Lipid and lipoprotein profile in HIV-infected patients treated with lopinavir/ritonavir as a component of the first combination antiretroviral therapy

We characterized lipid and lipoprotein changes associated with a lopinavir/ritonavir-containing regimen. We enrolled previously antiretroviral-naive patients participating in the Swiss HIV Cohort Study. Fasting blood samples (baseline) were retrieved retrospectively from stored frozen plasma and posttreatment (follow-up) samples were collected prospectively at two separate visits. Lipids and lipoproteins were analyzed at a single reference laboratory. Sixty-five patients had two posttreatment lipid profile measurements and nine had only one. Most of the measured lipids and lipoprotein plasma concentrations increased on lopinavir/ritonavir-based treatment. The percentage of patients with hypertriglyceridemia (TG >150?mg/dl) increased from 28/74 (38%) at baseline to 37/65 (57%) at the second follow-up. We did not find any correlation between lopinavir plasma levels and the concentration of triglycerides. There was weak evidence of an increase in small dense LDL-apoB during the first year of treatment but not beyond 1 year (odds ratio 4.5, 90% CI 0.7 to 29 and 0.9, 90% CI 0.5 to 1.5, respectively). However, 69% of our patients still had undetectable small dense LDL-apoB levels while on treatment. LDL-cholesterol increased by a mean of 17?mg/dl (90% CI -3 to 37) during the first year of treatment, but mean values remained below the cut-off for therapeutic intervention. Despite an increase in the majority of measured lipids and lipoproteins particularly in the first year after initiation, we could not detect an obvious increase of cardiovascular risk resulting from the observed lipid changes.

Plasma leptin and mRNA expression of lipogenesis and lipolysis-related factors in bovine adipose tissue around parturition

The objective was to study changes in plasma leptin concentration parallel to changes in the gene expression of lipogenic- and lipolytic-related genes in adipose tissue of dairy cows around parturition. Subcutaneous fat biopsies were taken from 27 dairy cows in week 8 antepartum (a.p.), on day 1 postpartum (p.p.) and in week 5 p.p. Blood samples were assayed for concentrations of leptin and non-esterified fatty acids (NEFA). Subcutaneous adipose tissue was analysed for mRNA abundance by real-time qRT-PCR encoding for leptin, adiponectin receptor 1 (AdipoR1), adiponectin receptor 2 (AdipoR2), hormones-sensitive lipase (HSL), perilipin (PLIN), lipoprotein lipase (LPL), acyl-CoA synthase long-chain family member 1 (ACSL1), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN) and glycerol-3-phosphate dehydrogenase 2 (GPD2). Body weight and body condition score of the cows were lower after parturition than before parturition. The calculated energy balance was negative in week 1 and 5 p.p., with higher negative energy balance in week 1 p.p. compared with that in week 5 p.p. On day 1 p.p., highest concentrations of NEFA (353.3 mumol/l) were detected compared with the other biopsy time-points (210.6 and 107.7 mumol/l, in week 8 a.p., and week 5 p.p. respectively). Reduced plasma concentrations of leptin during p.p. when compared with a.p. would favour increasing metabolic efficiency and energy conservation for mammary function and reconstitution of body reserves. Lower mRNA abundance of ACC and FASN expression on day 1 p.p. compared with other biopsy time-points suggests an attenuation of fatty acid synthesis in subcutaneous adipose tissue shortly after parturition. Gene expression of AdipoR1, AdipoR2, HSL, PLIN, LPL, ACSL1 and GPD2 was unchanged over time.

