Rat apolipoprotein A-IV metabolism

Earlier studies by Van 't Hoeft et al. (85, 160), in our laboratory, mainly focussed upon the catabolism of HDL apolipoproteins A-I and E. They found that the kidneys were an important organ involved in the catabolism of these proteins together with the liver. The present thesis mainly deals with HDL apo A-IV. Until very recently, apo A-IV metabolism was relatively unknown. This was due to the fact that, during isolation of HDL particles by density ultracentrifugation, apo A-IV was readily "stripped" and recovered in the "bottom" fraction, together with the bulk of the serum protein. Better isolation procedures enabled us to investigate the behaviour of apo A-IV in the rat, leading to expansion of our knowledge of lipoprotein metabolism in general. The first part (Chapter 2) outlines a sensitive electroimmunoassay for the determination of apo A-I, apo E, and apo A-IV in diluted samples. This method has been successfully used to analyse the distribution of these proteins in rat mesenteric lymph (Chapter 3) and rat serum (Chapter 4), following their fractionation by molecular sieve chromatography on agarose gels. The latter procedure was employed to obviate the well known problem of particle protein stripping which occurs during ultracentrifugation (60, 86-88). Chapter 4 describes the results of a study designed to compare the effects of gel filtration and ul tracentrifugation on HDL particle composition. Chapters 5 and 6 describe our studies on the catabolic sites of apolipoprotein A-IV containing lipoproteins. The final paper (Chapter 7) describes the analysis of HDL subclasses using specific immunoprecipitation

A functional polymorphism in the glucocorticoid receptor gene and its relation to cardiovascular disease risk in familial hypercholesterolemia

Context: Individuals with the functional ER22/23EK variant in the glucocorticoid receptor gene are relatively resistant to the downstream consequences of glucocorticoids. Evidence suggests that carriers have a more favorable cardiovascular risk profile, but the relationship between this ER22/23EK variant and cardiovascular disease has not been hitherto assessed. Objective: We, therefore, determined whether carriership of the ER22/23EK improves cardiovascular disease risk in patients with severe hypercholesterolemia. Design, Setting, and Participants: In a multicenter cohort study, 2024 patients with heterozygous familial hypercholesterolemia, aged 18 yr and older, were genotyped for the ER22/23EK polymorphism. Patients were identified at lipid clinics throughout The Netherlands between 1989 and 2002. Main Outcome Measures: The primary outcome measure was cardiovascular disease. Results: Seventy-six (7.8%) of 977 men and 72 (6.9%) of 1047 women were carriers of the ER22/23EK variant. A total of 395 men and 247 women had a cardiovascular event. In contrast to expected results, we observed no significant association of the ER22/23EK variant with cardiovascular disease risk (men: relative risk, 0.75; 95% confidence interval, 0.50-1.14; P = 0.2; women: relative risk, 1.37;95%confidence interval, 0.82-2.28;P = 0.2). However, we found a significant interaction between gender and the polymorphism on cardiovascular disease (P = 0.02). Conclusions: In this large cohort of individuals with very high risk of cardiovascular disease, the association between the functional ER22/23EK polymorphism and cardiovascular risk was not significant overall, although it varied significantly by gender. Copyrigh

Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice

OBJECTIVE - The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still undergoing debate. Therefore, we evaluated the effect of human CETP expression on atherosclerosis in APOE*3-Leiden (E3L) mice with a humanized lipoprotein profile. METHODS AND RESULTS - E3L mice were crossbred with human CETP transgenic mice. On a chow diet, CETP expression increased plasma total cholesterol (TC) (+43%; P<0.05). To evaluate the effects of CETP on the development of atherosclerosis, mice were fed a Western-type diet containing 0.25% cholesterol, leading to 4.3-fold elevated TC levels in both E3L and CETP.E3L mice (P<0.01). On both diets, CETP expression shifted the distribution of cholesterol from high-density lipoprotein (HDL) toward very-low-density lipoprotein (VLDL)/low-density lipoprotein (LDL). Moreover, plasma of CETP.E3L mice had reduced capacity (-3

Fasting and postprandial remnant-like particle cholesterol concentrations in obese participants are associated with plasma triglycerides, insulin resistance, and body fat distribution

Elevated plasma concentrations of remnant-like particle cholesterol (RLP-C) are atherogenic. However, factors that determine RLP-C are not fully understood. This study evaluates which factors affect RLP-C in the fasting and postprandial state, using multiple regression analyses in a large cohort of lean and obese participants. All participants (n = 740) underwent a test meal challenge containing 95 energy % (en%) fat (energy content 50% of predicted daily resting metabolic rate). Fasting and postprandial concentrations of circulating metabolites were measured over a 3-h period. Obese participants (n = 613) also participated in a 10-wk weight loss program (-2510 kJ/d), being randomized to either a low-fat or a high-fat diet (20-25 vs. 40-45en% fat). Postprandial RLP-C was associated with fasting RLP-C, waist:hip ratio (WHR), HOMA(IR) (homeostasis model assessment index for insulin resistance) (P < 0.001), and age, independently of BMI and gender [adjusted R(2) (adj. R(2)) = 0.70). These factors were also related to fasting RLP-C (P < 0.010), along with gender and physical activity (adj. R(2) = 0.23). The dietary intervention resulted in significantly lower fasting RLP-C concentrations, independently mediated by weight loss, improvements in HOMA(IR), and the fat content of the prescribed diet. However, after inclusion of plasma triglyceride (TG), HDL-cholesterol, and FFA concentrations in the models, HOMA(IR) and WHR no longer significantly predicted fasting RLP-C, although WHR remained a predictor of postprandial RLP-C (P = 0.002). Plasma TG was strongly associated with both fasting and postprandial RLP-C (P < 0.001). In conclusion, plasma RLP-C concentrations are mainly associated with plasma TG concentrations. Interestingly, the high-fat diet was more effective at decreasing fasting RLP-C concentrations in obese participants than the low-fat diet

Plasma phospholipid transfer protein activity is decreased in type 2 diabetes during treatment with atorvastatin: A role for apolipoprotein E?

