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Christina Christoffersen - One of the best experts on this subject based on the ideXlab platform.
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Apolipoprotein M and Risk of Type 2 Diabetes.
The Journal of clinical endocrinology and metabolism, 2020Co-Authors: Stefan Hajny, Lars Nielsen, M. Christoffersen, N. Dalila, Anne Tybjærg-hansen, Christina ChristoffersenAbstract:Context Recent studies have discovered a role of Apolipoprotein M (apoM) in energy MetabolisM, and observational analyses in huMans suggest an association with type 2 diabetes. The causal relationship reMains however elusive. Objective To investigate whether reduced plasMa apoM concentrations are causally linked to increased risk of type 2 diabetes. Design Prospective study design analyzed by Mendelian randoMization. Setting and participants Two cohorts reflecting the Danish general population: the Copenhagen City Heart Study (CCHS, n = 8589) and the Copenhagen General Population Study (CGPS; n = 93 857). Observational analyses included a subset of participants froM the CCHS with available plasMa apoM (n = 725). Genetic analyses included the coMplete cohorts (n = 102 446). During a Median follow-up of 16 years (CCHS) and 8 years (CGPS), 563 and 2132 participants developed type 2 diabetes. Main outcoMe Measures PlasMa apoM concentration, genetic variants in APOM, and type 2 diabetes. Results First, we identified an inverse correlation between plasMa apoM and risk of type 2 diabetes in a subset of participants froM the CCHS (hazard ratio between highest vs lowest quartile (reference) = 0.32; 95% confidence interval = 0.1-1.01; P for trend = .02). Second, genotyping of specific single nucleotide polyMorphisMs in APOM further revealed a 10.8% (P = 6.2 × 10-5) reduced plasMa apoM concentration in participants with variant rs1266078. Third, a Meta-analysis including data froM 599 451 individuals showed no association between rs1266078 and risk of type 2 diabetes. Conclusions The present study does not appear to support a causal association between plasMa apoM and risk of type 2 diabetes.
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Apolipoprotein M bound sphingosine 1 phosphate regulates blood brain barrier paracellular perMeability and transcytosis
bioRxiv, 2019Co-Authors: Mette Mathiesen Janiurek, Christina Christoffersen, Krzysztof Kucharz, Martin LauritzenAbstract:ABTRACT The blood-brain barrier (BBB) is forMed by the endothelial cells lining cerebral Microvessels. Here, we report that the BBB perMeability is Modified by Apolipoprotein M (apoM)-bound sphingosine 1-phosphate (S1P). We used two-photon Microscopy to Monitor changes in BBB perMeability in apoM-deficient Mice (apoM−/−), showing significant increases in paracellular BBB perMeability to sMall Molecules without structural changes in junctional coMplexes between endothelial cells. Lack of apoM-bound S1P increased vesicle-Mediated transfer of albuMin across endotheliuM of brain pial and penetrating arterioles, whereas transcytosis in capillaries and venules reMained unchanged. S1PR1 agonist SEW2871 rapidly norMalized BBB perMeability along both the paracellular and transcellular routes in apoM−/− Mice. Thus, apoM-bound S1P Maintains low paracellular BBB perMeability for sMall Molecules in all cerebral Microvessels and low levels of adsorptive transcytosis in penetrating arterioles. Modulation of apoM/S1P-dependent signaling May be a novel strategy for the protection of brain endothelial cells to preserve the BBB function.
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Apolipoprotein M/sphingosine-1-phosphate: novel effects on lipids, inflaMMation and kidney biology.
Current opinion in lipidology, 2019Co-Authors: Line S. Bisgaard, Christina ChristoffersenAbstract:Purpose of review In 2011, the crystal structure of Apolipoprotein M (apoM) and its capacity to bind sphingosine-1-phosphate (S1P) was characterized. Since then, a variety of studies has increased our knowledge on apoM biology and functionality. FroM being an unknown and hardly significant player in overall MetabolisM, apoM has gained significant interest. Recent findings Key discoveries in the last 2 years have indicated that the apoM/S1P coMplex has iMportant roles in lipid MetabolisM (affecting triglyceride turnover), inflaMMation (a Marker of severe sepsis and potentially providing anti-inflaMMatory signaling) and kidney biology (potential to protect against iMMunoglobulin A nephropathy). SuMMary Several studies suggest a potential for apoM/S1P as bioMarkers for inflaMMation, sepsis and nephropathy. Also, a novel chaperone is characterized and could have potential as a drug for treatMent in inflaMMation and nephropathy.
