Phospholipid Transfer Protein Activity Research Articles

The role of genetically-influenced phospholipid transfer protein activity in lipoprotein metabolism and coronary artery disease

The role of genetically-influenced phospholipid transfer protein activity in lipoprotein metabolism and coronary artery disease

Seasonal Factors Are Associated with Activities of Enzymes Involved in High-Density Lipoprotein Metabolism among Pregnant Females in Ghana

BackgroundSmall-quantity lipid-based nutrient supplements (SQ-LNS) during pregnancy and postnatally were previously shown to improve high-density lipoprotein (HDL) cholesterol efflux capacity (CEC) and length in the children of supplemented mothers at 18 mo of age in the International Lipid-Based Nutrient Supplements (iLiNS) DYAD trial in Ghana. However, the effects of SQ-LNS on maternal HDL functionality during pregnancy are unknown. ObjectiveThe goal of this cross-sectional, secondary outcome analysis was to compare HDL function in mothers supplemented with SQ-LNS vs. iron and folic acid (IFA) during gestation. MethodsHDL CEC and the activities of 3 HDL-associated enzymes were analyzed in archived plasma samples (N = 197) from a subsample of females at 36 weeks of gestation enrolled in the iLiNS-DYAD trial in Ghana. Correlations between HDL function and birth outcomes, inflammatory markers C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP), and the effects of season were explored to determine the influence of these factors on HDL function in this cohort of pregnant females. ResultsThere were no statistically significant differences in HDL CEC, plasma lecithin-cholesterol acyltransferase (LCAT) activity, cholesteryl ester transfer protein (CETP) activity, or phospholipid transfer protein (PLTP) activity between mothers supplemented with SQ-LNS compared with IFA control, and no statistically significant relationships between maternal HDL function and childbirth outcomes. LCAT activity was negatively correlated with plasma AGP (R = -0.19, P = 0.007) and CRP (R = -0.28, P < 0.001), CETP and LCAT activity were higher during the dry season compared to the wet season, and PLTP activity was higher in the wet season compared to the dry season. ConclusionsMothers in Ghana supplemented with SQ-LNS compared with IFA during gestation did not have measurable differences in HDL functionality, and maternal HDL function was not associated with childbirth outcomes. However, seasonal factors and markers of inflammation were associated with HDL function, indicating that these factors had a stronger influence on HDL functionality than SQ-LNS supplementation during pregnancy. Clinical Trial Registry numberThe study was registered as NCT00970866. https://clinicaltrials.gov/study/NCT00970866

Endotoxin Mass Concentration in Plasma Is Associated With Mortality in a Multicentric Cohort of Peritonitis-Induced Shock.

Objectives: To investigate the association of plasma LPS mass with mortality and inflammation in patients with peritonitis-induced septic shock (SS).Design: Longitudinal endotoxin and inflammatory parameters in a multicentric cohort of SS.Patients: Protocolized post-operative parameters of 187 SS patients collected at T1 (12 h max post-surgery) and T4 (24 h after T1).Intervention: Post-hoc analysis of ABDOMIX trial.Measurements and Results: Plasma concentration of LPS mass as determined by HPLC-MS/MS analysis of 3-hydroxymyristate, activity of phospholipid transfer protein (PLTP), lipids, lipoproteins, IL-6, and IL-10. Cohort was divided in low (LLPS) and high (HLPS) LPS levels. The predictive value for mortality was tested by multivariate analysis. HLPS and LLPS had similar SAPSII (58 [48.5; 67]) and SOFA (8 [6.5; 9]), but HLPS showed higher death and LPS to PLTP ratio (p < 0.01). LPS was stable in HLPS, but it increased in LLPS with a greater decrease in IL-6 (p < 0.01). Dead patients had a higher T1 LPS (p = 0.02), IL-6 (<0.01), IL-10 (=0.01), and day 3 SOFA score (p = 0.01) than survivors. In the group of SAPSII > median, the risk of death in HLPS (38%) was higher than in LLPS (24%; p < 0.01). The 28-day death was associated only with SAPSII (OR 1.06 [1.02; 1.09]) and HLPS (OR 2.47 [1; 6.11]) in the multivariate model. In HLPS group, high PLTP was associated with lower plasma levels of IL-6 (p = 0.02) and IL-10 (p = 0.05).Conclusions: Combination of high LPS mass concentration and high SAPS II is associated with elevated mortality in peritonitis-induced SS patients.