Plasma phospholipid transfer protein (PLTP) plays an important role in lipoprotein metabolism. PLTP activity is elevated in patients with diabetes, a condition with strongly elevated risk for coronary heart disease. The aim of this study was to test the hypothesis that statins reduce PLTP activity and to examine the potential role of apolipoprotein E (apoE). PLTP activity and apoE were measured in patients with type 2 diabetes from the DALI (Diabetes Atorvastatin Lipid Intervention) Study, a 30-week randomized double-blind placebo-controlled trial with atorvastatin (10 and 80 mg daily). At baseline, PLTP activity was positively correlated with waist circumference, HbA 1c, glucose, and apoE (all P < 0.05). Atorvastatin treatment resulted in decreased PLTP activity (10 mg atorvastatin: -8.3%, P < 0.05; 80 mg atorvastatin: -12.1%, P < 0.002). Plasma apoE decreased by 28 and 36%, respectively (P < 0.001). The decrease in apoE was strongly related to the decrease in PLTP activity (r = 0.565, P < 0.001). The change in apoE remained the sole determinant of the change in PLTP activity in

Acute elevation of plasma PLTP activity strongly increases pre-existing atherosclerosis

Objective - A transgenic mouse model was generated that allows conditional expression of human PLTP, based on the tetracycline-responsive gene system, to study the effects of an acute increase in plasma PLTP activity as may occur in inflammation. Methods and Results - The effects of an acute elevation of plasma PLTP activity on the metabolism of apolipoprotein B-containing lipoproteins and on diet-induced pre-existing atherosclerosis were determined in mice displaying a humanized lipoprotein profile (low-density lipoprotein receptor knockout background). Induced expression of PLTP strongly increases plasma VLDL levels in LDL receptor knockout mice, whereas VLDL secretion is not affected. The elevation in plasma triglyceride levels is explained by a PLTP-dependent inhibition of VLDL catabolism, which is caused, at least partly, by a decreased lipoprotein lipase activity. Together with the decreased plasma HDL levels, the acutely increased PLTP expression results in a highly atherogenic lipoprotein profile. Induction of PLTP expression leads to a further increase in size of pre-existing atherosclerotic lesions, even on a chow diet. In addition, the lesions contain more macrophages and less collagen relative to controls, suggesting a less stable lesion phenotype. Conclusion - In conclusion, acute elevation of PLTP activity destabilizes atherosclerotic lesions and aggravates pre-existing atherosclerosis

Gene-load score of the renin-angiotensin-aldosterone system is associated with coronary heart disease in familial hypercholesterolaemia

Aims: Familial hypercholesterolaemia (FH) is characterized by premature coronary heart disease (CHD). However, the incidence of CHD varies considerably among FH patients. Genetic variation in the renin-angiotensin-aldosterone system (RAAS) and the adrenalin/noradrenalin system may be of importance in determining the CHD risk in FH, because of their involvement in CHD. We investigated the association between CHD risk and combined genetic variation in the RAAS and adrenalin/noradrenalin system. Methods and results: In 2190 FH patients, we genotyped six RAAS polymorphisms and five adrenalin/noradrenalin polymorphisms. For each patient, we calculated two gene-load scores by counting the number of risk genotypes within each pathway. Four of the six RAAS polymorphisms and none of the polymorphisms in the adrenalin/noradrenalin system were significantly associated with CHD (P < 0.05). The RAAS gene-load score was significantly associated with CHD (Plinear trend< 0.001): in patients with a gene-load score of 5 or 6, the CHD risk was 2.3 times as high as in patients with

Fasting and postprandial remnant-like particle cholesterol concentrations in obese participants are associated with plasma triglycerides, insulin resistance, and body fat distribution

Elevated plasma concentrations of remnant-like particle cholesterol (RLP-C) are atherogenic. However, factors that determine RLP-C are not fully understood. This study evaluates which factors affect RLP-C in the fasting and postprandial state, using multiple regression analyses in a large cohort of lean and obese participants. All participants (n = 740) underwent a test meal challenge containing 95 energy % (en%) fat (energy content 50% of predicted daily resting metabolic rate). Fasting and postprandial concentrations of circulating metabolites were measured over a 3-h period. Obese participants (n = 613) also participated in a 10-wk weight loss program (-2510 kJ/d), being randomized to either a low-fat or a high-fat diet (20-25 vs. 40-45en% fat). Postprandial RLP-C was associated with fasting RLP-C, waist:hip ratio (WHR), HOMA(IR) (homeostasis model assessment index for insulin resistance) (P < 0.001), and age, independently of BMI and gender [adjusted R(2) (adj. R(2)) = 0.70). These factors were also related to fasting RLP-C (P < 0.010), along with gender and physical activity (adj. R(2) = 0.23). The dietary intervention resulted in significantly lower fasting RLP-C concentrations, independently mediated by weight loss, improvements in HOMA(IR), and the fat content of the prescribed diet. However, after inclusion of plasma triglyceride (TG), HDL-cholesterol, and FFA concentrations in the models, HOMA(IR) and WHR no longer significantly predicted fasting RLP-C, although WHR remained a predictor of postprandial RLP-C (P = 0.002). Plasma TG was strongly associated with both fasting and postprandial RLP-C (P < 0.001). In conclusion, plasma RLP-C concentrations are mainly associated with plasma TG concentrations. Interestingly, the high-fat diet was more effective at decreasing fasting RLP-C concentrations in obese participants than the low-fat diet