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Effect of Menopause and exercise training on plasMa Apolipoprotein M and sphingosine-1-phosphate
Journal of applied physiology (Bethesda Md. : 1985), 2018Co-Authors: Adelina Yafasova, Camilla M. Mandrup, Jon Egelund, Michael Nyberg, Bente Stallknecht, Ylva Hellsten, Lars Nielsen, Christina ChristoffersenAbstract:The Apolipoprotein M/sphingosine-1-phosphate (apoM/S1P) coMplex is involved in Maintaining a healthy endothelial barrier function. Our study is the first, to our knowledge, to show how Menopause af...
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Apolipoprotein M in patients with chronic kidney disease.
Atherosclerosis, 2018Co-Authors: Ida Mh. Sørensen, Christina Christoffersen, Lars Bo Nielsen, Marianne Bertelsen, Ellen Freese, Kristine Lindhard, Henrik Ullum, Bo Feldt-rasmussen, Susanne BroAbstract:Abstract Background and aiMs PlasMa Apolipoprotein M (APOM) is bound to HDL-particles and has anti-atherogenic effects. The present study explored whether plasMa APOM is reduced in patients with chronic kidney disease (CKD), and associated with cardiovascular disease (CVD). In addition, we tested the hypothesis that the excretion of APOM into the urine is increased in patients with kidney disease. Methods PlasMa saMples were collected froM a cohort of patients with CKD stages 1 to 5D (N = 409) and controls (N = 35). Urine was collected froM 47 subjects. PlasMa APOM was Measured with sandwich ELISA and urine APOM with coMpetitive ELISA. Results PlasMa APOM levels were reduced in patients with CKD stages 3-5D as coMpared to patients with CKD stages 1 + 2 and controls (p Fast-phase liquid chroMatography showed that plasMa APOM was priMarily associated with HDL-cholesterol (HDL-C) across CKD stages. Accordingly, when plasMa APOM values were corrected for HDL-C, a significant difference only persisted between patients with CKD stage 3 and stages 1 + 2 (p Conclusions The results show that the difference in plasMa APOM levels observed between patients with Mild and advanced CKD May Mainly be due to differences in plasMa HDL-C. Whether APOM plays a role in huMan ureMic atherogenesis warrants further experiMental studies.
Guang-hua Luo - One of the best experts on this subject based on the ideXlab platform.
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Apolipoprotein M proMotes cholesterol uptake and efflux froM Mouse Macrophages.
FEBS open bio, 2021Co-Authors: Shuang Yao, Guang-hua Luo, Fan Zheng, Yuxia Zhan, Lu ZhengAbstract:Apolipoprotein M (ApoM) exhibits various anti-atherosclerotic functions as a coMponent of high-density lipoprotein (HDL) particles. Scavenger receptor class B type I (SR-BI) is a classic HDL receptor that Mediates selective cholesterol uptake and enhances the efflux of cellular cholesterol to HDL. However, the effect of ApoM on cholesterol transport in Macrophages reMains unclear. In this study, we identified for the first tiMe that ApoM is expressed in Mouse Macrophages and is involved in cholesterol uptake, siMilar to SR-BI. NBD-cholesterol uptake and efflux in cells were characterized using fluorescence spectrophotoMetry. The uptake ratios of cholesterol by Macrophages froM ApoM-/- SR-BI-/- Mice were significantly lower than those froM ApoM+/+ SR-BI-/- and ApoM-/- SR-BI+/+ Mice. Real-tiMe fluorescence quantitative PCR was used to analyze the expression of cholesterol transport-related genes involved in cholesterol uptake. ApoM-enriched HDL (ApoM+ HDL) facilitated More cholesterol efflux froM Murine Macrophage Ana-1 cells than ApoM-free HDL (ApoM- HDL). However, recoMbinant huMan ApoM protein inhibited the ability of ApoM- HDL to induce cholesterol efflux. In conclusion, ApoM proMotes cholesterol uptake and efflux in Mouse Macrophages. A better understanding of ApoM function May lead to the developMent of novel therapeutic strategies for treating atherosclerotic diseases.
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Apolipoprotein M inhibits proliferation and Migration of larynx carcinoMa cells.
Scientific reports, 2020Co-Authors: Haixiang Xue, Guang-hua Luo, Jun Zhang, Ying Zhou, Tongbing Chen, Jisheng LiuAbstract:Prior studies have shown that Apolipoprotein M (APOM) is involved in the developMent of soMe cancers. Here we investigated the effects of APOM on larynx cancer (LC). 20 patients with vocal cord polyps and 18 patients with LC were included in this study. The protein and MRNA levels of the saMples were analysed using the Wes-ProteinSiMple systeM (or traditional Western blot) and PCR technology, respectively. APOM protein level in cancer tissues was lower than that in paracarcinoMatous (P = 0.0003) and polyp tissues (P 0.05). In suMMary, APOM inhibits the proliferation and Migration of LC cells, but May not be related to VDR, NFE2L3 and MMP-10, which needs further study.
