313 research outputs found
Insulin sensitivity of hepatic glucose and lipid metabolism in animal models of hepatic steatosis
No full textDe lever is betrokken bij de regulatie van zowel het koolhydraat als het vet metabolisme. De lever slaat glucose op als glycogeen, scheidt glucose uit, kan glucose maken uit bijvoorbeeld melkzuur en aminozuren (‘gluconeogenese’), zet glucose om in vet (‘de novo lipogenese’), verbrandt vetzuren in de beta-oxidatie (levert energie voor de gluconeogenese) en scheidt triglycerides uit in de circulatie in ‘very low density lipoprotein’ (VLDL) deeltjes. Insuline remt de glucoseproductie door de lever en stimuleert de omzetting van glucose in glycogeen, vetzuren en vet (triglycerides). Daarnaast onderdrukt insuline de uitscheiding van triglyceride-rijke VLDL-deeltjes. Indirect remt insuline ook de beta-oxidatie omdat het de vrijmaking van vetzuren uit triglycerides remt.
Een verhoogde triglyceride concentratie in de lever (vette lever of hepatische steatose) is geassocieerd met diverse componenten van het metabool syndroom (dyslipidemie, insulineresistentie, obesitas, hypertensie) en kan een voorloper zijn van bijvoorbeeld levercirrose. Uit de klinische praktijk is gebleken dat hepatische steatose is geassocieerd met insulineresistentie en diabetes mellitus type 2. In de studies beschreven in het proefschrift van Aldo Grefhorst werd met behulp van muismodellen het effect van hepatische steatose op de insulinegevoeligheid van het glucose- en vetmetabolisme onderzocht. Op deze manier is getracht de onderliggende moleculaire processen behorende bij deze associatie op te helderen. De gebruikte modellen waren de leptine-deficiënte ob/ob muis, activering van de novo lipogenese met synthetische agonisten van de liver X receptor, farmacologische remming van de beta-oxidation met TDGA en farmacologische remming van glucose-6-phosphatase met S4048. Insulinegevoeligheid werd onder andere gemeten met behulp van hyperinsulinemische euglycemische clamps in combinatie met infusies van stabiele isotopen.
In alle onderzochte muismodellen is sprake van ernstige hepatische steatose. Met uitzondering van de ob/ob muis, werd in geen van de modellen een afgenomen insulinegevoeligheid waargenomen. Aan de hand van deze studies kan dan ook geconcludeerd worden dat de hoeveelheid triglycerides in de lever op zich weinig zegt over de mate van hepatische insulinegevoeligheid. Andere factoren zijn waarschijnlijk belangrijke determinanten voor het optreden van insulineresistentie bij hepatische steatose. Te denken valt bijvoorbeeld aan de oorsprong van de triglycerides, de duur van de hepatische steatose, de locatie van de triglycerides in de lever, de grootte van de vetdruppels in de cellen en verhoogde concentraties van andere soorten lipiden.
Neural control of lipid metabolism and inflammation : implications for atherosclerosis
No full textThe brain is increasingly recognized as the regulator of body homeostasis and as possible treatment target for cardiovascular disease. This thesis further reveals the role of the autonomic nervous system (ANS) in the control of lipid metabolism and inflammation, and identified pathological consequences of disturbed regulation. Part I focuses on regulation of lipid metabolism by the ANS, with special attention for brown adipose tissue (BAT) as an emerging pharmacological target for therapy. We describe novel targets that modulate BAT, both directly (e.g. CB1R) and via the brain (e.g. MC4R, GLP-1R) to show that BAT activation improves dyslipidemia, glucose tolerance and T2D and even atherosclerosis. In addition, we identified the biological clock as an important regulator of BAT function and showed the consequences of disturbed circadian rhythmicity for lipid metabolism. Part II of this thesis describes studies on the regulation of inflammation by the ANS, with focus on the anti-inflammatory reflex. During this reflex, binding of acetylcholine to _7nAChR and subsequent intracellular signaling results in transcriptional repression of pro-inflammatory genes. We investigated the effects of hematopoietic _7nAChR deficiency and the consequences of selective parasympathetic and sympathetic denervation of the spleen for this reflex, and for inflammation and atherosclerotic plaque development.Autonomic nervous system, lipid metabolism, brown adipose tissue, inflammation, atherosclerosisUBL - phd migration 201
The role of ApoCI, LPL and CETP in plasma lipoprotein metabolism - studies in mice