Mass spectrometry-based analytical tools for the molecular protein characterization of human plasma lipoproteins

Lipoproteins are a heterogeneous population of blood plasma particles composed of apolipoproteins and lipids. Lipoproteins transport exogenous and endogenous triglycerides and cholesterol from sites of absorption and formation to sites of storage and usage. Three major classes of lipoproteins are distinguished according to their density: high-density (HDL), low-density (LDL) and very low-density lipoproteins (VLDL). While HDLs contain mainly apolipoproteins of lower molecular weight, the two other classes contain apolipoprotein B and apolipoprotein (a) together with triglycerides and cholesterol. HDL concentrations were found to be inversely related to coronary heart disease and LDL/VLDL concentrations directly related. Although many studies have been published in this area, few have concentrated on the exact protein composition of lipoprotein particles. Lipoproteins were separated by density gradient ultracentrifugation into different subclasses. Native gel electrophoresis revealed different gel migration behaviour of the particles, with less dense particles having higher apparent hydrodynamic radii than denser particles. Apolipoprotein composition profiles were measured by matrix-assisted laser desorption/ionization-mass spectrometry on a macromizer instrument, equipped with the recently introduced cryodetector technology, and revealed differences in apolipoprotein composition between HDL subclasses. By combining these profiles with protein identifications from native and denaturing polyacrylamide gels by liquid chromatography-tandem mass spectrometry, we characterized comprehensively the exact protein composition of different lipoprotein particles. We concluded that the differential display of protein weight information acquired by macromizer mass spectrometry is an excellent tool for revealing structural variations of different lipoprotein particles, and hence the foundation is laid for the screening of cardiovascular disease risk factors associated with lipoproteins.

Changes in plasma lipids with psychosocial stress are related to hypertension status and the norepinephrine stress response

Hypertension is a known risk factor for cardiovascular disease. Hypertensive individuals show exaggerated norepinephrine (NE) reactivity to stress. Norepinephrine is a known lipolytic factor. It is unclear if, in hypertensive individuals, stress-induced increases in NE are linked with the elevations in stress-induced circulating lipid levels. Such a mechanism could have implications for atherosclerotic plaque formation. In a cross-sectional, quasi-experimentally controlled study, 22 hypertensive and 23 normotensive men (mean +/- SEM, 45 +/- 3 years) underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. We measured plasma NE and the plasma lipid profile (total cholesterol [TC], low-density-lipoprotein cholesterol [LDL-C], high-density-lipoprotein cholesterol, and triglycerides) immediately before and after stress and at 20 and 60 minutes of recovery. All lipid levels were corrected for stress hemoconcentration. Compared with normotensives, hypertensives had greater TC (P = .030) and LDL-C (P = .037) stress responses. Independent of each other, mean arterial pressure (MAP) upon screening and immediate increase in NE predicted immediate stress change in TC (MAP: beta = .41, P = .003; NE: beta = .35, P = .010) and LDL-C (MAP: beta = .32, P = .024; NE: beta = .38, P = .008). Mean arterial pressure alone predicted triglycerides stress change (beta = .32, P = .043) independent of NE stress change, age, and BMI. The MAP-by-NE interaction independently predicted immediate stress change of high-density-lipoprotein cholesterol (beta = -.58, P < .001) and of LDL-C (beta = -.25, P < .08). We conclude that MAP and NE stress reactivity may elicit proatherogenic changes of plasma lipids in response to acute psychosocial stress, providing one mechanism by which stress might increase cardiovascular risk in hypertension.

Effects of growth hormone (GH) replacement therapy on low-density lipoprotein apolipoprotein B100 kinetics in adult patients with GH deficiency: a stable isotope study

GH replacement therapy has been shown to improve the dyslipidemic condition in a substantial proportion of patients with adult GH deficiency. The mechanisms are not yet fully elucidated. Low-density lipoprotein (LDL) apolipoprotein B100 (apoB) formation and catabolism are important determinants of plasma cholesterol concentrations. This study examined the effect of GH replacement therapy on LDL apoB metabolism using a stable isotope turnover technique. LDL apoB kinetics was determined in 13 adult patients with GH deficiency before and after 3 months GH/placebo treatment in a randomized, double-blind, placebo-controlled study. LDL apoB (13)C-leucine enrichment was determined by isotope-ratio mass spectrometry. Plasma volume was assessed by standardized radionuclide dilution technique. GH replacement therapy significantly decreased LDL cholesterol, LDL apoB concentrations, and LDL apoB pool size compared with placebo. Compared with baseline, GH replacement therapy resulted in a significant increase in plasma volume and fractional catabolic rate, whereas LDL formation rate remained unchanged. LDL lipid content did not significantly change after GH and placebo. This study suggests that short-term GH replacement therapy decreases the LDL apoB pool by increasing removal of LDL particles without changing LDL composition or LDL apoB production rate. In addition, it is possible that the beneficial effects of GH on the cardiovascular system contribute to these findings.