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.

The Role of Phospholipid Transfer Protein in the Development of Atherosclerosis.

Phospholipid transfer protein (PLTP), a member of lipid transfer protein family, is an important protein involved in lipid metabolism in the circulation. This article reviews recent PLTP research progresses, involving lipoprotein metabolism and atherogenesis. PLTP activity influences atherogenic and anti-atherogenic lipoprotein levels. Human serum PLTP activity is a risk factor for human cardiovascular disease and is an independent predictor of all-cause mortality. PLTP deficiency reduces VLDL and LDL levels and attenuates atherosclerosis in mouse models, while PLTP overexpression exerts an opposite effect. Both PLTP deficiency and overexpression result in reduction of HDL which has different size, inflammatory index, and lipid composition. Moreover, although both PLTP deficiency and overexpression reduce cholesterol efflux capacity, but this effect has no impact in macrophage reverse cholesterol transport in mice. Furthermore, PLTP activity is related with metabolic syndrome, thrombosis, and inflammation. PLTP could be target for the treatment of dyslipidemia and atherosclerosis, although some potential off-target effects should be noted.

Glucocorticoids impair HDL-mediated cholesterol efflux besides increased HDL cholesterol concentration: a proof of concept.

Glucocorticoids (GC) are associated with increased cardiovascular morbidity despite increased HDL-C concentration. HDL-mediated cholesterol efflux, a major anti-atherogenic property of HDL particles, is negatively associated with CVD risk. We aimed to determine whether HDL-mediated cholesterol efflux was influenced by GC. Prospective, observational study. Lipid parameters, HDL composition, HDL-mediated cholesterol efflux, cholesteryl ester transfer protein, phospholipid transfer protein and lecithin cholesterol acyl-transferase (LCAT) activities were determined in ten patients with giant cell arteritis before and 3 months after GC introduction and in seven control subjects. HDL concentration and composition, HDL-mediated cholesterol efflux and LCAT activity were determined in GC-treated mice. In patients, HDL-C concentration was higher after than before treatment GC-treatment (P = 0.002), while HDL-mediated cholesterol efflux was decreased (P = 0.008) and negatively associated with the proportion of cholesteryl ester in HDL (P = 0.04), independently of CRP. As well, in mice, HDL-C level was increased after GC exposure (P = 0.04) and HDL-mediated cholesterol efflux decreased (P = 0.04). GC-treated patients had higher cholesteryl ester content in HDL, higher HDL2-to-HDL3 ratio and higher LCAT activity than before treatment (P = 0.008, P = 0.02 and P = 0.004, respectively). We report, for the first time, that in patients with giant cell arteritis and mice treated with GC, HDL-mediated cholesterol efflux was impaired by GC besides an increased HDL-C level. This impaired HDL functionality, possibly related to HDL enrichment in cholesteryl ester, could contribute to the increased CVD risk observed in GC-treated patients. Further studies are needed in larger populations, to further decipher the effect of GC on HDL.

Serum lipopolysaccharide neutralizing capacity in ischemic stroke.

Periodontitis is associated with increased serum lipopolysaccharide (LPS) activity, which may be one mechanism linking periodontitis with the risk of cardiovascular diseases. As LPS-carrying proteins including lipoproteins modify LPS-activity, we investigated the determinants of serum LPS-neutralizing capacity (LPS-NC) in ischemic stroke. The association of LPS-NC and Aggregatibacter actinomycetemcomitans, a major microbial biomarker in periodontitis, was also investigated. The assay to measure LPS-NC was set up by spiking serum samples with E. coli LPS. The LPS-NC, LPS-binding protein (LBP), soluble CD14 (sCD14), lipoprotein profiles, apo(lipoprotein) A-I, apoB, and phospholipid transfer protein (PLTP) activity, were determined in 98 ischemic stroke patients and 100 age- and sex-matched controls. Serum and saliva immune response to A. actinomycetemcomitans, its concentration in saliva, and serotype-distribution were examined. LPS-NC values ranged between 51-83% in the whole population. Although several of the LPS-NC determinants differed significantly between cases and controls (PLTP, sCD14, apoA-I, HDL-cholesterol), the levels did not (p = 0.056). The main determinants of LPS-NC were i) triglycerides (β = -0.68, p<0.001), and ii) HDL cholesterol (0.260, <0.001), LDL cholesterol (-0.265, <0.001), PLTP (-0.196, 0.011), and IgG against A. actinomycetemcomitans (0.174, 0.011). Saliva A. actinomycetemcomitans concentration was higher [log mean (95% CI), 4.39 (2.35-8.19) vs. 10.7 (5.45-21) genomes/ml, p = 0.023) and serotype D more frequent (4 vs. 0%, p = 0.043) in cases than controls. Serotypeablity or serotypes did not, however, relate to the LPS-NC. Serum LPS-NC comprised low PLTP-activity, triglyceride and LDL cholesterol concentrations, as well as high HDL cholesterol and IgG against A. actinomycetemcomitans. The present findings let us to conclude that LPS-NC did not associate with stroke.

