Higher Phospholipid Transfer Protein Activity Research Articles

Increased Phospholipid Transfer Protein Activity Is Associated With Markers of Enhanced Lipopolysaccharide Clearance in Human During Cardiopulmonary Bypass.

Introduction: Lipopolysaccharide (LPS) is a component of gram-negative bacteria, known for its ability to trigger inflammation. The main pathway of LPS clearance is the reverse lipopolysaccharide transport (RLT), with phospholipid transfer protein (PLTP) and lipoproteins playing central roles in this process in experimental animal models. To date, the relevance of this pathway has never been studied in humans. Cardiac surgery with cardiopulmonary bypass is known to favor LPS digestive translocation. Our objective was to determine whether pre-operative PLTP activity and triglyceride or cholesterol-rich lipoprotein concentrations were associated to LPS concentrations in patients undergoing cardiac surgery with cardiopulmonary bypass.Methods: A post-hoc analysis was conducted on plasma samples obtained from patients recruited in a randomized controlled trial.Total cholesterol, high density lipoprotein cholesterol (HDLc), low density lipoprotein cholesterol (LDLc), triglyceride and PLTP activity were measured before surgery. LPS concentration was measured by mass spectrometry before surgery, at the end of cardiopulmonary bypass and 24 h after admission to the intensive care unit.Results: High PLTP activity was associated with lower LPS concentration but not with inflammation nor post-operative complications. HDLc, LDLc and total cholesterol were not associated with LPS concentration but were lower in patients developing post-operative adverse events. HDLc was negatively associated with inflammation biomarkers (CRP, PCT). Triglyceride concentrations were positively correlated with LPS concentration, PCT and were higher in patients with post-operative complications.Conclusion: Our study supports the role of PLTP in LPS elimination and the relevance of RLT in human. PLTP activity, and not cholesterol rich lipoproteins pool size seemed to be the limiting factor for RLT. PLTP activity was not directly related to post-operative inflammation and adverse events, suggesting that LPS clearance is not the main driver of inflammation in our patients. However, HDLc was associated with lower inflammation and was associated with favorable outcomes, suggesting that HDL beneficial anti-inflammatory effects could be, at least in part independent of LPS clearance.

Paraoxonase-1 activity is positively related to phospholipid transfer protein activity in type 2 diabetes mellitus: Role of large HDL particles

ObjectivesHigh density lipoprotein (HDL)-associated paraoxonase-1 (PON-1) exerts anti-oxidative properties, whereas phospholipid transfer protein (PLTP) is able to convert mature HDL into larger and smaller HDL particles. Here we tested associations of PON-1 with PLTP in type 2 diabetes mellitus (T2DM), a condition characterized by lower PON-1 activity and higher PLTP activity. Design and methodsSerum PON-1 (arylesterase activity), plasma PLTP activity (liposome-vesicle HDL system), and (apo)lipoproteins were measured in 81 T2DM subjects (mean age 59±9years; 31 women; no insulin treatment). In 48 participants, HDL subfractions were measured by nuclear magnetic resonance spectroscopy. ResultsIn univariate correlation analysis, PON-1 activity was positively related to PLTP activity (r=0.348, p=0.001). PLTP activity was positively related to blood pressure, body mass index and triglycerides, whereas PON-1 activity was positively to HDL cholesterol and apoA-I (p<0.05 to <0.01 for each). Both PLTP activity and PON-I activity were positively related to large HDL particles (r=0.379, p=0.008 and r=0.411, p=0.004, respectively). In multivariable linear regression analysis, PON-1 activity was associated with PLTP activity independent of clinical covariates and HDL cholesterol or apoA-I (β=0.340, p=0.001 and β=0.320, p=0.003, respectively). The association of PON-1 activity with PLTP activity was lost in analysis which included large HDL particles (large HDL: β=0.411, p=0.004). ConclusionsPON-1 activity is positively related to PLTP activity in T2DM, raising the possibility that PLTP could act to maintain PON-1. This association may in part be attributable to a common relationship of PON-1 and PLTP with large HDL particles.

High PLTP activity is associated with depressed left ventricular systolic function

Phospholipid transfer protein (PLTP) modulates lipoprotein metabolism and plays an important role in inflammation and oxidative stress. High PLTP activity is associated with atherosclerosis and its risk factors, which also predispose to left ventricular systolic (LV) dysfunction and/or congestive heart failure. However there are few data linking PLTP activity directly to LV function. According, we sought to determine the relation between PLTP activity and LV ejection fraction (EF) in a Chinese cohort of 732 patients referred for coronary angiography. Weak but significant correlations of PLTP activity levels were found with age (r = −0.09, p = 0.017), male gender (r = 0.09, p = 0.019), diabetes (r = 0.08, p = 0.036), TG (r = 0.11, p = 0.003), HDL-C (r = −0.18, p = <0.001), apo A (−0.30, p < 0.001) apo B (r = 0.20, p < 0.001), fibrinogen (r = 0.32, p < 0.001) and LVEF (r = −0.12, p = 0.003). Median PLTP activity levels were higher among patients with reduced than in normal LV systolic function (LVEF <50%) [26.7 pmol/microl/h (IQR 20.2, 38.6) vs. 19.9 pmol/microl/h (IQR 12.2, 31.0), p < 0.001]. There was a step-wise increase in median PLTP levels in patients with normal, mild, and moderate-severe degrees of LV dysfunction (19.9 pmol/microl/h vs. 25.1 pmol/microl/h vs. 34.7 pmol/microl/h, p < 0.001). Median PLTP activity levels were higher among patients with unstable rather than stable AP and non-CHD patients (25.9 pmol/microl/h vs 20.2 vs 21.9, p = 0.012). On multivariate analyzes, higher median PLTP activity levels were associated with depressed LV systolic function as a dichotomous variable and with lower LVEF as a continuous variable. In conclusion, higher PLTP activity is associated with depressed LV systolic function in a dose-dependent manner independent of coronary heart disease as well as to unstable CHD.

Plasma lipid transfer proteins and cardiovascular disease. The Framingham Heart Study

ObjectiveCholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are two genetically-related plasma proteins involved in the exchange of cholesteryl esters and phospholipids between high-density lipoproteins (HDL) and other lipoproteins. Although low CETP and high PLTP activity both result in higher concentrations of plasma HDL-cholesterol (HDL-C), there is no evidence that either of these changes is associated with a decrease in cardiovascular disease (CVD) in a general population. MethodsPlasma CETP and PLTP activities, measured by homogenous fluorometric assays using synthetic donor particle substrates, were related to the incidence of a first CVD event in Framingham Heart Study Offspring participants without CVD (n = 2679, mean age 59 y, 56% women) attending the 6th examination cycle (1995–98). Because of an effect modification by sex for both CETP and PLTP, analyzes were stratified by sex. ResultsDuring follow-up (mean 10.4 years) 187 participants experienced a first CVD event. In sex-specific Cox models, both CETP and PLTP as continuous and as binary variables were associated with significantly increased CVD in men, but not women. In men compared to a referent group with CETP ≥ median and PLTP < median, the multivariable-adjusted hazard ratio (HR) for new CVD events was significantly greater with either the combination of high CETP and high PLTP (HR 2.27, 95% CI 1.23–4.20); low CETP and low PLTP (HR 2.23, 95% CI 1.19–4.17); or low CETP and high PLTP (HR 2.85, 95% CI 1.53–5.31). In contrast, in women the multivariable-adjusted HR for new CVD events was non-significant and virtually equal to “1.0” with all combinations of high and low CETP or PLTP values. ConclusionsLower plasma CETP or higher PLTP activity was each associated with a significantly increased risk of CVD. Inexplicably, the increase in CVD associated with both lipid transfer proteins was confined to men.

Phospholipid Transfer Protein in the Placental Endothelium Is Affected by Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) causes alterations in fetal high-density lipoproteins (HDL). Because phospholipid transfer protein (PLTP) is important for HDL (re)assembly and is expressed in the human placenta, we hypothesized that circulating fetal and/or placental PLTP expression and activity are altered in GDM. PLTP levels and activity were determined in maternal and fetal sera from GDM and controls. Placental PLTP was immunolocalized, and its expression was measured in placental tissue. PLTP regulation by glucose/insulin was studied in human endothelial cells isolated from placental vessels (HPEC). Placental Pltp expression was up-regulated in GDM (1.8-fold, P < 0.05). PLTP protein (5-fold, P < 0.01) and activity (1.4- to 2.5-fold) were higher in fetal than in maternal serum. The placental endothelium was identified as a major PLTP location. Insulin treatment of HPEC significantly increased secreted PLTP levels and activity. In GDM, fetal cholesterol, HDL-triglycerides and phospholipids were elevated compared with controls. Fetal PLTP activity was higher than maternal but unaltered in GDM. HPEC contribute to the release of active PLTP into the fetal circulation. Pltp expression is increased in GDM with hyperglycemia and/or hyperinsulinemia contributing. High PLTP activity in fetal serum may enhance conversion of HDL into cholesterol-accepting particles, thereby increasing maternal-fetal cholesterol transfer.

