Results, meta-analysis and a first evaluation of UNOxR, the urinary nitrate-to-nitrite molar ratio, as a measure of nitrite reabsorption in experimental and clinical settings

Diabetes mellitus: pathophysiological changes and therap

Interactions between inflammation and lipid metabolism: Relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis

Dyslipidemia and inflammation are well known causal risk factors the development of atherosclerosis. The interplay between lipid metabolism and inflammation at multiple levels in metabolic active tissues may exacerbate the development of atherosclerosis, and will be discussed in this review. Cholesterol, fatty acids and modified lipids can directly activate inflammatory pathways. In addition, circulating (modified) lipoproteins modulate the activity of leukocytes. Vice versa, proinflammatory signaling (i.e. cytokines) in pre-clinical models directly affects lipid metabolism. Whereas the main lipid-lowering drugs all have potent anti-inflammatory actions, the lipid-modulating actions of anti-inflammatory agents appear to be less straightforward. The latter have mainly been evaluated in pre-clinical models and in patients with chronic inflammatory diseases, which will be discussed. The clinical trials that are currently conducted to evaluate the efficacy of anti-inflammatory agents in the treatment of cardiovascular diseases may additionally reveal potential (beneficial) effects of these therapeutics on lipid metabolism in the general population at risk for CVD

BMT decreases HFD-induced weight gain associated with decreased preadipocyte number and insulin secretion

Contains fulltext : 174709.pdf (publisher's version ) (Open Access)Experimental bone marrow transplantation (BMT) in mice is commonly used to assess the role of immune cell-specific genes in various pathophysiological settings. The application of BMT in obesity research is hampered by the significant reduction in high-fat diet (HFD)-induced obesity. We set out to characterize metabolic tissues that may be affected by the BMT procedure and impair the HFD-induced response. Male C57BL/6 mice underwent syngeneic BMT using lethal irradiation. After a recovery period of 8 weeks they were fed a low-fat diet (LFD) or HFD for 16 weeks. HFD-induced obesity was reduced in mice after BMT as compared to HFD-fed control mice, characterized by both a reduced fat (-33%; p<0.01) and lean (-11%; p<0.01) mass, while food intake and energy expenditure were unaffected. As compared to control mice, BMT-treated mice had a reduced mature adipocyte volume (approx. -45%; p<0.05) and reduced numbers of preadipocytes (-38%; p<0.05) and macrophages (-62%; p<0.05) in subcutaneous, gonadal and visceral white adipose tissue. In BMT-treated mice, pancreas weight (-46%; p<0.01) was disproportionally decreased. This was associated with reduced plasma insulin (-68%; p<0.05) and C-peptide (-37%; p<0.01) levels and a delayed glucose clearance in BMT-treated mice on HFD as compared to control mice. In conclusion, the reduction in HFD-induced obesity after BMT in mice is at least partly due to alterations in the adipose tissue cell pool composition as well as to a decreased pancreatic secretion of the anabolic hormone insulin. These effects should be considered when interpreting results of experimental BMT in metabolic studies

Apolipoprotein C-I plays a role in the pathogenesis of glomerulosclerosis

Diabetes mellitus: pathophysiological changes and therap

Apolipoprotein A5 deficiency aggravates high-fat diet-induced obesity due to impaired central regulation of food intake.

Mutations in apolipoprotein A5 (APOA5) have been associated with hypertriglyceridemia in humans and mice. This has been attributed to a stimulating role for APOA5 in lipoprotein lipase-mediated triglyceride hydrolysis and hepatic clearance of lipoprotein remnant particles. However, because of the low APOA5 plasma abundance, we investigated an additional signaling role for APOA5 in high-fat diet (HFD)-induced obesity. Wild-type (WT) and Apoa5-/- mice fed a chow diet showed no difference in body weight or 24-h food intake (Apoa5-/-, 4.5+/-0.6 g; WT, 4.2+/-0.5 g), while Apoa5-/- mice fed an HFD ate more in 24 h (Apoa5-/-, 2.8+/-0.4 g; WT, 2.5+/-0.3 g, P<0.05) and became more obese than WT mice. Also, intravenous injection of APOA5-loaded VLDL-like particles lowered food intake (VLDL control, 0.26+/-0.04 g; VLDL+APOA5, 0.11+/-0.07 g, P<0.01). In addition, the HFD-induced hyperphagia of Apoa5-/- mice was prevented by adenovirus-mediated hepatic overexpression of APOA5. Finally, intracerebroventricular injection of APOA5 reduced food intake compared to injection of the same mouse with artificial cerebral spinal fluid (0.40+/-0.11 g; APOA5, 0.23+/-0.08 g, P<0.01). These data indicate that the increased HFD-induced obesity of Apoa5-/- mice as compared to WT mice is at least partly explained by hyperphagia and that APOA5 plays a role in the central regulation of food intake.-Van den Berg, S. A. A., Heemskerk, M. M., Geerling, J. J., van Klinken, J.-B., Schaap, F. G., Bijland, S., Berbee, J. F. P., van Harmelen, V. J. A., Pronk, A. C. M., Schreurs, M., Havekes, L. M., Rensen, P. C. N., van Dijk, K. W. Apolipoprotein A5 deficiency aggravates high-fat diet-induced obesity due to impaired central regulation of food intake

