Plasma phospholipid transfer protein: A multifaceted protein with a key role in the assembly and secretion of apolipoprotein B-containing lipoproteins by the liver
Authors: Laurent Lagrost
Journal: Hepatology (2012)

See Article on Page 576 Phospholipid transfer protein (PLTP) is a secreted protein that is ubiquitously expressed in human tissues, with the liver as the major production site. It has been identified in earlier studies for its ability to bind and transfer a number of hydrophobic and amphipathic molecules in the bloodstream. It has been reported to facilitate the exchange of phospholipids, unesterified cholesterol, diacylglycerides, vitamin E (tocopherols), and lipopolysaccharides (LPS) between plasma lipoproteins, with functional consequences in vascular biology, brain physiology, reproductive biology, inflammation, and innate immunity.1 In plasma, PLTP is mainly transported by high-density lipoproteins (HDLs), and previous studies of PLTP focused on HDL. Earlier studies in mouse models provided direct support for an HDL-orientated function of PLTP, that is, with higher2 or lower3-5 levels of HDL cholesterol in transgenic mice overexpressing human PLTP and lower HDL cholesterol levels in PLTP-deficient mice.6 In fact, there is growing evidence that PLTP plays a pivotal role in HDL-mediated reverse cholesterol transport because of its ability (1) to generate nascent, preβ-HDL (i.e., the primary acceptors of cell-derived cholesterol), which dissociates from the surface of very-low-density lipoproteins (VLDLs) during lipolysis,7 (2) to form both preβ-HDL and large HDL2-like particles through intra-HDL remodeling,8-10 and (3) to facilitate cholesterol and phospholipid efflux from peripheral cells through an ABCA1-dependent pathway in the initiating step of reverse cholesterol transport11-13 (see Fig. 1). Recent genome-wide association studies brought evidence of the association of higher PLTP transcript levels in the liver with higher HDL cholesterol concentrations.14 However, beyond PLTP gene-expression levels, the consequences of plasma PLTP activity might be highly dependent on the metabolic context and on the plasma lipoprotein profile. For instance, plasma PLTP activity was found to be inversely associated with HDL-cholesterol levels, but positively associated with apolipoprotein B (apoB) levels in a cohort of Chinese patients who underwent diagnostic coronary angiography.15 PLTP and lipoprotein metabolism. Established functions of PLTP are depicted in blue color and in three distinct compartments, including hepatocytes ("liver"), plasma ("blood"), and extrahepatic tissues ("peripheral tissues"). It includes the following: (1) vitamin E transfer toward tissues; (2) VLDL assembly and secretion in the liver through the fusion of primordial apoB-containing lipoproteins (BLp) with lipid droplets and through the blockade of apoB destruction by ROS; (3) VLDL remodeling with the generation of LDL and nascent, preβ-HDL during the course of intravascular VLDL lipolysis; (4) cholesterol and phospholipid efflux toward HDL acceptors with the involvement of ABC transporters; (5) intravascular HDL remodeling through the formation of a transient fusion intermediate, which splits into preβ-HDL and HDL2-like particles; (6) disaggregation and transfer of bacterial LPS toward HDL acceptors, thus bypassing activation of TLR4; and, finally, (7) reverse transport of cholesterol and LPS to the liver for ultimate excretion into the bile. HDL; high-density lipprotein; LPS, lipopolysaccharides; PLTP, phospholipid transfer protein; VLDL, very-low-density lipoprotein. In wild-type mice, most of the plasma cholesterol is transported in the HDL fraction, with smaller amounts of cholesterol in VLDL and barely detectable amounts of cholesterol in the low-density lipoprotein (LDL) fraction. It is a major limitation of the mouse model, because plasma lipoprotein profiles in humans and rabbits normally display prominent non-HDL, apoB-containing lipoproteins. Interestingly, mice genetically engineered to have a human-like plasma lipoprotein profile (in particular, with human apoB synthesis in the liver and similar plasma apoB levels to those in humans) and expressing a PLTP-deficiency trait revealed a new, unexpected role of PLTP: the ability to increase both the liver production rate and plasma levels of apoB-containing lipoproteins.16 In these pioneering studies, plasma HDL levels were concomitantly decreased in apoB transgenic/PLTP-knocked out animals, indicating again the complexity of PLTP, which may be active within both the plasma and cell compartments.16 The complexity of PLTP is illustrated further by the increased secretion of VLDL, but with no change in plasma VLDL levels and with falling levels of HDL, which was reported in transgenic mice with elevated plasma phospholipid transfer protein.17 In this issue of HEPATOLOGY, the study by Yazdanyar and Jiang18 provides relevant data that bring new support to the hypothesis that liver PLTP plays a role in promoting VLDL production. Elegantly, these investigators re-expressed the endogenous