The Systemic Redox Status Is Maintained in Non-Smoking Type 2 Diabetic Subjects Without Cardiovascular Disease: Association with Elevated Triglycerides and Large VLDL.

Decreased circulating levels of free thiols (R-SH, sulfhydryl groups) reflect enhanced oxidative stress, which plays an important role in the pathogenesis of cardiometabolic diseases. Since hyperglycemia causes oxidative stress, we questioned whether plasma free thiols are altered in patients with type 2 diabetes mellitus (T2DM) without cardiovascular disease or renal function impairment. We also determined their relationship with elevated triglycerides and very low density lipoproteins (VLDL), a central feature of diabetic dyslipidemia. Fasting plasma free thiols (colorimetric method), lipoproteins, VLDL (nuclear magnetic resonance spectrometry), free fatty acids (FFA), phospholipid transfer protein (PLTP) activity and adiponectin were measured in 79 adult non-smoking T2DM subjects (HbA1c 51 ± 8 mmol/mol, no use of insulin or lipid lowering drugs), and in 89 non-smoking subjects without T2DM. Plasma free thiols were univariately correlated with glucose (r = 0.196, p < 0.05), but were not decreased in T2DM subjects versus non-diabetic subjects (p = 0.31). Free thiols were higher in subjects with (663 ± 84 µmol/L) versus subjects without elevated triglycerides (619 ± 91 µmol/L; p = 0.002). Age- and sex-adjusted multivariable linear regression analysis demonstrated that plasma triglycerides were positively and independently associated with free thiols (β = 0.215, p = 0.004), FFA (β = 0.168, p = 0.029) and PLTP activity (β = 0.228, p = 0.002), inversely with adiponectin (β = −0.308, p < 0.001) but not with glucose (β = 0.052, p = 0.51). Notably, the positive association of free thiols with (elevated) triglycerides appeared to be particularly evident in men. Additionally, large VLDL were independently associated with free thiols (β = 0.188, p = 0.029). In conclusion, circulating free thiols are not decreased in this cohort of non-smoking and generally well-controlled T2DM subjects. Paradoxically, higher triglycerides and more large VLDL particles are likely associated with higher plasma levels of thiols, reflecting lower systemic oxidative stress.

Phospholipid transfer protein (PLTP) deficiency attenuates high fat diet induced obesity and insulin resistance

Increased phospholipid transfer protein (PLTP) activity has been found to be associated with obesity, and metabolic syndrome in humans. However, whether or not PLTP has a direct effect on insulin sensitivity and obesity is largely unknown. Here we analyzed the effect by using PLTP knockout (PLTP−/−) mouse model. Although, PLTP−/− mice have normal body-weight-gain under chow diet, these mice were protected from high-fat-diet-induced obesity and insulin resistance, compared with wild type mice. In order to understand the mechanism, we evaluated insulin receptor and Akt activation and found that PLTP deficiency significantly enhanced phosphorylated insulin receptor and Akt levels in high-fat-diet fed mouse livers, adipose tissues, and muscles after insulin stimulation, while total Akt and insulin receptor levels were unchanged. Moreover, we found that the PLTP deficiency induced significantly more GLUT4 protein in the plasma membranes of adipocytes and muscle cells after insulin stimulation. Finally, we found that PLTP-deficient hepatocytes had less sphingomyelins and free cholesterols in the lipid rafts and plasma membranes than that of controls and this may provide a molecular basis for PLTP deficiency-mediated increase in insulin sensitivity. We have concluded that PLTP deficiency leads to an improvement in tissue and whole-body insulin sensitivity through modulating lipid levels in the plasma membrane, especially in the lipid rafts.

