Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells.

UNLABELLED: The role of Kupffer cells (KCs) in the pathophysiology of the liver has been firmly established. Nevertheless, KCs have been underexplored as a target for diagnosis and treatment of liver diseases owing to the lack of noninvasive diagnostic tests. We addressed the hypothesis that cholesteryl ester transfer protein (CETP) is mainly derived from KCs and may predict KC content. Microarray analysis of liver and adipose tissue biopsies, obtained from 93 obese subjects who underwent elective bariatric surgery, showed that expression of CETP is markedly higher in liver than adipose tissue. Hepatic expression of CETP correlated strongly with that of KC markers, and CETP messenger RNA and protein colocalized specifically with KCs in human liver sections. Hepatic KC content as well as hepatic CETP expression correlated strongly with plasma CETP concentration. Mechanistic and intervention studies on the role of KCs in determining the plasma CETP concentration were performed in a transgenic (Tg) mouse model expressing human CETP. Selective elimination of KCs from the liver in CETP Tg mice virtually abolished hepatic CETP expression and largely reduced plasma CETP concentration, consequently improving the lipoprotein profile. Conversely, augmentation of KCs after Bacille-Calemette-Guérin vaccination largely increased hepatic CETP expression and plasma CETP. Also, lipid-lowering drugs fenofibrate and niacin reduced liver KC content, accompanied by reduced plasma CETP concentration. CONCLUSIONS: Plasma CETP is predominantly derived from KCs, and plasma CETP level predicts hepatic KC content in humans.

Short-term effects of a standardized glucose load on region-specific aortic pulse wave velocity assessed by MRI.

PURPOSE: To assess the short-term effects of a standardized oral glucose load on regional aortic pulse wave velocity (PWV) using two-directional in-plane velocity encoded MRI. MATERIALS AND METHODS: A randomized, controlled intervention was performed in 16 male subjects (mean ± standard deviation: age: 59±7 years, body mass index: 28±3 kg/m2) with impaired fasting glucose. The intervention consisted of an oral glucose load (75 grams of carbohydrates in 300 mL water) at 1 study day and water (300 mL) at the other study day. PWV was measured using multislice two-directional in-plane velocity-encoded MRI. RESULTS: PWV in the proximal aorta at 1 h post-glucose load decreased compared with PWV 1-h post-water (delta PWV: -1.0±2.6 m/s versus 0.6±2.0 m/s, P=0.02). Eight responding subjects showed a significant decrease in PWV of the proximal aorta after the glucose load and had a decreased waist circumference (P=0.037) compared with nonresponders, being one of the major criteria of the metabolic syndrome. There was no significant change in PWV of the distal aorta at 1 h post-load comparing both intervention groups. CONCLUSION: A standardized oral glucose load induces a decrease of the proximal, but not of the distal, aortic PWV. Regional response of aortic PWV may be associated with features of the metabolic syndrome.

Aortic stiffness is associated with white matter integrity in patients with type 1 diabetes.

OBJECTIVE: To assess the association between aortic pulse wave velocity (PWV) as a marker of arterial stiffness and diffusion tensor imaging of brain white matter integrity in patients with type 1 diabetes using advanced magnetic resonance imaging (MRI) technology. METHODS: Forty-one patients with type 1 diabetes (23 men, mean age 44 ± 12 years, mean diabetes duration 24 ± 13 years) were included. Aortic PWV was assessed using through-plane velocity-encoded MRI. Brain diffusion tensor imaging (DTI) measurements were performed on 3-T MRI. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated for white and grey matter integrity. Pearson correlation and multivariable linear regression analyses including cardiovascular risk factors as covariates were assessed. RESULTS: Multivariable linear regression analyses revealed that aortic PWV is independently associated with white matter integrity FA (ß = -0.777, p = 0.008) in patients with type 1 diabetes. This effect was independent of age, gender, mean arterial pressure, body mass index, smoking, duration of diabetes and glycated haemoglobin levels. Aortic PWV was not significantly related to grey matter integrity. CONCLUSIONS: Our data suggest that aortic stiffness is independently associated with reduced white matter integrity in patients with type 1 diabetes. KEY POINTS: Aortic stiffness is associated with brain injury. Aortic stiffness exposes small vessels to high pressure fluctuations and flow. Aortic stiffness is associated with microvascular brain injury in diabetes. This suggests a vascular contribution to early subtle microstructural deficits.

Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development.

OBJECTIVE: Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development. APPROACH AND RESULTS: Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P<0.05). In addition, Angptl4 overexpression decreased macrophage content (-41%; P<0.05) and numbers of monocytes adhering to the endothelium wall (-37%; P<0.01). Finally, plasma Angptl4 was independently and negatively associated with carotid artery sclerosis measured by 3-T MRI in subjects with metabolic syndrome and low-grade systemic inflammation. CONCLUSIONS: Angptl4 suppresses foam cell formation to reduce atherosclerosis development. Stimulation of Angptl4 in macrophages by oxidized low-density lipoprotein may protect against lipid overload.

