Elevation of plasma phospholipid transfer protein in transgenic mice increases VLDL secretion

Abstract

Two lipid transfer proteins are active in human plasma, cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP). Mice by nature do not express CETP. Additional inactivation of the PLTP gene resulted in reduced secretion of VLDL and subsequently in decreased susceptibility to diet-induced atherosclerosis. The aim of this study is to assess possible effects of differences in PLTP expression on VLDL secretion in mice that are proficient in CETP and PLTP. We compared human CETP transgenic (huCETPtg) mice with mice expressing both human lipid transfer proteins (huCETPtg/huPLTPtg). Plasma cholesterol in huCETPtg mice was 1.5-fold higher compared with huCETPtg/huPLTPtg mice ( P Ͻ 0.001). This difference was mostly due to a lower HDL level in the huCETPtg/huPLTPtg mice, which subsequently could lead to the somewhat decreased CETP activity and concentration that was found in huCETPtg/huPLTPtg mice ( P Ͻ 0.05). PLTP activity was 2.8-fold increased in these animals ( P Ͻ 0.001). The human PLTP concentration was 5 g/ml. Moderate overexpression of PLTP resulted in a 1.5-fold higher VLDL secretion compared with huCETPtg mice ( P Ͻ 0.05). The composition of nascent VLDL was similar in both strains. These results indicate that elevated PLTP activity in huCETPtg mice results in an increase in VLDL secretion. In addition, PLTP overexpression decreases plasma HDL cholesterol as well as CETP. Phospholipid transfer protein (PLTP) is an important modulator of plasma HDL levels, size, and composition (1-5). HDL is considered to protect against atherosclerosis by transporting cellular cholesterol from cells in the arterial wall to the liver for further excretion via the bile, as well as by exerting anti-inflammatory and anti-oxidant effects (6-8).The role of PLTP in atherosclerosis was recently evaluated in PLTP deficient mice (5). PLTP deficiency in hyperlipidemic mouse models resulted in decreased atherosclerosis. In vitro experiments with cultured hepatocytes from PLTP deficient mice revealed a defect in VLDL secretion. These effects on VLDL secretion provided an explanation for the decreased atherosclerosis found in PLTP deficient mice (5).Earlier we reported anti-atherogenic properties in mice overexpressing human PLTP (huPLTPtg). Despite lower HDL levels, plasma from these mice is more effective in preventing in vitro accumulation of cholesterol by macrophages and is able to generate more pre ␤ -HDL (3, 9). Studies in mice with adenovirus-mediated overexpression of human PLTP showed similar effects on HDL subclass distribution (10, 11).Thus, depending on the metabolic setting, PLTP may have anti-or pro-atherogenic properties that require further investigation. Presently, we aimed to evaluate whether VLDL secretion is affected by variations in PLTP activity. For this purpose, we crossbred transgenic mice for human CETP (huCETPtg) with huPLTPtg mice (9) and obtained huCETPtg/huPLTPtg mice. These mice provide a unique model to study the role of PLTP in VLDL metabolism in the presence of CETP, whi...

Plasma Phospholipid Transfer Protein Activity Is Decreased in Type 2 Diabetes During Treatment With Atorvastatin

“…In accordance with this mechanism, overexpression of human PLTP in transgenic mice results in elevated rates of hepatic VLDL secretion (43). Indeed, a number of clinical studies have reported the existence of a link between plasma apoB or LDL cholesterol and PLTP activity (20,41), but in the present study, we were unable to find evidence for this association.…”

Increased Fecal Bile Acid Excretion in Transgenic Mice With Elevated Expression of Human Phospholipid Transfer Protein

“…We recently found a modest increase (Ͻ1.5-fold) of VLDL secretion in PLTPoverexpressing mice. 18,34 In the present study, however, we found strongly decreased levels of plasma triglycerides in the PLTP-overexpressing mice. This is in agreement with studies in which adenovirus-mediated overexpression of PLTP was studied.…”

Elevated plasma phospholipid transfer protein activity is a determinant of carotid intima-media thickness in type 2 diabetes mellitus

“…Overexpression of PLTP enhances pre-β-HDL formation [6], thereby stimulating cholesterol removal and preventing cholesterol accumulation in macrophages [7]. Besides these potentially anti-atherogenic actions, PLTP also has pro-atherogenic potential, as evidenced by stimulation of hepatic apolipoprotein (apo) B secretion and by effects on HDL levels in mouse models [8][9][10]. Moreover, PLTP has the ability to transfer the antioxidant α-tocopherol between lipoproteins, and it has been demonstrated that experimental PLTP deficiency results in an increased α-tocopherol content in LDL, thereby protecting these lipoproteins against oxidation [11].…”