Papers by C. Christoffersen
International Journal of Molecular Sciences, 2013
Apolipoprotein M (apoM) is a plasma apolipoprotein that mainly associates with high-density lipop... more Apolipoprotein M (apoM) is a plasma apolipoprotein that mainly associates with high-density lipoproteins. Hence, most studies on apoM so far have investigated its effect on and association with lipid metabolism and atherosclerosis. The insight into apoM biology recently took a major turn. ApoM was identified as a carrier of the bioactive lipid sphingosine-1-phosphate (S1P). S1P activates five different G-protein-coupled receptors, known as the S1P-receptors 1-5 and, hence, affects a wide range of biological processes, such as lymphocyte trafficking, angiogenesis, wound repair and even virus suppression and cancer. The ability of apoM to bind S1P is due to a lipophilic binding pocket within the lipocalin structure of the apoM molecule. Mice overexpressing apoM have increased plasma S1P concentrations, whereas apoM-deficient mice have decreased S1P levels. ApoM-S1P is able to activate the S1P-receptor-1, affecting the function of endothelial cells, and apoM-deficient mice display impaired endothelial permeability in the lung. This
Circulation Research, 2010
Rationale : Plasma apolipoprotein (apo)M is mainly associated with high-density lipoprotein (HDL)... more Rationale : Plasma apolipoprotein (apo)M is mainly associated with high-density lipoprotein (HDL). HDL-bound apoM is antiatherogenic in vitro. However, plasma apoM is not associated with coronary heart disease in humans, perhaps because of a positive correlation with plasma low-density lipoprotein (LDL). Objective : We explored putative links between apoM and very-low-density (VLDL)/LDL metabolism and the antiatherogenic potential of apoM in vivo. Methods and Results : Plasma apoM was increased ≈2.1 and ≈1.5 fold in mice lacking LDL receptors ( Ldlr −/− ) and expressing dysfunctional LDL receptor–related protein 1 ( Lrp1 n2/n2 ), respectively, but was unaffected in apoE-deficient ( ApoE −/− ) mice. Thus, pathways controlling catabolism of VLDL and LDL affect plasma apoM. Overexpression (≈10-fold) of human apoM increased (50% to 70%) and apoM deficiency decreased (≈25%) plasma VLDL/LDL cholesterol in Ldlr −/− mice, whereas apoM did not affect plasma VLDL/LDL in mice with intact LDL r...
Journal of Lipid Research, 2012
Supplementary key words lipoprotein • low-density lipoprotein metabolism • apolipoprotein • famil... more Supplementary key words lipoprotein • low-density lipoprotein metabolism • apolipoprotein • familial hypercholesterolemia HDL-associated apoM was recently shown to be a physiological carrier of sphingosine-1-phosphate (S1P) (1). S1P affects vascular integrity, and the S1P-dependent effects of HDL are dependent on apoM. Moreover, several studies have suggested that apoM can accelerate effl ux of cholesterol from foam cells, delay oxidation of LDL, and increase production of pre--HDL, suggesting that apoM affects antiatherogenic functions of HDL (2-4). However, little is known about the plasma metabolism of apoM. ApoM is anchored in HDL via a retained hydrophobic signal peptide (5). Loss of the signal peptide abolishes apoM's binding to HDL, causing rapid clearance of the truncated apoM in the kidney. Even though >90% of plasma apoM resides in HDL plasma, apoM concentration has consistently been shown to be positively correlated with plasma LDL cholesterol in humans (6-8). Moreover, HDL-associated plasma apoM is increased 2-fold in Ldlr Ϫ / Ϫ mice lacking functional LDL receptors (9). These observations might refl ect that plasma apoM is controlled by the rate of LDL receptor-mediated clearance of apoBcontaining particles. LDL receptor binding and internalization of LDL represent a major pathway controlling plasma LDL levels (10, 11), and the ligand binding domain of the LDL receptor, as well as the LDL receptor binding domain in apoB, have been extensively characterized (12, 13). The clinical diagnosis of familial hypercholesterolemia (FH) and impaired clearance of LDL can be caused by mutations in the LDLR and APOB genes (14). Genetic studies Abstract ApoM is mainly associated with HDL. Nevertheless, we have consistently observed positive correlations of apoM with plasma LDL cholesterol in humans. Moreover, LDL receptor defi ciency is associated with increased plasma apoM in mice. Here, we tested the idea that plasma apoM concentrations are affected by the rate of LDL receptormediated clearance of apoB-containing particles. We measured apoM in humans each carrying one of three different LDL receptor mutations (n = 9) or the apoB3500 mutation (n = 12). These carriers had increased plasma apoM (1.34 ± 0.13 µM, P = 0.003, and 1.23 ± 0.10 µM, P = 0.02, respectively) as compared with noncarriers (0.93 ± 0.04 µM). When we injected human apoM-containing HDL into Wt (n = 6) or LDL receptor-defi cient mice (n = 6), the removal of HDLassociated human apoM was delayed in the LDL receptordefi cient mice. After 2 h, 54 ± 5% versus 90 ± 8% (P < 0.005) of the initial amounts of human apoM remained in the plasma of Wt and LDL receptor-defi cient mice, respectively. Finally, we compared the turnover of radio-iodinated LDL and plasma apoM concentrations in 45 normocholesterolemic humans. There was a negative correlation between plasma apoM and the fractional catabolic rate of LDL (r = ؊ 0.38, P = 0.009). These data suggest that the plasma clearance of apoM, despite apoM primarily being associated with HDL, is infl uenced by LDL receptor-mediated clearance of apoB-containing particles.-Christoffersen, C.
Cell reports, Jan 2, 2018
Apolipoprotein M (apoM) is the carrier of sphingosine-1-phosphate (S1P) in plasma high-density li... more Apolipoprotein M (apoM) is the carrier of sphingosine-1-phosphate (S1P) in plasma high-density lipoproteins. S1P is a bioactive lipid interacting with five receptors (S1P1-5). We show that lack of apoM in mice increases the amount of brown adipose tissue (BAT), accelerates the clearance of postprandial triglycerides, and protects against diet-induced obesity (i.e., a phenotype similar to that induced by cold exposure or β3-adrenergic stimulation). Moreover, the data suggest that the phenotype of apoM-deficient mice is S1P dependent and reflects diminished S1P1 stimulation. The results reveal a link between the apoM/S1P axis and energy metabolism.
Atherosclerosis Supplements, 2009
European Journal of Echocardiography, 2003
Page 1. Abstracts S53 487 Early changes of left atrial reservoir function after cardioversion of ... more Page 1. Abstracts S53 487 Early changes of left atrial reservoir function after cardioversion of paroxysmal atrial fibrillation predict relapse of arrhythmia. P. Barbier, R. Chiodelli, M. Alimento, E. Assanelli, G. Marenzi, MD Guazzi. ...
Cardiovascular Research, 2014
ABSTRACT Purpose: Apolipoprotein M (apoM) is a plasma lipoprotein that mainly associates with hig... more ABSTRACT Purpose: Apolipoprotein M (apoM) is a plasma lipoprotein that mainly associates with high-density lipoproteins (HDL) and that serves as a carrier of the bioactive lipid Sphingosine-1-Phosphate (S1P). Recent studies indicate that S1P binding to G-protein-coupled receptors, known as S1P-receptors, in the heart activates signalling pathways promoting cardiomyocyte survival, but downstream targets are largely unknown. Here, we investigate the putative role of the apoM-S1P axis in relation to cardioprotection against ischemia/reperfusion (IR) injury. Methods and Results: ApoM transgenic (Apom-Tg) mice, in which plasma S1P is increased by &gt;250%, and wild-type (WT) mice were subjected to 30 min of left coronary artery ligation and 24 hrs reperfusion in vivo. We found a reduction of infarct size in Apom-Tg mice (15±1%) in comparison with WT mice (29±4%, N=8-9, p&lt;0.01). In agreement, neutrophil infiltration into the infarcted area was lower in Apom-Tg mice (14.8±0.2% vs. 25.9±5.1 in WT, N=3, p&lt;0.05). Interestingly, 5 min of S1P treatment at the onset of reperfusion reduced infarct size in response to 30 min of no-flow global ischemia (control: 23±3%, S1P-treated: 11±2%, N=5, p&lt;0.05) in ex vivo Langendorff perfused hearts, suggesting that S1P exerts a direct protective effect on cardiomyocytes. Moreover, the sensitivity to ex vivo IR of Apom-Tg mice was not different from WT mice, further supporting that the cardioprotective effect observed in vivo is due to increased plasmatic S1P in these mice. To obtain further insight into the mechanism underlying S1P-induced cardioprotection, neonatal rat ventricular cardiomyocytes were treated for 5 min with S1P after pre-incubation with PKC kinase inhibitors or with specific antagonists of S1P receptors. We found by Western blot that S1P induced phosphorylation of the gap junction protein Connexin43 (Cx43) on Serine 368 by a PKC-dependent mechanism and that this phosphorylation was mediated by S1P2 and S1P3 but not by S1P1 receptors. Finally, 5 min of S1P treatment reduced gap junctional communication between cardiomyocytes (9±1 cells, N=29) in comparison to control conditions (15±2 cells, N=34, p&lt;0.01), as assessed by dye coupling assay. Conclusion: Increased plasma apoM-S1P in mice protects the heart against IR injury. The molecular mechanism might involve reduced cardiomyocyte death by activation of S1P2 and S1P3 receptors, which leads to PKC-dependent phosphorylation of Cx43 and reduction of cell-to-cell coupling.
Atherosclerosis Supplements, 2011
Atherosclerosis Supplements, 2011
Oral presentations and susceptibility to degradation. Aim of the study is to evaluate the role of... more Oral presentations and susceptibility to degradation. Aim of the study is to evaluate the role of N-glycosylation in ANGPTL3 trafficking and stability. Methods: By using a bioinformatic approach we identified 4 putative human ANGPTL3 N-glycosylation sites at aminoacid position 23, 115, 296, 357. Wild type ANGPTL3 was cloned into a pcDNA 3.1 6xhys and V5 tag vector. Mutants were generated at these sites by changing the asparagine into a glutamine after in situ mutagenesis. Human embryonic kidney cells (HEK 293A) were transiently transfected with recombinant wild type and mutants. ANGPTL3 protein processing, secretion and stability was evaluated in cell lysate and medium by enzymatic digestion, western blotting and protein purification. Results: We found ANGPTL3 to be N-glycosylated at position 115, 296 and 357. Defect in N-glycosylation at position 296 determined a severe reduction in protein secretion. Extracellular protein stability was not affected by lack of glycosylation at any site. Conclusions: N-Glycosylation of the aminoacid 296 but not 115 and 357 is required for complete ANGPTL3 secretion and may be contributing to determine lower lipoprotein levels in humans.
Atherosclerosis Supplements, 2007
IT genotype in hypertensive group. Lowering effect on HDL cholesterol levels by 6A6A/GG combinati... more IT genotype in hypertensive group. Lowering effect on HDL cholesterol levels by 6A6A/GG combination of genotypes showed significance in normotensive group.
The Journal of Lipid Research, 2015
Cardiovascular Endocrinology, 2014
ABSTRACT
Current Opinion in Lipidology, 2015
This review will address recent findings on apolipoprotein M (apoM) and its ligand sphingosine-1-... more This review will address recent findings on apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) in lipid metabolism and inflammatory diseases. ApoM&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s likely role(s) in health and disease has become more diverse after the discovery that apoM functions as a chaperone for S1P. Hence, apoM has recently been implicated in lipid metabolism, diabetes and rheumatoid arthritis through in-vivo, in-vitro and genetic association studies. It remains to be established to which degree such associations with apoM can be attributed to its ability to bind S1P. The apoM/S1P axis and its implications in atherosclerosis and lipid metabolism have been thoroughly studied. Owing to the discovery of the apoM/S1P axis, the scope of apoM research has broadened. ApoM and S1P have been implicated in lipid metabolism, that is by modulating HDL particles. Also, the importance in regulating endothelial function is being investigated. Furthermore, both apoM and S1P have been linked to diabetes and glucose and insulin metabolism. Finally, genetic variations in the apoM gene are associated with lipid disturbances, diabetes and rheumatoid arthritis. These findings suggest not only diverse effects of apoM, but also the important question of whether apoM mainly acts as a S1P carrier, if apoM carries other substances with biological effects as well, or whether the apoM protein has effects on its own.
Atherosclerosis Supplements - ATHEROSCLER SUPPL, 2011
Trends in Endocrinology & Metabolism, 2009
The recently discovered apolipoprotein M (apoM) is a plasma protein of the lipocalin family assoc... more The recently discovered apolipoprotein M (apoM) is a plasma protein of the lipocalin family associated with the lipoproteins (mainly high-density lipoproteins, or HDLs). Expression of the apoM gene in the liver is regulated by transcription factors that control key steps in hepatic lipid and glucose metabolism. Although the concentration of plasma apoM correlates with that of cholesterol, apoM was not identified as a risk factor for cardiovascular disease in two prospective studies. In genetically modified mice, however, changes in plasma apoM concentration caused quantitative and qualitative changes in HDLs, and overexpression of the apoM gene reduced atherosclerosis. In conclusion, it seems that apoM plays a part in lipoprotein metabolism; however, the biological impact of apoM in humans remains to be determined.
The FASEB Journal, 2003
Congestive heart failure is accompanied by increased cardiac brain natriuretic peptide (BNP) gene... more Congestive heart failure is accompanied by increased cardiac brain natriuretic peptide (BNP) gene expression with elevated plasma concentrations of BNP and its precursor, proBNP. We investigated if myocardial ischemia in the absence of overt heart failure may be another mechanism for increased myocardial BNP expression. The BNP expression was examined in hypoxic myocardium of patients undergoing coronary bypass grafting surgery, in patients with coronary artery disease and normal left ventricular function undergoing percutaneous transluminal intervention therapy, and in heart failure patients without coronary artery disease. BNP mRNA was quantified by real-time PCR, and plasma BNP and proBNP concentrations were measured with radioimmunoassays. Quantitative analysis of BNP mRNA in atrial and ventricular biopsies from coronary bypass grafting patients revealed close associations of plasma BNP and proBNP concentrations to ventricular, but not atrial, BNP mRNA levels. Plasma BNP and proBNP concentrations were markedly increased in patients with coronary artery disease but without concomitant left ventricular dysfunction. These results are compatible with the notion that myocardial ischemia, even in the absence of left ventricular dysfunction, augments cardiac BNP gene expression and increases plasma BNP and proBNP concentrations. Thus, elevated BNP and proBNP concentrations do not necessarily reflect heart failure but may also result from cardiac ischemia.
Regulatory Peptides, 2012
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Papers by C. Christoffersen