No full textThis thesis contributes to a better understanding of the roles of apoCI, LPL, and CETP in lipoprotein metabolism. Our data illustrate that the activity of LPL, and thereby the level of plasma TG, is crucially determined by the relative abundance of apolipoproteins. In addition, we showed that LPL is an important determinant in remnant-particle clearance in the absence of the three main apoE-recognizing receptors. Finally, we demonstrated that CETP presents a pro-atherogenic factor in mice resembling a human lipid distribution over lipoproteins and that atorvastatin and fenofibrate treatment influence HDL-metabolism via inhibition of CETP, which may thus add to their therapeutic benefit. Since there were initial concerns that inhibition of CETP would reduce the flux of cholesteryl esters from the periphery back to the liver, thereby possibly increasing the risk for atherosclerosis, it is of interest that we found that fenofibrate-mediated inhibition of CETP did not hamper the total flux of HDL-cholesteryl esters. This holds promise for therapies based on CETP inhibition.LEI Universiteit LeidenThe studies described in this thesis were supported by a grant from the Netherlands Organization of Scientific Research (NWO/ZonMW 908-02-097). The studies were performed at the Gaubius Laboratories of TNO-Quality of Life and the Leiden University Medical Center, the NetherlandsDe pathogenese, kliniek en behandeling van arterieel en veneus vaatlijde
Modulation of genes involved in inflammation and cell death in atherosclerosis-susceptible mice
No full textIn this thesis we focus on atherosclerosis as the main cause of cardiovascular disease. Since inflammation and cell death are important processes in the onset and progression of atherosclerosis, we investigate the role of several genes involved in inflammation and cell death in the vessel wall and their effect on atherosclerosis. We use several ways to modulate gene expression. Examples from different chapters are whole body deletion of TNF (2), local gene targeting of Fas Ligand to the cap of the plaque (3), conditional gene targeting of mdm2, thereby upregulating p53 (4), and beta-galactosidase (5), and pharmacological targeting of PPARs (6). In this thesis we use various mouse models of atherosclerosis, such as the apoE deficient mouse, the "humanized" apoE3*Leiden mouse and accelerated atherosclerosis induced by collar placement.TNO-Quality of life, The Gaubius Laboratory, Netherlands Organization of Scientific Research(NWO/ZonMW), Astra Zeneca, Sweden, Leids Universitair Fonds (LUF)UBL - phd migration 201
Hyperlipidemia, inflammation and atherosclerosis : roles of apolipoprotein C1 and cholesteryl ester transfer protein
No full textThe main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e. transgenic and knock-out mouse models). Many of these genes exert their role in atherosclerosis development as a result of effects on lipoprotein metabolism and inflammation. Transgenic mouse models have also been proven to be suitable for evaluating the mechanisms underlying the anti-atherosclerotic action of experimental drugs aimed to reduce atherogenic lipoprotein levels. However, thus far no suitable animal model was present to evaluate the mechanism of action of anti-atherosclerotic effect of HDL-raising therapeutic strategies. In this thesis, we further explored the role of apolipoprotein CI (apoCI) and cholesteryl ester transfer protein (CETP) in lipoprotein metabolism, inflammation, and atherosclerosis. Furthermore, we developed a mouse model that will be suitable for testing potential high-density-lipoprotein (HDL) raising therapies as a novel strategy to treat CVD.LEI Universiteit LeidenTNO-Quality of Life, F. Hoffmann-la Roche Ltd., Merck, Sharp &Dohme B.V., Boehringer-Ingelheim B.V., Pfizer B.V., Hope Farms Woerden, Astra Zeneca B.V.Vasculaire biologie en interventi
The role of apolipoprotein CI in lipid metabolism and bacterial sepsis
No full textThe research described in this thesis focussed on the role of apolipoproteins in lipid metabolism, inflammation and bacterial sepsis, with specific emphasis on apoCI. From studies in human APOC1_-transgenic and apoc1-/- mice, we were able to identify apoCI as a potent inhibitor of triglyceride hydrolysis by inhibiting lipoprotein lipase. Since APOC1 mice have thus increased VLDL levels, and VLDL protects against bacterial infection, we studied whether apoCI could play a role in inflammation and infection. We found that apoCI was able to bind lipopolysaccharide (LPS), the main toxic component of Gram-negative bacteria. Interestingly, although other apolipoproteins which have been studied have anti-inflammatory properties, we found that apoCI is a pro-inflammatory protein. By enhancing the biological response towards LPS and Gram-negative bacteria, apoCI dose-dependently improved the anti-bacterial attack, and protected against intrapulmonal Klebsiella pneumoniae-induced sepsis. Consistent with these experimental findings we also found that subjects with high plasma apoCI levels were less prone to infection-related mortality during follow-up, independent of plasma lipid levels. Likewise, survivors of severe sepsis showed higher plasma apoCI levels as compared to non-survivors, again independent of lipid levels. Taken together, our findings indicate that apoCI is an important determinant of the inflammatory response in mice and humans.LEI Universiteit LeidenVasculaire biologie en interventi
Dietary vegetable oil and wood derived plant stanol esters reduce atherosclerotic lesion size and severity in apoE*3-Leiden transgenic mice.
