Boudewijn Klop

Dyslipidemia in Obesity: Mechanisms and Potential Targets

Obesity has become a major worldwide health problem. In every single country in the world, the incidence of obesity is rising continuously and therefore, the associated morbidity, mortality and both medical and economical costs are expected to increase as well. The majority of these complications are related to co-morbid conditions that include coronary artery disease, hypertension, type 2 diabetes mellitus, respiratory disorders and dyslipidemia. Obesity increases cardiovascular risk through risk factors such as increased fasting plasma triglycerides, high LDL cholesterol, low HDL cholesterol, elevated blood glucose and insulin levels and high blood pressure. Novel lipid dependent, metabolic risk factors associated to obesity are the presence of the small dense LDL phenotype, postprandial hyperlipidemia with accumulation of atherogenic remnants and hepatic overproduction of apoB containing lipoproteins. All these lipid abnormalities are typical features of the metabolic syndrome and may be associated to a pro-inflammatory gradient which in part may originate in the adipose tissue itself and directly affect the endothelium. An important link between obesity, the metabolic syndrome and dyslipidemia, seems to be the development of insulin resistance in peripheral tissues leading to an enhanced hepatic flux of fatty acids from dietary sources, intravascular lipolysis and from adipose tissue resistant to the antilipolytic effects of insulin. The current review will focus on these aspects of lipid metabolism in obesity and potential interventions to treat the obesity related dyslipidemia.

Erythrocyte-Bound Apolipoprotein B in Relation to Atherosclerosis, Serum Lipids and ABO Blood Group

Introduction Erythrocytes carry apolipoprotein B on their membrane, but the determining factors of erythrocyte-bound apolipoprotein B (ery-apoB) are unknown. We aimed to explore the determinants of ery-apoB to gain more insight into potential mechanisms. Methods Subjects with and without CVD were included (N = 398). Ery-apoB was measured on fresh whole blood samples using flow cytometry. Subjects with ery-apoB levels ≤0.20 a.u. were considered deficient. Carotid intima media thickness (CIMT) was determined as a measure of (subclinical) atherosclerosis. Results Mean ery-apoB value was 23.2% lower in subjects with increased CIMT (0.80±0.09 mm, N = 140) compared to subjects with a normal CIMT (0.57±0.08 mm, N = 258) (P = 0.007, adjusted P<0.001). CIMT and ery-apoB were inversely correlated (Spearman’s r: –0.116, P = 0.021). A total of 55 subjects (13.6%) were considered ery-apoB deficient, which was associated with a medical history of CVD (OR: 1.86, 95% CI 1.04–3.33; adjusted OR: 1.55; 95% CI 0.85–2.82). Discontinuation of statins in 54 subjects did not influence ery-apoB values despite a 58.4% increase in serum apolipoprotein B. Subjects with blood group O had significantly higher ery-apoB values (1.56±0.94 a.u.) when compared to subjects with blood group A (0.89±1.15 a.u), blood group B (0.73±0.1.12 a.u.) or blood group AB (0.69±0.69 a.u.) (P-ANOVA = 0.002). Conclusion Absence or very low values of ery-apoB are associated with clinical and subclinical atherosclerosis. While serum apolipoprotein B is not associated with ery-apoB, the ABO blood group seems to be a significant determinant.

Postprandial Inflammation: Targeting Glucose and Lipids

Many risk factors have been identified as being responsible for the process of atherogenesis. Several of these risk factors are related to inflammation, which is an obligatory feature of the atherosclerotic plaque. Increasing evidence suggests that postprandial lipoproteins and glucose may be involved in the inflammatory process preceding the development of atherosclerosis. During the postprandial situation, remnants of chylomicrons and very low-density lipoproteins bind to circulating leukocytes and endothelial cells, leading to a state of acute activation with the expression of integrins on different cells, the generation of oxidative stress, production of cytokines and complement activation. Elevated plasma glucose levels may also induce leukocyte activation in humans. In addition, advanced glycation end products, formed during hyperglycemia, cause inflammation and endothelial damage. This chain of events results in a situation of acute inflammation causing endothelial dysfunction, which may be one of the earliest defects in atherogenesis. Interestingly, while this may occur several times each day after each meal, there is only limited information on the contribution of different nutrients on the postprandial inflammatory processes. In this review, we will focus on the available evidence and we will discuss the role of lifestyle and pharmaceutical interventions in modulating postprandial inflammation.