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Negative Correlation Between SeruM Levels of HoMocysteine and Apolipoprotein M.
Current molecular medicine, 2019Co-Authors: Jiang Wei, Yuehua Feng, Jun Zhang, Xiaoying Zhang, Lu Zheng, Q. Jiang, Guang-hua LuoAbstract:Background: HoMocysteine (Hcy) has been suggested as an independent risk factor for atherosclerosis. Apolipoprotein M (apoM) is a constituent of the HDL particles. The goal of this study was to exaMine the seruM levels of hoMocysteine and apoM and to deterMine whether hoMocysteine influences apoM synthesis. Methods: SeruM levels of apoM and Hcy in 17 hyperhoMocysteineMia (HHcy) patients and 19 controls were Measured and their correlations were analyzed. Different concentrations of hoMocysteine (Hcy) and LY294002, a specific phosphoinositide 3-kinase (PI3K) inhibitor, were used to treat HepG2 cells. The MRNA levels were deterMined by RT-PCR and the apoM protein Mass was Measured by western blot. Results: We found that decreased seruM apoM levels corresponded with seruM HDL levels in HHcy patients, while the seruM apoM levels showed a statistically significant negative correlation with the seruM Hcy levels. Moreover, apoM MRNA and protein levels were significantly decreased after the adMinistration of Hcy in HepG2 cells, and this effect could be abolished by addition of LY294002. Conclusions: Present study deMonstrates that Hcy downregulates the expression of apoM by MechanisMs involving the PI3K signal pathway. (Less)
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Increased Apolipoprotein M induced by lack of scavenger receptor BI is not activated via HDL-Mediated cholesterol uptake in hepatocytes
Lipids in health and disease, 2018Co-Authors: Yuehua Feng, Jiang Wei, Jun Zhang, Lu Zheng, Guang-hua LuoAbstract:Background Scavenger receptor BI (SR-BI) is a classic high-density lipoprotein (HDL) receptor, which Mediates selective lipid uptake froM HDL cholesterol esters (HDL-C). Apolipoprotein M (ApoM), as a coMponent of HDL particles, could influence preβ-HDL forMation and cholesterol efflux. The aiM of this study was to deterMine whether SR-BI deficiency influenced the expression of ApoM.
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effect of Apolipoprotein M on the expression of sphingosine 1 phosphate receptor 1
Chin J Obes Metab Dis(Electronic Edition), 2017Co-Authors: Min Wang, Guang-hua Luo, Youpu Zhang, Bo Huang, Hong Liu, Xiaoying ZhangAbstract:Objective To investigate the effect of Apolipoprotein M (apoM) on the expression of sphingosine-1-phosphate receptor 1 (S1P1). Methods In the vitro experiMent, lentiviruses with apoM gene (the experiMental group) and without apoM gene (the control group) were used to infect the endothelial cells of huMan uMbilical vein (EA.hy926 cells). Then the total MRNAs and proteins were obtained froM the cell lines with stable expression, and RT-PCR was used to detect the expression level of apoM, RT-PCR and Western Blot were used to detect the expression level of S1P1 receptor. In the vivo experiMent, 8~10 week-old and 25-graM-weight healthy wild-type apoM gene (apoM+/+, the experiMental group)and apoM knockout (apoM-/-, the control group) C57BL/6 Mice were selected, with 8 Mice in each group. After they were sacrificed, the liver MRNAs were extracted froM the aortas and reversely transcribed to cDNAs. Then RT-PCR was used to detect the expression level of apoM and S1P1 MRNA. The expressions levels of apoM MRNA, S1P1 MRNA and protein were coMpared between the experiMental and control group in the vitro and vivo experiMents. Results (1) The expression levels of S1P1 MRNA and protein of the EA.hy926 cells in the experiMental group were significantly higher than those of the EA.hy 926 cells in the control group (P<0.05); (2) the expression levels of S1P1 MRNA and protein in the aorta of apoM+/+ Mice were significantly higher than those of the apoM-/- Mice (P<0.05). Conclusion ApoM can increase the expression level of S1P1 MRNA and protein in vivo and vitro. Key words: Apolipoprotein M; Sphingosine-1-phosphate receptor 1; MRNA; Receptor expression
Xiaoying Zhang - One of the best experts on this subject based on the ideXlab platform.
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Negative Correlation Between SeruM Levels of HoMocysteine and Apolipoprotein M.
