL particles and preβ-HDL that can participate in cholesterol removal from cells (Vikstedt et al. 2007a), and (2) it transfers post-lipolytic VLDL surface phospholipids to HDL (Albers and Cheung 2004; Siggins et al. 2007). Functions of PLTP which may influence the formation of atherosclerotic lesions include the generation of acceptors for lipid efflux from cells, regulation of plasma HDL levels, protection of lipoproteins from oxidation, and regulation of production of atherogenic lipoproteins (Jiang et al. 2001).

In human plasma, two distinct forms of PLTP are present, one with high activity (HA-PLTP) and the other with low activity (LA-PLTP) (Oka et al. 2000; Karkkainen et al. 2002). It was reported that phospholipid transfer activity is a prerequisite for efficient PLTP-mediated HDL enlargement (Huuskonen et al. 2000) and that enrichment of triglyceride in the HDL core could promote such fusion (Rye et al. 1998). Of these two forms, only the high specific activity PLTP promotes macrophage cholesterol efflux via fusion of HDL particles that leads to the release of lipid-poor preβ-mobile apoA-I particles which act as efficient cholesterol acceptors (Vikstedt et al. 2007a). The mechanisms by which LA-PLTP is generated and its physiological functions are currently unknown. However, since apoE is able to interact with PLTP, and apoE-containing proteoliposomes can activate inactive or low active PLTP, the presence of apoE in PLTP complexes is expected to enhance PLTP activity. This is consistent with the suggestion that apoE may play a role in regulating the PLTP activity level in plasma (Janis et al. 2005). HAand LA-PLTP forms are surface-active proteins, and the low active form was demonstrated to dock more strongly onto a phospholipid monolayer surface as compared to HA-PLTP form (Setala et al. 2007). It is therefore possible that LA-PLTP form could play other important lipid transfer-independent functions such as signaling on cell surface as suggested (Albers et al. 2012).

Although the role of PLTP in lipoprotein metabolism and atherogenesis has been intensively studied in gene-targeted mouse models and using in vitro experiments, the physiological role of PLTP in human metabolism is far from being resolved. Genetic approach has provided some evidence that genetic variation at the PLTP locus affects its phospholipid transfer activity and HDL particle size and might highlight its relevance in cholesterol efflux process (Vergeer et al. 2010a). PLTPdeficient mice have a marked decrease in HDL and apoA-I (Jiang et al. 1999) but reduced atherosclerosis in the background of apoE-/or apoB-transgenic mice (Jiang et al. 2001). It has also been reported that macrophage-derived PLTP contributes significantly to total plasma PLTP activity and deficiency of PLTP in macrophages leads to reduced atherosclerosis in LDLr-/ mice (Vikstedt et al. 2007b). There is also an interesting interaction between PLTP and CETP since it was demonstrated that purified PLTP enhances cholesteryl ester transfer from HDL3 to VLDL (Tollefson et al. 1988), although PLTP has no cholesterol ester transfer activity of its own. Moreover, CETP transgenic/PLTP KO mice have significantly lower plasma CETP activity as compared to that of CETP transgenic mice (Kawano et al. 2000). Currently, the physiological relevance of this PLTPCETP interaction in HDL metabolism is poorly understood.

 
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