Glucose-dependent leukocyte activation in patients with type 2 diabetes mellitus, familial combined hyperlipidemia and healthy controls

BACKGROUND Leukocyte activation has been associated with vascular complications in type 2 diabetes mellitus (T2DM). Hyperglycemia may be involved in this leukocyte activation. Our aim was to investigate the role of elevated glucose concentrations on leukocyte activation in patients with a wide range of insulin sensitivity. METHODS Leukocyte activation was determined after ingestion of 75 gram glucose in subjects with T2DM, familial combined hyperlipidemia (FCH) and healthy controls. Leukocyte activation markers were measured by flow cytometry. Postprandial changes were calculated as the area under the curve (AUC), and the incremental area under the curve corrected for baseline values (dAUC). RESULTS 51 Subjects (20 T2DM, 17 FCH and 14 controls) were included. Fasting neutrophil CD66b expression and CD66b-AUC were respectively 36% and 39% higher in T2DM patients than in controls (p=0.004 and p=0.003). Fasting neutrophil CD66b expression correlated positively with glucose-AUC (Spearmans rho 0.481, p<0.001) and HbA1c (rho 0.433, p=0.002). Although fasting monocyte CD11b expression was not significantly different between subjects, monocyte CD11b-AUC was 26% higher in T2DM than in controls (p=0.006). Similar trends were observed for FCH patients. Monocyte CD11b-dAUC correlated positively with glucose-AUC (rho 0.322, p=0.022) and HbA1c (rho 0.319, p=0.023). CONCLUSIONS These data suggest that both acute and chronic hyperglycemia, associated with insulin resistance as seen in T2DM and FCH, are involved in the increased fasting and postprandial leukocyte activation observed in these conditions.

The use of the non-fasting lipid profile for lipid-lowering therapy in clinical practice – Point of view

Current guidelines for the management of dyslipidaemias recommend measuring lipid profiles in the fasting state. The primary lipid targets are traditionally plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. However, triglycerides, apolipoprotein (apo) B and non-high-density lipoprotein-cholesterol (non-HDL-C) are also suitable parameters to assess cardiovascular risk and to guide lipid-lowering therapy. The advantage of the use of these variables is that they can be used in both the fasting and non-fasting state. In most cases, postprandial lipid profiles in combination with apo B are as useful as fasting lipid profiles for the differentiation between familial lipid disorders, such as heterozygous familial hypercholesterolemia, familial combined hyperlipidemia and familial hypertriglyceridemia. This article will address the interpretation, applications and limitations of a non-fasting lipid profile for daily clinical practice.

The postprandial situation as a pro-inflammatory condition

Postprandial lipemia has been associated with cardiovascular disease. The current pathophysiological concept is that postprandial remnant lipoproteins migrate into the subendothelial space and that remnants activate circulating leukocytes and endothelial cells. Activated monocytes adhere to endothelial adhesion molecules, facilitating subendothelial migration of monocytes. These cells differentiate into macrophages, with the risk of foam cell formation, due to uptake of remnants and modified lipoproteins. Evidence is emerging that specific interventions may reduce the atherogenic postprandial inflammation. Fruits rich in polyphenols, virgin olive oil, carotenoids and exercise have recently been found to reduce postprandial inflammation. Pharmaceutical interventions with fibrates or statins not only improve the overall lipid profile, but reduce postprandial inflammation as well. This review will deal with the current concept of postprandial inflammation in relation to the development of atherosclerosis and potential interventions to reduce postprandial inflammation.