Normal VLDL metabolism despite altered lipoprotein composition in type 1 diabetes mellitus

Patients with type 1 diabetes are at increased risk of cardiovascular disease, which may be related to abnormal lipid metabolism. Secretion and clearance of VLDL apolipoprotein B100 (apoB) are important determinants of plasma lipid concentrations and are known to be influenced by hormones, including insulin and growth hormone.

Effects of growth hormone (GH) replacement therapy on very low density lipoprotein apolipoprotein B100 kinetics in patients with adult GH deficiency: a stable isotope study

Patients with adult GH deficiency are often dyslipidemic and may have an increased risk of cardiovascular disease. The secretion and clearance of very low density lipoprotein apolipoprotein B 100 (VLDL apoB) are important determinants of plasma lipid concentrations. This study examined the effect of GH replacement therapy on VLDL apoB metabolism using a stable isotope turnover technique. VLDL apoB kinetics were determined in 14 adult patients with GH deficiency before and after 3 months GH or placebo treatment in a randomized double blind, placebo-controlled study using a primed constant [1-(13)C]leucine infusion. VLDL apoB enrichment was determined by gas chromatography-mass spectrometry. GH replacement therapy increased plasma insulin-like growth factor I concentrations 2.9 +/- 0.5-fold (P < 0.001), fasting insulin concentrations 1.8 +/- 0.6-fold (P < 0.04), and hemoglobin A1C from 5.0 +/- 0.2% to 5.3 +/- 0.2% (mean +/- SEM; P < 0.001). It decreased fat mass by 3.4 +/- 1.3 kg (P < 0.05) and increased lean body mass by 3.5 +/- 0.8 kg (P < 0.01). The total cholesterol concentration (P < 0.02), the low density lipoprotein cholesterol concentration (P < 0.02), and the VLDL cholesterol/VLDL apoB ratio (P < 0.005) decreased. GH therapy did not significantly change the VLDL apoB pool size, but increased the VLDL apoB secretion rate from 9.2 +/- 2.0 to 25.9 +/- 10.3 mg/kg x day (P < 0.01) and the MCR from 11.5 +/- 2.7 to 20.3 +/- 3.2 mL/min (P < 0.03). No significant changes were observed in the placebo group. This study suggests that GH replacement therapy improves lipid profile by increasing the removal of VLDL apoB. Although GH therapy stimulates VLDL apoB secretion, this is offset by the increase in the VLDL apoB clearance rate, which we postulate is due to its effects in up-regulating low density lipoprotein receptors and modifying VLDL composition.

Attributional styles and stress-related atherogenic plasma lipid reactivity in essential hypertension.