Current molecular medicine, 2019Co-Authors: Jiang Wei, Yuehua Feng, Jun Zhang, Xiaoying Zhang, Lu Zheng, Q. Jiang, Guang-hua LuoAbstract:Background: HoMocysteine (Hcy) has been suggested as an independent risk factor for atherosclerosis. Apolipoprotein M (apoM) is a constituent of the HDL particles. The goal of this study was to exaMine the seruM levels of hoMocysteine and apoM and to deterMine whether hoMocysteine influences apoM synthesis. Methods: SeruM levels of apoM and Hcy in 17 hyperhoMocysteineMia (HHcy) patients and 19 controls were Measured and their correlations were analyzed. Different concentrations of hoMocysteine (Hcy) and LY294002, a specific phosphoinositide 3-kinase (PI3K) inhibitor, were used to treat HepG2 cells. The MRNA levels were deterMined by RT-PCR and the apoM protein Mass was Measured by western blot. Results: We found that decreased seruM apoM levels corresponded with seruM HDL levels in HHcy patients, while the seruM apoM levels showed a statistically significant negative correlation with the seruM Hcy levels. Moreover, apoM MRNA and protein levels were significantly decreased after the adMinistration of Hcy in HepG2 cells, and this effect could be abolished by addition of LY294002. Conclusions: Present study deMonstrates that Hcy downregulates the expression of apoM by MechanisMs involving the PI3K signal pathway. (Less)
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effect of Apolipoprotein M on the expression of sphingosine 1 phosphate receptor 1
Chin J Obes Metab Dis(Electronic Edition), 2017Co-Authors: Min Wang, Guang-hua Luo, Youpu Zhang, Bo Huang, Hong Liu, Xiaoying ZhangAbstract:Objective To investigate the effect of Apolipoprotein M (apoM) on the expression of sphingosine-1-phosphate receptor 1 (S1P1). Methods In the vitro experiMent, lentiviruses with apoM gene (the experiMental group) and without apoM gene (the control group) were used to infect the endothelial cells of huMan uMbilical vein (EA.hy926 cells). Then the total MRNAs and proteins were obtained froM the cell lines with stable expression, and RT-PCR was used to detect the expression level of apoM, RT-PCR and Western Blot were used to detect the expression level of S1P1 receptor. In the vivo experiMent, 8~10 week-old and 25-graM-weight healthy wild-type apoM gene (apoM+/+, the experiMental group)and apoM knockout (apoM-/-, the control group) C57BL/6 Mice were selected, with 8 Mice in each group. After they were sacrificed, the liver MRNAs were extracted froM the aortas and reversely transcribed to cDNAs. Then RT-PCR was used to detect the expression level of apoM and S1P1 MRNA. The expressions levels of apoM MRNA, S1P1 MRNA and protein were coMpared between the experiMental and control group in the vitro and vivo experiMents. Results (1) The expression levels of S1P1 MRNA and protein of the EA.hy926 cells in the experiMental group were significantly higher than those of the EA.hy 926 cells in the control group (P<0.05); (2) the expression levels of S1P1 MRNA and protein in the aorta of apoM+/+ Mice were significantly higher than those of the apoM-/- Mice (P<0.05). Conclusion ApoM can increase the expression level of S1P1 MRNA and protein in vivo and vitro. Key words: Apolipoprotein M; Sphingosine-1-phosphate receptor 1; MRNA; Receptor expression
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Apolipoprotein M regulates the uptake and efflux of cholesterol in Ana-1 cells
Chinese Journal of Endocrinology and Metabolism, 2017Co-Authors: Fan Zheng, Jun Zhang, Shuang Yao, Guanghua Lou, Xiaoying ZhangAbstract:Objective To understand the role of Apolipoprotein M(apoM) in the uptake and efflux of cholesterol. Methods Ana-1 cells were incubated with different concentrations of NBD-cholesterol to observe the effect of cholesterol concentration and incubation tiMe on cholesterol uptake. The peritoneal Macrophages froM diverse genotypes of Mice were harvested and the efficiencies of cholesterol intake were detected. After incubated with 10μMol/L NBD-cholesterol for 4 hours, the Ana-1 cells were then dealt with different inducing fluid, respectively, suppleMented with or without apoM. NBD-cholesterol uptake and efflux rate were reflected by fluorescent intensity. Results Uptake of NBD-cholesterol in Ana-1 cells was concentration dependent in vitro. The peak of cholesterol uptake by Macrophages appeared at 6 hours, and it was not associated with the concentration of cholesterol or Macrophage genotype. In platforM stage, the uptake rate of cholesterol in ApoM-/-SR-BⅠ-/- Mice was significantly lower than that of the SR-BⅠ-/- Mice and ApoM-/- Mice(t=6.8、13.66, P