Low phospholipid transfer protein (PLTP) is a risk factor for peripheral atherosclerosis

ObjectivePhospholipid transfer protein (PLTP) facilitates cholesterol efflux from cells, intravascular HDL remodelling and transfer of vitamin E and endotoxin. In humans, the relationship of PLTP to atherosclerosis is unknown. However, strong coronary risk factors like obesity, diabetes, cigarette smoking and inflammation increase circulating levels of active PLTP. The aim of the present, cross-sectional study was to analyze the relationship of PLTP to peripheral arterial disease, a marker of generalized atherosclerosis, independently of potentially confounding factors like obesity, diabetes and smoking. MethodsWe performed a case control study in 153 patients with symptomatic peripheral arterial disease (PAD) and 208 controls free of vascular disease. Smokers and patients with diabetes mellitus were excluded. A lipoprotein-independent assay was used for measurement of circulating bioactive PLTP and an ELISA utilizing a monoclonal antibody was used to analyze PLTP mass. ResultsPLTP activity was significantly decreased in patients with PAD 5.5 (4.6–6.4)(median (25th–75th percentile)) versus 5.9 (5.1–6.9)μmol/mL/h in controls (p=0.001). In contrast, PLTP mass was similar in patients with PAD 8.5μg/mL (7.3–9.5) and in controls 8.3μg/mL (6.9–9.7) (p=0.665). Multivariate logistic regression analysis revealed that PLTP activity is independently associated with the presence of PAD. PLTP activity was similar in patients with and without lipid-lowering drugs (p=0.396). ConclusionOur results show that in non-diabetic, non-smoking subjects low rather than high PLTP activity is a marker for the presence of peripheral arterial disease and that distribution of PLTP between high-activity and low-activity forms may be compromised in atherosclerosis.

Plasma apolipoprotein E concentration is an important determinant of phospholipid transfer protein activity in type 2 diabetes mellitus

Phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins and plays an important role in HDL metabolism. PLTP exists as a high-activity and a low-activity form in the circulation. In vitro studies have shown that apolipoprotein (apo) E is involved in maintaining PLTP in the active form, while the low-activity form is associated with apo AI. We have therefore investigated whether plasma apo AI, B and E concentrations are important determinants of plasma PLTP activity in type 2 diabetes, a condition associated with increased plasma PLTP activity. Plasma PLTP activity was assayed by measuring the transfer of radiolabelled phosphatidylcholine from liposomes to HDL; apo AI and B by rate nephelometry and apo E by a 2-point turbidimetric assay. Type 2 diabetic patients (n = 230) had higher PLTP activity than controls (n = 97) (2374 +/- 628 nmol/mL/h versus 1862 +/- 585 respectively, p < 0.01). They also had increased fasting triglyceride and low HDL. Plasma apo B (p < 0.01) and apo E (p < 0.05) were increased, whereas apo AI was reduced (p < 0.01). Univariate analysis showed that plasma PLTP activity correlated mainly with apolipoproteins AI and E. Stepwise regression analysis showed that apo E was the main determinant of plasma PLTP activity, accounting for 23% of its variability in the diabetic subjects and 8% in the controls respectively. The associations between plasma apo AI and E concentrations and PLTP activity suggest that these apolipoproteins are important regulators of PLTP activity in vivo. The increase in PLTP activity in type 2 diabetes is partly related to the changes in these apolipoproteins.

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

The plasma activity of phospholipid transfer protein (PLTP), which has putative pro- and anti-atherogenic roles in lipoprotein metabolism, is increased in type 2 diabetes mellitus. We analysed the relationship between carotid artery intima-media thickness (IMT), an established marker of atherosclerosis, and PLTP activity in diabetic patients and control subjects. The IMT (mean of three segments in both carotid arteries by ultrasonography), clinical variables, plasma PLTP activity (phospholipid vesicle-HDL system), lipoproteins, C-reactive protein and insulin were measured in 87 non-smoking men and women, who had type 2 diabetes mellitus, no cardiovascular disease, and were not on insulin or lipid-lowering medication, and in 83 age-matched control subjects. In diabetic patients, carotid IMT (p=0.02), pulse pressure (p=0.003), plasma PLTP activity (p<0.001), triglycerides (p=0.01), C-reactive protein (p<0.01) and insulin (p<0.001) were higher, whereas HDL cholesterol was lower (p<0.001) than in control subjects. Multiple stepwise linear regression analysis demonstrated that in type 2 diabetic patients IMT was independently associated with age (p<0.001), sex (p=0.001), pulse pressure (p=0.003), plasma PLTP activity (p=0.03) and HDL cholesterol (p=0.03), but not with very low density lipoprotein+LDL cholesterol, triglycerides, C-reactive protein and insulin (all p>0.20). The relationship between plasma PLTP activity and IMT was not significant in control subjects. Plasma PLTP activity is a positive determinant of IMT in type 2 diabetes mellitus, suggesting that high PLTP activity is involved in accelerated atherosclerosis in this disease.