Phospholipid transfer protein and alpha-1 antitrypsin regulate Hck kinase activity during neutrophil degranulation

Excessive neutrophil degranulation is a common feature of many inflammatory disorders, including alpha-1 antitrypsin (AAT) deficiency. Our group has demonstrated that phospholipid transfer protein (PLTP) prevents neutrophil degranulation but serine proteases, which AAT inhibits, cleave PLTP in diseased airways. We propose to identify if airway PLTP activity can be restored by AAT augmentation therapy and how PLTP subdues degranulation of neutrophils in AAT deficient subjects. Airway PLTP activity was lower in AAT deficient patients but elevated in the airways of patients on augmentation therapy. Functional AAT protein (from PiMM homozygotes) prevented PLTP cleavage unlike its mutated ZZ variant (PiZZ). PLTP lowered leukotriene B4 induced degranulation of primary, secondary and tertiary granules from neutrophils from both groups (n = 14/group). Neutrophils isolated from Pltp knockout mice have enhance neutrophil degranulation. Both AAT and PLTP reduced neutrophil degranulation and superoxide production, possibly though their inhibition of the Src tyrosine kinase, Hck. Src kinase inhibitors saracatinib and dasatinib reduced neutrophil degranulation and superoxide production. Therefore, AAT protects PLTP from proteolytic cleavage and both AAT and PLTP mediate degranulation, possibly via Hck tyrosine kinase inhibition. Deficiency of AAT could contribute to reduced lung PLTP activity and elevated neutrophil signaling associated with lung disease.

Salivary biomarkers in association with periodontal parameters and the periodontitis risk haplotype

Genetic factors play a role in periodontitis. Here we examined whether the risk haplotype of MHC class III region BAT1-NFKBIL1-LTA and lymphotoxin-α polymorphisms associate with salivary biomarkers of periodontal disease. A total of 455 individuals with detailed clinical and radiographic periodontal health data were included in the study. A 610 K genotyping chip and a Sequenom platform were used in genotyping analyses. Phospholipid transfer protein activity, concentrations of lymphotoxin-α, IL-8 and myeloperoxidase, and a cumulative risk score (combining Porphyromonas gingivalis, IL-1β and matrix metalloproteinase-8) were examined in saliva samples. Elevated IL-8 and myeloperoxidase concentrations and cumulative risk scores associated with advanced tooth loss, deepened periodontal pockets and signs of periodontal inflammation. In multiple logistic regression models adjusted for periodontal parameters and risk factors, myeloperoxidase concentration (odds ratio (OR); 1.37, P = 0.007) associated with increased odds for having the risk haplotype and lymphotoxin-α concentration with its genetic variants rs2857708, rs2009658 and rs2844482. In conclusion, salivary levels of IL-8, myeloperoxidase and cumulative risk scores associate with periodontal inflammation and tissue destruction, while those of myeloperoxidase and lymphotoxin-α associate with genetic factors as well.

Plasma lecithin:cholesterol acyltransferase and phospholipid transfer protein activity independently associate with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent condition which contributes to atherogenic apolipoprotein B dyslipoproteinemias. Lecithin:cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) are both synthesized by the liver and are important in lipid metabolism. Here, we interrogated the impact of NAFLD on plasma LCAT and PLTP activities. Plasma LCAT activity (exogenous substrate assay) and PLTP activity (phospholipid vesicles-HDL assay) were determined in 348 subjects (279 men; 81 subjects with type 2 diabetes (T2DM); 123 with metabolic syndrome (MetS)). A Fatty Liver Index (FLI) ≥60 was used as a proxy of NAFLD. Insulin resistance was determined by homoeostasis model assessment (HOMA-IR). A total of 147 participants had an FLI ≥60 coinciding with T2DM and MetS (P<0.001 for each). Plasma LCAT activity and PLTP activity were on average 12% and 5% higher, respectively, in subjects with an FLI≥60 (P<0.001 for each). In age- and sex-adjusted partial linear regression analysis, LCAT activity and PLTP activity were positively related to various obesity measures and HOMA-IR (P<0.001 for each). In multivariable linear regression analyses adjusted for age and sex, LCAT activity was associated with an FLI≥60 independent of T2DM and MetS, the waist/hip ratio, or HOMA-IR (β=0.307 to 0.366, P<0001 for all models). PLTP activity was also associated with an FLI≥60 independent of these variables (β=0.151 to 0223, P=0.013 to 0.001). NAFLD, as inferred from an FLI≥60, confers higher plasma LCAT and to a lesser extent PLTP activity, even when taking account of T2DM, MetS, central obesity and insulin resistance.

