Liver phospholipid transfer protein (PLTP) expression with a PLTP-null background promotes very low-density lipoprotein production in mice.

Phospholipid transfer protein (PLTP) belongs to a family of lipid transfer/lipopolysaccharide-binding proteins, including lipopolysaccharide-binding protein (LBP), bactericidal/permeability-increasing protein (BPI), and CETP (1). In terms of lipid transfer activity, PLTP has its own characteristics. It has no neutral lipid transfer activity. PLTP circulates bound to HDL, and mediates the net transfer of phospholipids between unilaminar vesicles into HDL, and also the exchange of phospholipids between lipoproteins. The net transfer of phospholipids into HDL results in the formation of a larger, less dense species. Plasma PLTP is also a nonspecific lipid transfer protein. Several studies have indicated that PLTP is capable of transferring all common phospholipids. Besides them, it also efficiently transfers diacylglycerol, α-tocopherol, cerebroside, and lipopolysaccharides (2). Although CETP can also transfer phospholipids, there is no redundancy in the functions of PLTP and CETP in the mouse model (3). It has been shown that PLTP can act like the putative fusion factor to enlarge HDL particles (4). Huuskonen et al. reported that phospholipid transfer activity is a prerequisite for efficient PLTP-mediated HDL enlargement (5). Rye et al. reported that enrichment of triglyceride in the HDL core could promote such fusion (6). PLTP transgenic mice showed a 2.5- to 4.5-fold increase in PLTP activity in plasma, as compared with controls. This resulted in a 30-40% reduction of plasma HDL cholesterol levels. PLTP gene knockout (KO) mice demonstrated a complete loss of phospholipid transfer activity (7). These animals showed a marked decrease in HDL cholesterol and apoA-I levels, demonstrating the important role of PLTP-mediated transfer of surface components of triglyceride-rich lipoprotein in the maintenance of HDL levels (7-9). Overall, PLTP overexpression or deficiency causes a significant reduction of HDL levels in the circulation, and we still cannot explain that adequately. Apolipoprotein B (apoB) is the major protein component of VLDL and chylomicron (CM), which transport triglyceride from the liver and intestine, respectively, into the bloodstream (10). ApoB exists in two forms, apoB48 and apoB100 (11, 12). Increased hepatic apoB-containing lipoprotein (BLp) synthesis is the principal defect in subjects with familial combined hyperlipidemia (13, 14), and is also an important component of the dyslipidemia of diabetes and obesity (15, 16). Accumulating evidence suggests that the formation of apoB100-BLp (17) and apoB48-BLp (18, 19) is accomplished sequentially. The “two-step” model postulates that the initial product is a primordial particle, formed during apoB translation in the endoplasmic reticulum (ER). It is clear that microsomal triglyceride transfer protein (MTP) is involved in the early stage (1st step) of apoB lipidation. However, the mechanism involved in the later stage (2nd step) is still not well understood. We have unexpectedly found that PLTP deficiency causes a significant impairment in hepatic secretion of VLDL (20). Likewise, it has been reported that animals over-expressing PLTP exhibit hepatic VLDL over-production (21). Associations of plasma PLTP activity with elevated apoB levels (22) have been found in humans, as well. In a recent study, Masson et al. found that human PLTP transgenic rabbits showed a significant increase of BLp, but not of HDL cholesterol, in the circulation. These animals demonstrated increased atherosclerotic lesions after a high-fat diet feeding, as compared with controls (23). Nevertheless, the surprising discovery that PLTP affects BLp secretion from the liver must be explored fully. The liver is one of the major sites of lipoprotein production and degradation, as well as PLTP expression. To investigate the role of PLTP in lipoproteins homeostasis, we initially planned to prepare a liver-specific KO mouse model using the Cre-Loxp system under the control of an albumin promoter. Finally, we created a unique mouse model that expresses PLTP acutely and specifically in the liver, with a PLTP-null background. We studied lipoprotein metabolism, VLDL secretion, and VLDL lipidation in these animals, concluding that liver PLTP-mediated VLDL production is one of the driving forces for plasma lipoprotein metabolism.