No full textAtherosclerosis 2001 Aug;157(2):375-81 Related Articles, Books, LinkOut Dietary vegetable oil and wood derived plant stanol esters reduce atherosclerotic lesion size and severity in apoE*3-Leiden transgenic mice. Volger OL, Mensink RP, Plat J, Hornstra G, Havekes LM, Princen HM. Gaubius Lab. TNO-PG, PO Box 2215, 2301 CE Leiden, The Netherlands. The hypolipidemic and anti-atherosclerotic effects of vegetable oil- and wood-based dietary plant stanol esters were compared in female apoE*3-Leiden transgenic mice at relevant plasma cholesterol levels. The plant stanol esters derived from vegetable oil (sitostanol 65.7%, campestanol 30.1%) had different contents of sitostanol and campestanol than the plant stanol esters derived from wood (sitostanol 87.6%, campestanol 9.5%) or from a mixture of vegetable oil and wood (sitostanol 73.0%, campestanol 24.7%). The mice (10 per group) received for 38 weeks a control diet or diets containing 1.0% (w/w) plant stanol esters derived from either vegetable oil, wood or a mixture of both. Vegetable oil (-46%), wood (-42%) and vegetable oil/wood (-51%) plant stanol esters decreased the plasma cholesterol levels (P<0.0001) by reducing the cholesterol content in plasma very low density-, intermediate density- and to a lesser extent in low density-lipoprotein. Plant stanol ester feeding did not change plasma triglyceride levels. Dietary plant stanol esters reduced the atherosclerotic lesion area by 91+/-13% (vegetable oil), 97+/-4% (wood) and 78+/-34% (vegetable oil/wood) (P<0.0001) and the severity from regular intimal fatty streaks/mild plaques (on average type 2--3 lesions) in controls to individual intimal foam cells (<type 1 lesions) in the treatment groups (P<0.0001). Plant stanol esters had no effect on adherence of monocytes to the vessel wall. Feeding of plant stanol esters dramatically reduced, independent of its sources, the extent and severity of atherosclerotic lesions, by decreasing VLDL-, IDL- and to a lesser extent LDL-cholesterol in apoE*3-Leiden transgenic mice
Extravascular inflammation in experimental atherosclerosis : the role of the liver and lungs
No full textIn this thesis, the role of the liver and lungs in atherosclerosis development were studied. The liver plays an important role in lipid metabolism and inflammation, the two main processes involved in atherogenesis. We show that continuous enhanced inflammation in hepatocytes increased the hepatic production of VLDL and aggravated atherosclerosis development in hyperlipidemic APOE*3-Leiden (E3L) mice as compared to control E3L mice. Poor lung function, most commonly caused by chronic obstructive pulmonary disease (COPD), is a risk factor for atherosclerosis development. To this end, we investigated whether elastase-induced alveolar wall destruction, a model for COPD, would worsen atherosclerosis development in E3L mice. No difference in atherosclerotic lesion size was observed between mice after elastase or vehicle instillation, indicating that alveolar destruction per se is not responsible for the increased risk for atherosclerosis in COPD patients. Furthermore, we studied the anti-atherosclerotic effects of resveratrol which can be found in red wine and Asian medicinal herbs. Hyperlipidemic E3L.CETP mice were fed a diet without (control) or with resveratrol, atorvastatin, or both. Resveratrol protected against atherosclerosis development, but did not add to the anti-atherogenic effects of atorvastatin. Finally, the clinical implications and future perspectives of these results are discussed.Dutch Heart FoundationUBL - phd migration 201
Cell cycle and apoptosis genes in atherosclerosis
No full textThe work described in this thesis was aimed at identifying the role of cell cycle and apoptosis genes in atherosclerosis. Atherosclerosis is the primary cause of cardiovascular disease, a disorder occurring in the large and medium-sized arteries of the body. Although in the beginning 90s promising lipid lowering therapies predicted a strong reduction in cardiovascular deaths, in westernized societies it is still the underlying cause of about 40% of all deaths, indicating that treatment of atherosclerosis goes beyond lipid lowering solely. In addition to lipids, continuous cell growth (cell cycle) and cell death (i.e. apoptosis and necrosis) processes play a central role in the development of atherosclerosis. To investigate the role of several cell cycle and apoptosis genes (i.e. p53, Rb and Mdm2) in atherosclerosis we generated and characterized several mouse models based on site-specific recombinase (SSR) technology. The studies described in this thesis show that next to therapies aiming at lifestyle interventions, lipid therapies and regulation of inflammation, targeting cell cycle and apoptosis genes on lesional or cellular level might prove the most effective way to reduce the burden of atherosclerosis.TNO-Quality of Life, Gaubius Laboratories (afdeling: Vascular and Metabolic Diseases)UBL - phd migration 201
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