Hepatocyte-specific IKKbeta expression aggravates atherosclerosis development in APOE*3-Leiden mice

Item does not contain fulltextOBJECTIVE: The liver is the key organ involved in systemic inflammation, but the relation between hepatic inflammation and atherogenesis is poorly understood. Since nuclear factor-kappaB (NF-kappaB) is a central regulator of inflammatory processes, we hypothesized that chronically enhanced hepatic NF-kappaB activation, through hepatocyte-specific expression of IkappaB kinase-beta (IKKbeta) (LIKK), will aggravate atherosclerosis development in APOE*3-Leiden (E3L) mice. METHODS AND RESULTS: E3L.LIKK and E3L control littermates were fed a Western-type diet for 24 weeks. E3L.LIKK mice showed a 2.3-fold increased atherosclerotic lesion area and more advanced atherosclerosis in the aortic root with less segments without atherosclerotic lesions (11% vs. 42%), and more segments with mild (63% vs. 44%) and severe (26% vs. 14%) lesions. Expression of LIKK did not affect basal levels of inflammatory parameters, but plasma cytokine levels tended to be higher in E3L.LIKK mice after lipopolysaccharide (LPS) administration. E3L.LIKK mice showed transiently increased plasma cholesterol levels, confined to (V)LDL. This transient character resulted in a mild (+17%) increased cumulative plasma cholesterol exposure. CONCLUSION: We conclude that selective activation of NF-kappaB in hepatocytes considerably promotes atherosclerosis development which is (at least partly) explained by an increased sensitivity to proinflammatory triggers and transiently increased plasma cholesterol levels

BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice

BACKGROUND AND AIMS: Bacille-Calmette-Guerin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on cholesterol metabolism, the main driver of atherosclerosis development, has remained underexposed in previous studies. Therefore, we aimed to elucidate the effect of BCG on cholesterol metabolism in addition to inflammation and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established model of human-like lipoprotein metabolism. METHODS: Hyperlipidemic APOE*3-Leiden.CETP mice were fed a Western-type diet containing 0.1% cholesterol and were terminated 6 weeks after a single intravenous injection with BCG (0.75 mg; 5 x 10(6) CFU). RESULTS: BCG-treated mice exhibited hepatic mycobacterial infection and hepatomegaly. The enlarged liver (+53%, p = 0.001) coincided with severe immune cell infiltration and a higher cholesterol content (+31%, p = 0.03). Moreover, BCG reduced plasma total cholesterol levels (-34%, p = 0.003), which was confined to reduced nonHDL-cholesterol levels (-36%, p = 0.002). This was due to accelerated plasma clearance of cholesterol from intravenously injected [(14)C]cholesteryl oleate-labelled VLDL-like particles (t(1/2) -41%, p = 0.002) as a result of elevated hepatic uptake (+25%, p = 0.05) as well as reduced intestinal cholestanol and plant sterol absorption (up to -37%, p = 0.003). Ultimately, BCG decreased foam cell formation of peritoneal macrophages (-18%, p = 0.02) and delayed atherosclerotic lesion progression in the aortic root of the heart. BCG tended to decrease atherosclerotic lesion area (-59%, p = 0.08) and reduced lesion severity. CONCLUSIONS: BCG reduces plasma nonHDL-cholesterol levels and delays atherosclerotic lesion formation in hyperlipidemic mice

Dossier dopage. Questions à patrick Laure; Et toi le dopage? Au collège des Bons Raisins; Entretien avec Michel Boyon

Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-delta, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise