IntroductionThe current way to assess the risk of cardiovascular disease (CVD) is to measure conventional lipid and lipoprotein cholesterol fractions. Despite the success of statin treatment,... Show moreIntroductionThe current way to assess the risk of cardiovascular disease (CVD) is to measure conventional lipid and lipoprotein cholesterol fractions. Despite the success of statin treatment, residual cardiovascular risk remains high. Therefore, the value of extensive serum apolipoprotein (apo) profiling to assess the risk of ST-segment elevation myocardial infarction (STEMI) and of major adverse cardiac events (MACE) in patients with STEMI was investigated in a case-control design.Methods and resultsSerum apo levels were measured using liquid chromatography and mass spectrometry in 299 healthy individuals and 220 patients with STEMI. First, the association of apo profiles in baseline samples with risk of STEMI was examined, and second, the association of apo profiles at baseline with risk of recurrent MACE in patients with STEMI in a longitudinal study design was studied. High baseline (>1.25g/L) apoA1 levels were associated with a decreased risk of STEMI [odds ratio (OR) 0.17; 95% CI 0.11-0.26], whereas high apoB (>1.00g/L) levels (OR 2.17; 95% CI 1.40-3.36) and apoB/apoA1 ratio (OR per 1 SD (OR/SD): 2.16; 95% CI 1.76-2.65) were associated with an increased risk. Very-low-density-lipoprotein (VLDL)-associated apos gave conflicting results. Neither conventional lipid levels nor apo levels were associated with MACE in the STEMI group.ConclusionIn conclusion, apoA1, apoB, and apoB/apoA1 were strongly associated with risk of STEMI. No clear relation between VLDL-associated apos and the risk of STEMI was found. Neither baseline serum apos nor lipids predicted MACE in statin-treated patients during long-term follow-up after a first STEMI. Show less
In dit proefschrift wordt onderzoek beschreven waarin een aantal door lipiden gereguleerde genen op bepaalde witte bloedcellen (macrofagen) zijn onderzocht voor nieuwe behandelmethoden ter... Show moreIn dit proefschrift wordt onderzoek beschreven waarin een aantal door lipiden gereguleerde genen op bepaalde witte bloedcellen (macrofagen) zijn onderzocht voor nieuwe behandelmethoden ter voorkoming of behandeling van atherosclerose (slagaderverkalking). Dit wordt gedaan met behulp van de beenmergtransplantatie techniek, waarmee specifiek witte bloedcellen __ waaronder ook macrofagen __ worden vervangen. De in het proefschrift beschreven genen die met behulp van de beenmergtransplantatietechniek zijn onderzocht zijn: ATP-binding cassette transporter (ABC)A1, ABCG1, apolipoproteine (apo)E, en adipose triglyceride lipase (ATGL). Deze genen worden gereguleerd door lipiden en spelen een belangrijke rol in de lipiden homeostase van cellen. Allereerst bleek dat ABCA1 en apoE in macrofagen op verschillende wijze een beschermende werking hebben met betrekking tot atherosclerose, en dat ze gezamenlijk ontstekingsremmend werken. In overeenstemming met deze resultaten bleken ABCG1 en apoE in macrofagen geheel onafhankelijk van elkaar een beschermende rol te spelen in de ontwikkeling van atherosclerose. Afwezigheid van ATGL __ verantwoordelijk voor de afbraak van vetten - in macrofagen leidde verrassenderwijs tot een vermindering van atherosclerose. De afwezigheid van ABCA1 bleek te beschermen tegen een acute hartaanval. Daarnaast bleek dat macrofaag ABCA1 veranderingen in de milt teweegbrengt, maar dat dit geen gevolgen heeft voor de ontwikkeling van atherosclerose. Show less
The 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_... Show moreThe 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. Show less
This 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,... Show moreThis 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. Show less