mouse PLTP gene in a PLTP-null background with a low level of PLTP activity in the circulation. It was found to produce dramatic increases in the liver production and circulating level of apoB-containing lipoproteins, but with no effect on the production of apoAI-containing lipoproteins and no substantial effect on circulating HDL, which retained the same features and the same level whether animals expressed the PLTP gene or not. Noticeably, and in addition to the liver, a number of peripheral tissues are known to make significant amounts of PLTP in humans, thus contributing significantly to circulating levels of PLTP in human plasma. In addition, like rabbits but unlike rats and mice, humans produce apoB100-containing VLDL in the liver and express a functional plasma cholesteryl ester transfer protein (CETP), which is currently recognized as a major factor in regulating the distribution of cholesteryl esters between HDL and apoB-containing lipoproteins. This raises an important question as to the prominent function of PLTP in vivo: Is PLTP, in a human-like situation, chiefly involved in the production of apoB100-containing lipoproteins in the liver or in the metabolism of HDL in blood and peripheral tissues? In recent rabbit studies, a human PLTP transgene was placed under the control of the human eF1-α gene promoter, which, in contrast to the study by Yazdanyar and Jiang,18 resulted in widespread expression in various tissues (with substantial levels of human PLTP messenger RNAs detected not only in the liver, but also in adipose tissue, the pancreas, kidney, lung, brain, heart, and spleen of human PLTP transgenic rabbits).19 It resulted in increased plasma PLTP activity, increased cholesterol content of plasma apoB-containing lipoproteins, and increased formation of aortic fatty streaks in animals fed a cholesterol-rich diet, but with no significant change in plasma HDL cholesterol levels. It suggests further that the prominent and final consequence of PLTP expression on circulating apoB-containing lipoproteins versus HDL could actually be governed by the predominance of one lipoprotein class over the other. When VLDL and LDL predominate, as it is the case in humans and rabbits, PLTP expression would accentuate cholesterol accumulation in these lipoproteins only, with no major effect on HDL. One important insight provided by the study by Yazdanyar and Jiang18 concerns the molecular mechanism of the PLTP-mediated up-regulation of the production of apoB-containing lipoproteins by the liver. It was shown to involve increased VLDL lipidation in hepatocyte microsomal lumen, which, they suggest, results from a PLTP-facilitated fusion process of primordial apoB-containing lipoproteins with apoB-free lipid droplets, thus enhancing VLDL secretion into the plasma compartment (see Fig. 1). This builds on the previously recognized mechanism involving the PLTP-mediated enrichment of the liver with vitamin E, leading to decreased levels of reactive oxygen species (ROS) in the liver, and to decreased destruction of newly synthesized apoB through post–endoplasmic reticulum presecretory proteolysis20 (see Fig. 1). Because there is compelling evidence that PLTP plays a role in increasing the production and circulating levels of proatherogenic apoB-containing lipoproteins, targeting liver PLTP may be a promising strategy in fighting against atherosclerosis and cardiovascular disease. However, it must be remembered that PLTP belongs to the lipid transfer/lipopolysaccharide-binding protein (LT/LBP) gene family, including the LPS-binding protein (LPB), the neutrophil bactericidal permeability increasing protein (BPI), and CETP. It is part of a superfamily including the short and long PLUNC (palate, lung, and nasal epithelium clone) proteins that are involved in LPS metabolism and innate immunity. LPS are located at the surface of Gram-negative bacteria and activate the TLR4 (Toll-like receptor 4) of immune cells to produce proinflammatory mediators. Lipoproteins are known to be effective LPS carriers, and previous studies reported that PLTP promotes the transfer of LPS to lipoproteins, thus leading to its neutralization, transport back to the liver, and elimination in the bile.21-24 In combination with lipoproteins (mostly HDL in mice), PLTP was found to mediate reverse LPS transport in a multistep process involving sequentially the disaggregation of LPS, its binding to lipoprotein carriers, and its ultimate biliary excretion25 (see Fig. 1). The PLTP-mediated reverse LPS transport pathway was associated with stronger resistance to endotoxic shock and to a higher survival rate in LPS-injected mice. Liver PLTP might be necessary at both ends of reverse LPS transport by providing lipoprotein material for LPS binding in the initial step and by offering a unique route for its irreversible detoxification through biliary excretion in the final step (see Fig. 1). Laurent Lagrost, Ph.D.*, * Institut National de la Santé et de la Recherche Médicale, UMR866 "Lipids, Nutrition, Cancer", Faculté de Médecine, Université de Bourgogne, Dijon, France.