Plasma angiopoietin-like 4 is related to phospholipid transfer protein activity in diabetic and non-diabetic subjects: role of enhanced low grade inflammation

BackgroundAngiopoietin-like 4 (ANGPTL4) inhibits lipoprotein lipase, whereas phospholipid transfer protein (PLTP) enhances hepatic triglyceride secretion. Both factors may be upregulated by inflammatory pathways. Since the extent to which these circulating factors are interrelated is unknown, we determined the relationship between plasma ANGPTL4 and PLTP activity, and assessed whether such a relationship could be explained by high sensitivity C-reactive protein (hsCRP) levels as a marker of low-grade chronic inflammation.MethodsFasting plasma ANGPTL4, PLTP activity (liposome-vesicle high density lipoprotein system) and hsCRP were measured in 41 type 2 diabetic (T2DM) subjects and 36 non-diabetic subjects.ResultsPlasma ANGPTL4 and PLTP activity were increased in T2DM (p < 0.001 for each), coinciding with elevated hsCRP, triglycerides and non-esterified fatty acids (NEFA) (p = 0.031 to 0.001). In univariate analysis, ANGTLP4 was correlated with PLTP activity (Rs = 0.309, p = 0.006), whereas both factors were related to hsCRP and NEFA levels (Rs = 0.304 to 0.411, p < 0.01 to < 0.001). In multivariable linear regression analysis adjusting for age, sex, glucose, total cholesterol, triglycerides and NEFA, ANGPTL4 and PLTP activity each remained positively associated with hsCRP (β = 0.315, p = 0.003 and β = 0.299, p = 0.034, respectively). Plasma ANGPTL4 remained positively associated with PLTP activity when taking account of age, sex, glucose, total cholesterol, triglycerides and NEFA (β = 0.315, p = 0.003). Notably, this association disappeared after further adjustment for hsCRP (β = 0.131, p = 0.25).ConclusionsIn conclusion, plasma ANGPTL4 and PLTP activity are interrelated, which may at least in part be explained by low-grade chronic inflammation. A pro-inflammatory state could affect triglyceride metabolism via concerted effects on ANGPTL4 and PLTP.

PhosphoLipid transfer protein (PLTP) exerts a direct pro-inflammatory effect on rheumatoid arthritis (RA) fibroblasts-like-synoviocytes (FLS) independently of its lipid transfer activity.

Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with modification of lipids profile and an increased risk of cardiovascular events related to inflammation. Plasma phospholipid transfer protein (PLTP) exerts a lipid transfer activity through its active form. PLTP can also bind to receptors such as ATP-binding cassette transporter A1 (ABCA1). In addition to its role in lipoprotein metabolism and atherosclerosis, the latest advances came in support of a complex role of PLTP in the regulation of the inflammatory response, both with pro-inflammatory or anti-inflammatory properties. The aim of the present study was to decipher the role of PLTP in joint inflammation and to assess its relevance in the context of RA. PLTP expression was examined by western-blot and by immunochemistry. ABCA1 expression was analyzed by flow cytometry. Lipid transfer activity of PLTP and pro-inflammatory cytokines were measured in sera and synovial fluid (SF) from RA patients and controls (healthy subjects or osteoarthritis patients [OA]). FLS were treated with both lipid-transfer active form and inactive form of recombinant human PLTP. IL-8, IL-6, VEGF and MMP3 produced by FLS were assessed by ELISA, and proliferation by measuring 3H-Thymidine incorporation. RA synovial tissues showed higher PLTP staining than OA and PLTP protein levels were also significantly higher in RA-FLS. In addition, RA, unlike OA patients, displayed elevated levels of PLTP activity in SF, which correlated with pro-inflammatory cytokines. Both lipid-transfer active and inactive forms of PLTP significantly increased the production of cytokines and proliferation of FLS. ABCA1 was expressed on RAFLS and PLTP activated STAT3 pathway. To conclude, PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation and FLS proliferation, independently of its lipid transfer activity. These results suggest a pro-inflammatory role for PLTP in RA.

