Moderate exercise increases affinity of large very low density lipoproteins for hydrolysis by lipoprotein lipase

Context: Postprandial triglyceride (TG) concentration is independently associated with cardiovascular disease risk. Exercise reduces postprandial TG concentrations but the mechanisms responsible are unclear. Objective: To determine the effects of exercise on affinity of chylomicrons, large very low density lipoproteins (VLDL1) and smaller VLDL (VLDL2) for lipoprotein lipase (LPL) mediated TG hydrolysis. Design: Within-participant cross-over study. Setting: A University metabolic investigation unit. Participants: Ten overweight/obese men. Interventions: Participants undertook two oral fat tolerance tests, separated by 7–14 days, in which they had blood taken fasting and for 4 hours after a high-fat mixed meal. On the afternoon before one test, they performed a 90-minute treadmill walk at 50% maximal oxygen uptake (EX); no exercise was performed before the control test (CON). Main outcome measures: Circulating TG-rich lipoprotein concentrations; affinity of chylomicrons, VLDL1, VLDL2 for LPL-mediated TG hydrolysis. Results: Exercise significantly reduced fasting VLDL1-TG concentration (CON: 0.49(0.33–0.72) mmol.l−1, EX: 0.36(0.22–0.59) mmol.l−1, [geometric means (95% confidence interval)]; p=0.04). Time-averaged postprandial chylomicron-TG (CON: 0.55±0.10 mmol.l−1, EX: 0.39±0.08 mmol.l−1, [mean±SEM], p=0.03) and VLDL1-TG (CON: 0.85±0.13 mmol.l−1, EX: 0.66±0.10 mmol.l−1, p=0.01) concentrations were both lower in EX than CON. Affinity of VLDL1 for LPL-mediated TG hydrolysis increased by 2.2(1.3–3.7) fold (geometric mean (95% confidence interval)) (p=0.02) in the fasted state and 2.6(1.8–2.6) fold (p=0.001) postprandially. Affinity of chylomicrons and VLDL2 was not significantly different between trials. Conclusions: Exercise increases affinity of VLDL1 for LPL-mediated TG hydrolysis both fasting and postprandially. This mechanism is likely to contribute to exercise's TG-lowering effect

Accelerated ageing and renal dysfunction links lower socioeconomic status and dietary phosphate intake

Background: We have sought to explore the impact of dietary Pi intake on human age related health in the pSoBid cohort (n=666) to explain the disparity between health and deprivation status in this cohort. As hyperphosphataemia is a driver of accelerated ageing in rodent models of progeria we tested whether variation in Pi levels in man associate with measures of biological ageing and health. Results: We observed significant relationships between serum Pi levels and markers of biological age (telomere length (p=0.040) and DNA methylation content (p=0.028), gender and chronological age (p=0.032). When analyses were adjusted for socio-economic status and nutritional factors, associations were observed between accelerated biological ageing (telomere length, genomic methylation content) and dietary derived Pi levels among the most deprived males, directly related to the frequency of red meat consumption. Conclusions: Accelerated ageing is associated with high serum Pi levels and frequency of red meat consumption. Our data provide evidence for a mechanistic link between high intake of Pi and age-related morbidities tied to socio-economic status

Cellular and humoral immunity in a wild mammal: Variation with age & sex and association with overwinter survival

Immune defenses are expected to be crucial for survival under the considerable parasite pressures experienced by wild animals. However, our understanding of the association between immunity and fitness in nature remains limited due to both the complexity of the vertebrate immune system and the often‐limited availability of immune reagents in nonmodel organisms. Here, we use methods and reagents developed by veterinary researchers for domestic ungulates on blood samples collected from a wild Soay sheep population, to evaluate an unusually broad panel of immune parameters. Our evaluation included different innate and acquired immune cell types as well as nematode parasite‐specific antibodies of different isotypes. We test how these markers correlate with one another, how they vary with age‐group and sex, and, crucially, whether they predict overwinter survival either within or among demographic groups. We found anticipated patterns of variation in markers with age, associated with immune development, and once these age trends were accounted for, correlations among our 11 immune markers were generally weak. We found that females had higher proportions of naïve T cells and gamma–delta T cells than males, independent of age, while our other markers did not differ between sexes. Only one of our 11 markers predicted overwinter survival: sheep with higher plasma levels of anti‐nematode IgG antibodies were significantly more likely to survive the subsequent high mortality winter, independent of age, sex, or weight. This supports a previous finding from this study system using a different set of samples and shows that circulating antibody levels against ecologically relevant parasites in natural systems represent an important parameter of immune function and may be under strong natural selection. Our data provide rare insights into patterns of variation among age‐ and sex groups in different T‐cell subsets and antibody levels in the wild, and suggest that certain types of immune response—notably those likely to be repeatable within individuals and linked to resistance to ecologically relevant parasites—may be most informative for research into the links between immunity and fitness under natural conditions

The hypotensive effect of acute and chronic AMP-activated protein kinase activation in normal and hyperlipidemic mice