OBJECTIVE Hypertension and an atherogenic lipid profile are known risk factors for coronary heart disease (CHD). Hypertensives show greater changes in atherogenic plasma lipids to acute stress than normotensives. In this study, we investigated whether attribution of failure is associated with lipid stress reactivity in hypertensive compared with normotensive men. METHODS 18 normotensive and 17 hypertensive men (mean±SEM; 45±2.2 years) underwent an acute standardized psychosocial stress task that can be viewed as a situation of experimentally induced failure. We assessed external-stable (ES), external-variable (EV), internal-stable (IS), and internal-variable (IV) attribution of failure and psychological control variables (i.e. extent of depression and neuroticism). Moreover, total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and norepinephrine were measured immediately before and several times after stress. RESULTS ES moderated TC- and LDL-C-stress reactivity in hypertensives as compared to normotensives (interaction mean arterial pressure [MAP]-by-ES for TC: F=3.71, p=.015; for LDL-C: F=3.61, p=.016). TC and LDL-C levels were highest in hypertensives with low ES immediately after stress (p≤.039). In contrast, hypertensives with high ES did not differ from normotensives in TC and LDL-C immediately after stress (p's>.28). Controlling for norepinephrine, depression, and neuroticism in addition to age and BMI did not significantly change results. There were no significant associations between lipid baseline levels or aggregated lipid secretion and IS, IV, or EV (p's>.23). CONCLUSION Our data suggest that ES may independently protect from elevated lipid stress reactivity in hypertensive individuals. ES thus might be a protective factor against CHD in hypertension.

Circulating oxidized low-density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58-year-old men (AIR study).

OBJECTIVES Hypothetically the atherogenic effect of the metabolic syndrome may be mediated through the increased occurrence of small LDL-particles which are easily modified to atherogenic oxidized LDL (ox-LDL). The aim of this study was to test this concept by examining the association between circulating ox-LDL, LDL-particle size, and the metabolic syndrome. DESIGN AND RESULTS A population-based sample of clinically healthy 58-year-old men (n = 391) was recruited. Ox-LDL was measured by ELISA (specific monoclonal antibody, mAb-4E6) and LDL-particle size by gradient gel electrophoresis. The results showed that ox-LDL significantly correlated to factors constituting the metabolic syndrome; triglycerides (r = 0.43), plasma insulin (r = 0.20), body mass index (r = 0.20), waist-to-hip ratio (r = 0.21) and HDL (r = -0.24); (P < 0.001). Ox-LDL correlated also to LDL-particle size (r = -0.42), Apo-B (r = 0.70), LDL (r = 0.65); (P < 0.001) and, furthermore, with Apo A-1 (r = -0.13) and heart rate (r = 0.13); (P < 0.01). CONCLUSION The metabolic syndrome was accompanied by high plasma ox-LDL concentrations compared with those without the syndrome. Ox-LDL levels were associated with most of the risk factors constituting the metabolic syndrome and was, in addition related to small LDL-particle size. To our knowledge the present study is the first one to demonstrate that circulating ox-LDL levels are associated with small LDL-particle size in a population representative sample of clinically healthy middle-aged men. The high degree of intercorrelation amongst several factors makes it difficult to clarify the independent role of any specific factor.

Circulating oxidized low-density lipoprotein is associated with echolucent plaques in the femoral artery independently of hsCRP in 61-year-old men.

OBJECTIVES The aim of the study was to test the hypothesis that circulating markers of inflammation (high-sensitive C-reactive protein, hsCRP) and oxidative modification of lipids (oxidized low-density lipoprotein, oxLDL) were associated with the occurrence of echolucent rather than echogenic femoral artery plaques in a cross-sectional population based cohort of 513, 61-year-old men. BACKGROUND The relationships between circulating oxLDL, hsCRP and the occurrence of echolucent plaques in the femoral artery have not previously been investigated. METHODS The levels of circulating oxLDL and hsCRP were determined in plasma by ELISA. Plaque occurrence, size and echogenicity were measured by B-mode ultrasound in the right femoral artery. Assessment of plaque echogenicity was based on the classification (grades 1-4) proposed by Gray-Weale et al. RESULTS A higher frequency of echolucent femoral plaques was observed in subjects with the metabolic syndrome and current smokers (p=0.01 and p<0.001, respectively) as well as with increasing levels of oxLDL and hsCRP (p=0.002 and p=0.005, respectively). In a multiple logistic regression analysis oxLDL and current smokers turned out to be independent associated with the presence of echolucent femoral artery plaques. CONCLUSIONS The results of the present study support our hypothesis that circulating oxLDL is a marker of an unstable echolucent plaque phenotype in the femoral artery in man.