28 research outputs found
Insulin decreases plasma cholesteryl ester transfer but not cholesterol esterification in healthy subjects as well as in normotriglyceridaemic patients with type 2 diabetes
Background. Plasma cholesterol esterification (EST) and subsequent cholesteryl ester transfer (CET) from high-density lipoproteins (HDLs) towards apolipoprotein (apo) B-containing lipoproteins are key steps in HDL metabolism. Materials and methods. The effects of exogenous hyperinsulinaemia on plasma CET and EST, measured with isotope methods, were evaluated in 10 male normotriglyceridaemic (plasma triglycerides < 2.0 mmol L-1) patients with type 2 diabetes and 10 individually matched healthy subjects during a two-step hyperinsulinaemic euglycaemic clamp over 6-7 h. Results. No between-group differences in baseline plasma lipid parameters were observed, but the HDL cholesteryl ester content was lower (P < 0.02) and the HDL triglyceride content was higher (P < 0.05) in diabetic patients. Baseline CET and EST were similar in the groups. In both groups, hyperinsulinaemia decreased plasma triglycerides (P < 0.01) and the HDL triglyceride content (P < 0.01) compared with saline infusion in healthy subjects, whereas the HDL cholesteryl ester content increased (P < 0.05 vs. saline infusion) in diabetic patients. CET was similarly decreased by hyperinsulinaemia in both groups (P < 0.01 vs. saline infusion). In contrast, the change in EST in either group was not different from that during saline administration. In the combined group, baseline CET was positively correlated with plasma triglycerides (R(s) = 0.68, P < 0.01). The HDL cholesteryl ester content was negatively (R(s) = -0.48, P < 0.05) and the HDL triglyceride content was positively (R(s) = 0.64, P < 0.01) correlated with CET. Conclusion. Insulin infusion decreases plasma CET in conjunction with a fall in triglycerides but does not decrease cholesterol esterification in healthy and type 2 diabetic subjects, indicating that acute hyperinsulinaemia has a different effect on these processes involved in HDL metabolism. Despite unaltered fasting plasma CET, HDL core lipid composition was abnormal in diabetic patients, suggesting-that additional mechanisms may contribute to changes in HDL metabolism in diabetes mellitus
Dialysis of isolated low density lipoprotein induces a loss of lipophilic antioxidants and increases the susceptibility to oxidation in vitro
We determined the effects of different dialysis conditions on the antioxidant content, duration of the lag phase and oxidation rate of LDL. Dialysis for 22 h resulted in a 56%–66% reduction in the concentrations of β-carotene, lycopene and α-tocopherol. The lag phase of copper-induced oxidation of freshly isolated LDL was considerably longer than that of LDL dialysed for 22 or 44 h. Our data show that dialysis may result in LDL preparations with antioxidant compositions that are not truly representative of freshly isolated lipoproteins
Dietary trans fatty acids increase serum cholesterylester transfer protein activity in man
The average diet may provide some 8–10 g/day of unsaturated fatty acids with a trans double bond. Previous studies showed that dietary trans fatty acids may simultaneously raise low-density lipoprotein (LDL) cholesterol and reduce high-density lipoprotein (HDL) cholesterol. Human plasma contains a protein (CETP) which transfers cholesterylesters from HDL to lipoproteins of lower density. We hypothesized that CETP could play a role in the effect of trans fatty acids on lipoproteins and measured the activity levels of CETP in serum samples from a 9-week study in which 55 volunteers were fed three controlled diets with different fatty acid profiles. Mean activity was 114 (% of reference serum) after consumption of a high trans fatty acid diet, as opposed to 96 after linoleic acid and 97 after stearic acid (P < 0.02). We conclude that the increased activity of CETP may contribute to the rise in LDL cholesterol and the fall in HDL cholesterol seen on diets with high contents of trans fatty acids
Elevation of plasma phospholipid transfer protein in transgenic mice increases VLDL secretion
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 < 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 <
0.05). PLTP activity was 2.8-fold increased in these animals (P < 0.001).