AMP-activated protein kinase (AMPK) is present in the arterial wall and is activated in response to cellular stressors that raise AMP relative to ADP/ATP. Activation of AMPK in vivo lowers blood pressure but the influence of hyperlipidemia on this response has not been studied. ApoE-/- mice on high fat diet for 6 weeks and age-matched controls were treated with the AMPK activator, AICAR daily for two weeks. Under anesthesia, the carotid artery was cannulated for blood pressure measurements. Aortic tissue was removed for in vitro functional experiments and AMPK activity was measured in artery homogenates by Western blotting. ApoE-/- mice had significantly raised mean arterial pressure; chronic AICAR treatment normalized this but had no effect in normolipidemic mice, whereas acute administration of AICAR lowered mean arterial pressure in both groups. Chronic AICAR treatment increased phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase in normolipidemic but not ApoE-/- mice. In aortic rings, AMPK activation induced vasodilation and an anticontractile effect, which was attenuated in ApoE-/- mice. This study demonstrates that hyperlipidemia dysregulates the AMPK pathway in the arterial wall but this effect can be reversed by AMPK activation, possibly through improving vessel compliance

Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation

The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation

Omega-3 fatty acids improve postprandial lipaemia in patients with nephrotic range proteinuria

<b>Background</b>: Patients with nephrotic range proteinuria have a marked increase in the risk of cardiovascular disease. Qualitative and quantitative changes in lipids and lipoproteins contribute to this increased risk with an abundance of atherogenic triglyceride (TG) rich apolipoprotein B containing lipoproteins. TG rich lipoproteins predominate postprandially and are associated with increased risk of coronary heart disease (CHD). Omega-3 fatty acids derived from fish oils have been shown to have beneficial effects on lipids and lipoproteins in patients without proteinuria. <b>Methods</b>: 17 patients with nephrotic range proteinuria and 17 age and sex matched controls were studied. Postprandial lipaemia was assessed in patients and controls, before and after 8 weeks treatment with 4 g daily of omega-3 fatty acids (Omacor). A standard fat load (90 g) was administered and blood sampling was performed in the fasting state and at 2, 4, 6 and 8 h after the fat load. Chylomicrons and VLDL1 density fraction was isolated from plasma by density ultracentrifugation. Postprandial chylomicron and VLDL1 triglyceride concentrations were measured and quantified using the incremental area under the curve (AUC) method. <b>Results</b>: Baseline postprandial chylomicron TG AUC was greater in patients compared with controls: median 18.5 mmol/l h (interquartile range 8.9–32.6) vs 9.3 mmol/l h (4.8–14.4) p = 0.05. Following treatment patient chylomicron AUC fell [mean reduction 6.8 mmol/l h (95% CI 0.1–13.6) p = 0.05]. No significant reduction in chylomicron AUC was observed in the controls [mean reduction 3.9 mmol/l h (95% CI −3.6 to 11.5)]. As a result, following 8 weeks treatment with omega-3 fatty acids, patient and control chylomicron AUC were no longer significantly different [patients 13.5 mmol/l h (7.4–22.9), controls 7.2 mmol/l h (4.6–14.5) both median and IQR, p = nsd]. VLDL1 TG AUC did not differ at baseline between patients and controls. Furthermore, there was no significant effect on VLDL1 AUC following treatment in either group. <b>Conclusions</b>: We have shown that there is an excess of postprandial chylomicron density fraction in patients with nephrotic range proteinuria, which is reduced by treatment with omega-3 fatty acids. We suggest that this would be an ideal therapy in combination with statins for this high risk group of patients

Maternal obesity is associated with the formation of small dense LDL and hypoadiponectinemia in the third trimester

CONTEXT: Maternal obesity is associated with high plasma triglyceride, poor vascular function, and an increased risk for pregnancy complications. In normal-weight pregnant women, higher triglyceride is associated with increased small, dense low-density lipoprotein (LDL). HYPOTHESIS: In obese pregnancy, increased plasma triglyceride concentrations result in triglyceride enrichment of very low-density lipoprotein-1 particles and formation of small dense LDL via lipoprotein lipase. DESIGN: Women (n = 55) of body mass index of 18-46 kg/m(2) were sampled longitudinally at 12, 26, and 35 weeks\u27 gestation and 4 months postnatally. SETTING: Women were recruited at hospital antenatal appointments, and study visits were in a clinical research suite. OUTCOME MEASURES: Plasma concentrations of lipids, triglyceride-rich lipoproteins, lipoprotein lipase mass, estradiol, steroid hormone binding globulin, insulin, glucose, leptin, and adiponectin were determined. RESULTS: Obese women commenced pregnancy with higher plasma triglyceride, reached the same maximum, and then returned to higher postnatal levels than normal-weight women. Estradiol response to pregnancy (trimester 1-3 incremental area under the curve) was positively associated with plasma triglyceride response (r(2) adjusted 25%, P \u3c.001). In the third trimester, the proportion of small, dense LDL was 2-fold higher in obese women than normal-weight women [mean (SD) 40.7 (18.8) vs 21.9 (10.9)%, P =.014], and 35% of obese, 14% of overweight, and none of the normal-weight women displayed an atherogenic LDL subfraction phenotype. The small, dense LDL mass response to pregnancy was inversely associated with adiponectin response (17%, P =.013). CONCLUSIONS: Maternal obesity is associated with an atherogenic LDL subfraction phenotype and may provide a mechanistic link to poor vascular function and adverse pregnancy outcome