ANGPTL3 serum concentration and rare genetic variants in Finnish population

Genetic variants of angiopoietin-like protein 3 (ANGPTL3) are associated with serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) concentration in GWASs. ANGPTL3 deficiency causes declined TG, total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) serum concentration, a phenotype defined as familial combined hypolipidaemia (FHBL2). Our aim is to establish whether ANGPTL3 serum protein concentration correlates with lipoproteins and lipids in hyper- or hypolipidaemic subjects, and whether ANGPTL3 sequence variants are associated with untypical lipid profiles. Additionally, 10 subjects with very low lipoprotein concentrations were sequenced for ANGPTL3 for possible loss-of-function (LOF) variants. Study subjects were selected from Finnish FINRISK and Health 2000 surveys. ANGPTL protein concentrations were measured by ELISA method. As a result, ANGPTL3 serum concentration correlated positively with age, phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) activities, but not with any of the lipid or lifestyle attributes. No ANGPTL3 variants were found among sequenced samples. Subjects who carried ANGPTL3 sequence variants rs12563308 (n = 4) and rs199772471 (n = 1) had abnormally high TC and LDL-C concentrations. Whole exome sequencing data of these five subjects were further analyzed for rare and deleterious missense variants in genes associated with cholesterol metabolism. In conclusion, ANGPTL3 serum protein concentration did not predict lipid concentrations, unlike apolipoprotein C-III (apoC-III) which positively correlated with most of the lipid attributes. ANGPTL3 variant screen yielded five carriers with abnormally high TC concentration; the actual genetic causality, however, could not be verified.

Capsaicin Supplementation Improved Risk Factors of Coronary Heart Disease in Individuals with Low HDL-C Levels.

Low high-density lipoprotein cholesterol (HDL-C) is associated with an increased risk of coronary heart disease (CHD). This study aimed to evaluate the effects of capsaicin intervention on the serum lipid profile in adults with low HDL-C. In a randomized, double-blind, controlled clinical trial, 42 eligible subjects were randomly assigned to the capsaicin (n = 21, 4 mg of capsaicin daily) or to the control group (n = 21, 0.05 mg of capsaicin daily) and consumed two capsaicin or control capsules, which contained the powder of the skin of different peppers, twice daily for three months. Thirty-five subjects completed the trial (18 in the capsaicin group and 17 in the control group). The baseline characteristics were similar between the two groups. Compared with the control group, fasting serum HDL-C levels significantly increased to 1.00 ± 0.13 mmol/L from 0.92 ± 0.13 mmol/L in the capsaicin group (p = 0.030), while levels of triglycerides and C-reactive protein and phospholipid transfer protein activity moderately decreased (all p < 0.05). Other lipids, apolipoproteins, glucose, and other parameters did not significantly change. In conclusion, capsaicin improved risk factors of CHD in individuals with low HDL-C and may contribute to the prevention and treatment of CHD.

Overexpression and deletion of phospholipid transfer protein reduce HDL mass and cholesterol efflux capacity but not macrophage reverse cholesterol transport

Phospholipid transfer protein (PLTP) may affect macrophage reverse cholesterol transport (mRCT) through its role in the metabolism of HDL. Ex vivo cholesterol efflux capacity and in vivo mRCT were assessed in PLTP deletion and PLTP overexpression mice. PLTP deletion mice had reduced HDL mass and cholesterol efflux capacity, but unchanged in vivo mRCT. To directly compare the effects of PLTP overexpression and deletion on mRCT, human PLTP was overexpressed in the liver of wild-type animals using an adeno-associated viral (AAV) vector, and control and PLTP deletion animals were injected with AAV-null. PLTP overexpression and deletion reduced plasma HDL mass and cholesterol efflux capacity. Both substantially decreased ABCA1-independent cholesterol efflux, whereas ABCA1-dependent cholesterol efflux remained the same or increased, even though preβ HDL levels were lower. Neither PLTP overexpression nor deletion affected excretion of macrophage-derived radiocholesterol in the in vivo mRCT assay. The ex vivo and in vivo assays were modified to gauge the rate of cholesterol efflux from macrophages to plasma. PLTP activity did not affect this metric. Thus, deviations in PLTP activity from the wild-type level reduce HDL mass and ex vivo cholesterol efflux capacity, but not the rate of macrophage cholesterol efflux to plasma or in vivo mRCT.

Serum Lipid Transfer Proteins in Hypothyreotic Patients Are Inversely Correlated with Thyroid-Stimulating Hormone (TSH) Levels.