Erythrocyte-associated apolipoprotein B and its relationship with clinical and subclinical atherosclerosis

Eur J Clin Invest 2012; 42 (4): 365–370

Daytime triglyceride variability in men and women with different levels of triglyceridemia

BACKGROUND Triglyceride (TG) levels measured in either the fasting or non-fasting state predict the risk of cardiovascular disease (CVD). Since CVD risk assessment is affected by variability in TG, the aim of the study was to investigate intra-individual variability of non-fasting TG. METHODS Capillary triglyceride (cTG) levels were measured in 246 free-living individuals at six time-points during the day on three separate occasions. Intra-individual variability in cTG was assessed by calculating the standard deviation of three measures at each time-point. Subjects were analyzed by gender and by fasting TG level. RESULTS In the fasting state, intra-individual variability was similar in males and females (0.28 and 0.35 mmol/l, respectively), but increased significantly in male but not in female subjects during the day, i.e., 0.28 to 0.69, and 0.35 to 0.36 mmol/l, resp. Subjects with higher fasting TG levels had greater absolute variability in both fasting and non-fasting TG. CONCLUSIONS The variability in non-fasting TG is greater in males and in individuals with higher levels of TG. Since greatest variability in non-fasting TG occurs very late in the day, it is unlikely to affect the assessment of CVD risk, which is based on a blood sample taken during daylight hours.

Effects of Metformin on the Regulation of Free Fatty Acids in Insulin Resistance: A Double-Blind, Placebo-Controlled Study

Introduction. Impaired free fatty acid (FFA) metabolism is closely linked to insulin resistance. Our aim was to evaluate plasma FFA changes in insulin resistance in a physiological situation after improvement of insulin sensitivity by metformin. Methods. A double-blind, placebo-controlled intervention with metformin was carried out in patients with insulin resistance. Nineteen patients were randomized to receive metformin 850 mg b.i.d. during 6 weeks or placebo. Participants underwent a mental stress test and an oral glucose tolerance test (OGTT) before and after treatment. Results. Fasting plasma glucose, FFA, and HOMA-IR tended to decrease after metformin, suggesting improved insulin sensitivity. FFA concentrations during the mental stress test showed a similar pattern after metformin, albeit lower at all time points, in contrast to the placebo group. The decrease in fasting plasma FFAs was positively associated to the decrease in HbA1c (r = 0.70; P = 0.03) and in fasting glucose (r = 0.74; P = 0.01). The suppression of plasma FFAs during OGTT did not change by metformin or placebo. Conclusion. Metformin in insulin resistance did not lead to improved FFA dynamics despite a trend of improved insulin sensitivity. Metformin most likely decreases plasma FFAs mainly by suppressing fasting FFA concentrations and not by suppression of acute stress-induced lipolysis.

Chylomicrons: A Key Biomarker and Risk Factor for Cardiovascular Disease and for the Understanding of Obesity

Cardiovascular disease can be considered a condition of chronic low-grade inflammation. Postprandial hyperlipidemia and obesity can both exacerbate inflammatory processes. Postprandial lipemia stimulates the activation of leukocytes, the production of chemokines, and activation of the complement system. Obesity is also associated with postprandial hyperlipidemia by hepatic overproduction of very low-density lipoprotein (VLDL) and consequently delayed clearance of intestinally derived chylomicrons due to competition for the same metabolic pathways. Insulin resistance is one of the key elements leading to hepatic VLDL overproduction and is also a key factor in the generation of inflammation. These metabolic derangements cause accumulation of atherogenic remnant lipoproteins, which is also a proatherogenic mechanism. Change in lifestyle is the most important therapeutic strategy to stop this vicious circle of postprandial hyperlipidemia, obesity, inflammation, insulin resistance, and cardiovascular disease.