Inflammation increases plasma angiopoietin-like protein 4 in patients with the metabolic syndrome and type 2 diabetes.

BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase and associates with dyslipidemia. The expression of ANGPTL4 is regulated by free fatty acids (FFA) that activate lipid-sensing peroxisome proliferator-activated receptors (PPARs), but FFA can also activate pattern recognition receptors including Toll-like receptor 4 (TLR4) in macrophages. OBJECTIVE: To assess whether systemic low-grade inflammation is a determinant for plasma ANGPTL4 levels in patients with the metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). DESIGN: We studied 335 male participants: healthy controls (Controls), patients with the MetS without inflammation (MetS-I) and with low-grade inflammation (MetS+I), and patients with T2DM. All patients without diabetes included in the present study were initially matched for waist circumference. In plasma, ANGPTL4, C reactive protein (CRP) and metabolic parameters were determined. Underlying mechanisms were examined using human macrophages in vitro. RESULTS: As compared with Controls, plasma ANGPTL4 levels were increased in patients with MetS-I, MetS+I, and T2DM. Furthermore, ANGPTL4 was increased in T2DM compared with MetS-I. In fact, plasma CRP correlated positively with plasma ANGPTL4. In vitro studies showed that TLR 3/4 activation largely increased the expression and release of ANGPTL4 by macrophages. CONCLUSIONS: Plasma ANGPTL4 levels in humans are predicted by CRP, a marker of inflammation, and ANGPTL4 expression by macrophages is increased by inflammatory stimuli.

Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis.

BACKGROUND: Glucose, insulin and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) are markers of insulin resistance. The objective of this study is to compare fasting glucose, fasting insulin concentrations and HOMA-IR in strength of association with incident cardiovascular disease. METHODS: We searched the PubMed, MEDLINE, EMBASE, Web of Science, ScienceDirect and Cochrane Library databases from inception to March, 2011, and screened reference lists. Cohort studies or nested case-control studies that investigated the association between fasting glucose, fasting insulin or HOMA-IR and incident cardiovascular disease, were eligible. Two investigators independently performed the article selection, data extraction and risk of bias assessment. Cardiovascular endpoints were coronary heart disease (CHD), stroke or combined cardiovascular disease. We used fixed and random-effect meta-analyses to calculate the pooled relative risk for CHD, stroke and combined cardiovascular disease, comparing high to low concentrations of glucose, insulin or HOMA-IR. Study heterogeneity was calculated with the I(2) statistic. To enable a comparison between cardiovascular disease risks for glucose, insulin and HOMA-IR, we calculated pooled relative risks per increase of one standard deviation. RESULTS: We included 65 studies (involving 516,325 participants) in this meta-analysis. In a random-effect meta-analysis the pooled relative risk of CHD (95% CI; I(2)) comparing high to low concentrations was 1.52 (1.31, 1.76; 62.4%) for glucose, 1.12 (0.92, 1.37; 41.0%) for insulin and 1.64 (1.35, 2.00; 0%) for HOMA-IR. The pooled relative risk of CHD per one standard deviation increase was 1.21 (1.13, 1.30; 64.9%) for glucose, 1.04 (0.96, 1.12; 43.0%) for insulin and 1.46 (1.26, 1.69; 0.0%) for HOMA-IR. CONCLUSIONS: The relative risk of cardiovascular disease was higher for an increase of one standard deviation in HOMA-IR compared to an increase of one standard deviation in fasting glucose or fasting insulin concentration. It may be useful to add HOMA-IR to a cardiovascular risk prediction model.

Neurocognitive function in dopamine-ß-hydroxylase deficiency.

Dopamine-ß-hydroxylase (DßH) deficiency is a rare genetic syndrome characterized by the complete absence of norepinephrine in the peripheral and the central nervous system. DßH-deficient patients suffer from several physical symptoms, which can be treated successfully with L-threo-3,4-dihydroxyphenylserine, a synthetic precursor of norepinephrine. Informal clinical observations suggest that DßH-deficient patients do not have obvious cognitive impairments, even when they are not medicated, which is remarkable given the important role of norepinephrine in normal neurocognitive function. This study provided the first systematic investigation of neurocognitive function in human DßH deficiency. We tested 5 DßH-deficient patients and 10 matched healthy control participants on a comprehensive cognitive task battery, and examined their pupil dynamics, brain structure, and the P3 component of the electroencephalogram. All participants were tested twice; the patients were tested once ON and once OFF medication. Magnetic resonance imaging scans of the brain revealed that the patients had a smaller total brain volume than the control group, which is in line with the recent hypothesis that norepinephrine has a neurotrophic effect. In addition, the patients showed an abnormally small or absent task-evoked pupil dilation. However, we found no substantial differences in cognitive performance or P3 amplitude between the patients and the control participants, with the exception of a temporal-attention deficit in the patients OFF medication. The largely spared neurocognitive function in DßH-deficient patients suggests that other neuromodulators have taken over the function of norepinephrine in the brains of these patients.