BackgroundPlasma cholesteryl ester transfer protein (CETP) activity is often decreased in patients with hypothyroidism, whereas less is known about the phospholipid transfer protein (PLTP). We aimed to evaluate simultaneously serum CETP and PLTP activity in patients diagnosed with hypothyroidism.Material/MethodsThe selection criteria for control group members (without thyroid dysfunction) in this case to case study were levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides similar to those in study group patients (101 patients diagnosed with hypothyroidism). Serum CETP and PLTP activities were measured by homogenous fluorometric assays using synthetic donor particle substrates.ResultsSerum CETP and PLTP activities in hypothyreotic patients were lower (p<0.001) compared with those in healthy subjects. This lowering was associated with significant changes in HDL-C subclasses: decrease in HDL2- and increase in HDL3 cholesterol levels. Multiple linear regression analyses adjusted for age, sex, body mass index, smoking habits, and alcohol drinking showed a strong association between hypothyroidism and activity of lipid transfer proteins. A linear inverse relationship between thyroid-stimulating hormone (TSH) and CETP (r=−0.21; p<0.01) and between TSH and PLTP (r=−0.24; p<0.001) was shown. There also was a positive correlation (p<0.001) between CETP and HDL2 cholesterol (r=0.27) and between PLTP and HDL2 cholesterol (r=0.37). A negative correlation between CETP and HDL3 cholesterol (r=−0.22: p<0.01) and between PLTP and HDL3 cholesterol (r=−0.24; p<0.001) has been demonstrated as well.ConclusionsThe decreased HDL2 and increased HDL3 cholesterol levels in subjects with hypothyroidism are consequences of decreased activity of lipid transfer proteins. These changes are early symptoms of lipid disturbances in hypothyroidism.

Overexpressed PLTP in macrophage may promote cholesterol accumulation by prolonged endoplasmic reticulum stress

It is well known that phospholipid transfer protein (PLTP) is involved in the lipid metabolism and development of atherosclerosis (AS). Abundant PLTP is considered to be expressed on the foam cells derived from monocyte/macrophages in atherosclerotic plaques, suggesting that high level of active PLTP may promote the formation of foam cells. However, the exact role of PLTP on the process of macrophage derived foam cell formation remains unclear. The accumulation of free cholesterol (FC) in the cytoplasm may lead to the prolonged endoplasmic reticulum stress (ERs) and the imbalance of intracellular cholesterol homeostasis. Different PLTP level definitely alternates the phospholipids (PL) and cholesterol level in plasma, strongly suggesting that active PLTP may change the level of FC and PL intracellularly, which subsequently induced the ERs in macrophage. Thus, we hypothesize that high level of PLTP may promote the accumulation of cholesterol in macrophage via the alteration ratio of FC to PL. Therefore, validating this hypothesis may clarify the role of PLTP in macrophage ERs in AS and also raise a novel strategy in the regression of AS plaques via restoring intracellular membrane lipid homeostasis and attenuating ERs.

Plasma phospholipid transfer protein activity is inversely associated with betaine in diabetic and non-diabetic subjects.

BackgroundThe choline metabolite, betaine, plays a role in lipid metabolism, and may predict the development of cardiovascular disease and type 2 diabetes mellitus (T2DM). Phospholipid transfer protein (PLTP) and lecithin:cholesterol acyltransferase (LCAT) require phosphatidylcholine as substrate, raising the possibility that there is an intricate relationship of these protein factors with choline metabolism. Here we determined the relationships of PLTP and LCAT activity with betaine in subjects with and without T2DM.MethodsPlasma betaine (nuclear magnetic resonance spectroscopy), PLTP activity (liposome-vesicle HDL system), LCAT activity (exogenous substrate assay) and (apo)lipoproteins were measured in 65 type 2 diabetic (T2DM) and in 55 non-diabetic subjects.ResultsPLTP and LCAT activity were elevated in T2DM (p < 0.05), whereas the difference in betaine was not significant. In age-, sex- and diabetes status-controlled correlation analysis, betaine was inversely correlated with triglycerides and positively with HDL cholesterol (p < 0.05 to 0.01). PLTP and LCAT activity were positively correlated with triglycerides and inversely with HDL cholesterol (p < 0.05 to 0.001). PLTP (r = −0.245, p = 0.006) and LCAT activity (r = −0.195, p = 0.035) were correlated inversely with betaine. The inverse association of PLTP activity with betaine remained significant after additional adjustment for body mass index and lipoprotein variables (β = −0.179, p = 0.034), whereas its association with LCAT activity lost significance (β = −0.056, p = 0.44).ConclusionsBetaine may influence lipoprotein metabolism via an effect on PLTP activity.