The human PLTP concentration was 5 microg/ml. Moderate overexpression of
PLTP resulted in a 1.5-fold higher VLDL secretion compared with huCETPtg
mice (P < 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
Evaluation of phospholipid transfer protein and cholesteryl ester transfer protein as contributors to the generation of pre beta-high-density lipoproteins
High-density lipoproteins (HDLs) are considered anti-atherogenic because
they mediate peripheral cell cholesterol transport to the liver for
excretion and degradation. An important step in this reverse
cholesterol-transport pathway is the uptake of cellular cholesterol by a
specific subclass of small, lipid-poor apolipoprotein A-I particles
designated pre beta-HDL. The two lipid-transfer proteins present in human
plasma, cholesteryl ester transfer protein (CETP) and phospholipid
transfer protein (PLTP), have both been implicated in the formation of pre
beta-HDL. In order to investigate the relative contribution of each of
these proteins, we used transgenic mouse models. Comparisons were made
between human CETP transgenic mice (huCETPtg), human PLTP transgenic mice
(huPLTPtg) and mice transgenic for both lipid-transfer proteins
(huCETPtg/huPLTPtg). These animals showed elevated plasma levels of CETP
activity, PLTP activity or both activities, respectively. We evaluated the
generation of pre beta-HDL in mouse plasma by immunoblotting and crossed
immuno-electrophoresis. Generation of pre beta-HDL was equal in huCETPtg
and wild-type mice. In contrast, in huPLTPtg and huCETPtg/huPLTPtg mice,
pre beta-HDL generation was 3-fold higher than in plasma from either
wild-type or huCETPtg mice. Our findings demonstrate that, of the two
plasma lipid-transfer proteins, PLTP rather than CETP is responsible for
the generation of pre beta-HDL. These data support the hypothesis of a
role for PLTP in the initial stage of reverse cholesterol transport
Elevation of plasma phospholipid transfer protein increases the risk of atherosclerosis despite lower apolipoprotein B-containing lipoproteins.
Plasma phospholipid transfer protein (PLTP) transfers phospholipids
between lipoproteins and mediates HDL conversion. PLTP-overexpressing mice
have increased atherosclerosis. However, mice do not express cholesteryl
ester transfer protein (CETP), which is involved in the same metabolic
pathways as PLTP. Therefore, we studied atherosclerosis in heterozygous
LDL receptor-deficient (LDLR(+/-)) mice expressing both human CETP and
human PLTP. We used two transgenic lines with moderately and highly
elevated plasma PLTP activity. In LDLR(+/-)/huCETPtg mice, cholesterol is
present in both LDL and HDL. Both are decreased in
LDLR(+/-)/huCETPtg/huPLTPtg mice (>50%). An atherogenic diet resulted in
high levels of VLDL+LDL cholesterol. PLTP expression caused a strong PLTP
dose-dependent decrease in VLDL and LDL cholesterol (-26% and -69%) and a
decrease in HDL cholesterol (-70%). Surprisingly, atherosclerosis was
increased in the two transgenic lines with moderately and highly elevated
plasma PLTP activity (1.9-fold and 4.4-fold, respectively), indicating
that the adverse effect of the reduction in plasma HDL outweighs the
beneficial effect of the reduction in apolipoprotein B (apoB)-containing
lipoproteins. The activities of the antiatherogenic enzymes paraoxonase
and platelet-activating factor acetyl hydrolase were both PLTP
dose-dependently reduced ( approximately -33% and -65%, respectively). We
conclude that expression of PLTP in this animal model results in increased
atherosclerosis in spite of reduced apoB-containing lipoproteins, by
reduction of HDL and of HDL-associated antioxidant enzyme activities
Increased risk of atherosclerosis by elevated plasma levels of phospholipid transfer protein.
Plasma phospholipid transfer protein (PLTP) is thought to be involved in
the remodeling of high density lipoproteins (HDL), which are
atheroprotective. It is also involved in the metabolism of very low
density lipoproteins (VLDL). Hence, PLTP is thought to be an important
factor in lipoprotein metabolism and the development of atherosclerosis.
We have overexpressed PLTP in mice heterozygous for the low density
lipoprotein (LDL) receptor, a model for atherosclerosis. We show that
increased PLTP activity results in a dose-dependent decrease in HDL, and a
moderate stimulation of VLDL secretion (</=1.5-fold). The mice were given
a high fat, high cholesterol diet, which resulted in hypercholesterolemia
in all animals. HDL concentrations were dramatically reduced in
PLTP-overexpressing animals when compared with LDL receptor controls,
whereas VLDL + LDL cholesterol levels were identical. Susceptibility to
atherosclerosis was increased in a PLTP dose-responsive manner. We
conclude that PLTP increases susceptibility to atherosclerosis by lowering
HDL concentrations, and therefore we suggest that an increase in PLTP is a
novel, long term risk factor for atherosclerosis in humans