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decreased splenic cd4 t lyMphocytes in Apolipoprotein M gene deficient Mice
BioMed Research International, 2015Co-Authors: Zhigang Wang, Guang-hua Luo, Yuehua Feng, Lu Zheng, Hongyao Liu, Yun Liang, Zhonghua Liu, Peng Shao, Maria Berggrensoderlund, Xiaoying ZhangAbstract:Spleen T-lyMphocytes, especially CD4(+) T-cells, have been deMonstrated to be involved in broad iMMunoModulation and host-defense activity in vivo. Apolipoprotein M gene (apoM) May have an iMportant role in the regulation of iMMunoprocess and inflaMMation, which could be hypothesized to the apoM containing sphingosine-1-phosphate (S1P). In the present study we deMonstrate that the splenic CD4(+) T-lyMphocytes were obviously decreased in the apoM gene deficient (apoM(-/-)) Mice coMpared to the wild type (apoM(+/+)). Moreover, these Mice were treated with lipopolysaccharide (LPS) and it was found that even More pronounced decreasing CD4(+) T-lyMphocytes occurred in the spleen coMpared to the apoM(+/+) Mice. The siMilar phenoMena were found in the ratio of CD4(+)/CD8(+) T-lyMphocytes. After adMinistration of LPS, the hepatic MRNA levels of tuMor necrosis factor-α (TNF-α) and Monocyte cheMotactic protein-1 (MCP-1) were Markedly increased; however, there were no statistical differences observed between apoM(+/+) Mice and apoM(-/-) Mice. The present study deMonstrated that apoM Might facilitate the Maintenance of CD4(+) T-lyMphocytes or could Modify the T-lyMphocytes subgroups in Murine spleen, which May further explore the iMportance of apoM in the regulation of the host iMMunoModulation, although the detailed MechanisM needs continuing investigation.
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Decreased Splenic CD4(+) T-LyMphocytes in Apolipoprotein M Gene Deficient Mice
BioMed research international, 2015Co-Authors: Zhigang Wang, Guang-hua Luo, Yuehua Feng, Lu Zheng, Maria Berggren-söderlund, Hongyao Liu, Yun Liang, Zhonghua Liu, Peng Shao, Xiaoying ZhangAbstract:Spleen T-lyMphocytes, especially CD4(+) T-cells, have been deMonstrated to be involved in broad iMMunoModulation and host-defense activity in vivo. Apolipoprotein M gene (apoM) May have an iMportant role in the regulation of iMMunoprocess and inflaMMation, which could be hypothesized to the apoM containing sphingosine-1-phosphate (S1P). In the present study we deMonstrate that the splenic CD4(+) T-lyMphocytes were obviously decreased in the apoM gene deficient (apoM(-/-)) Mice coMpared to the wild type (apoM(+/+)). Moreover, these Mice were treated with lipopolysaccharide (LPS) and it was found that even More pronounced decreasing CD4(+) T-lyMphocytes occurred in the spleen coMpared to the apoM(+/+) Mice. The siMilar phenoMena were found in the ratio of CD4(+)/CD8(+) T-lyMphocytes. After adMinistration of LPS, the hepatic MRNA levels of tuMor necrosis factor-α (TNF-α) and Monocyte cheMotactic protein-1 (MCP-1) were Markedly increased; however, there were no statistical differences observed between apoM(+/+) Mice and apoM(-/-) Mice. The present study deMonstrated that apoM Might facilitate the Maintenance of CD4(+) T-lyMphocytes or could Modify the T-lyMphocytes subgroups in Murine spleen, which May further explore the iMportance of apoM in the regulation of the host iMMunoModulation, although the detailed MechanisM needs continuing investigation.
Lars Nielsen - One of the best experts on this subject based on the ideXlab platform.
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Apolipoprotein M and Risk of Type 2 Diabetes.
The Journal of clinical endocrinology and metabolism, 2020Co-Authors: Stefan Hajny, Lars Nielsen, M. Christoffersen, N. Dalila, Anne Tybjærg-hansen, Christina ChristoffersenAbstract:Context Recent studies have discovered a role of Apolipoprotein M (apoM) in energy MetabolisM, and observational analyses in huMans suggest an association with type 2 diabetes. The causal relationship reMains however elusive. Objective To investigate whether reduced plasMa apoM concentrations are causally linked to increased risk of type 2 diabetes. Design Prospective study design analyzed by Mendelian randoMization. Setting and participants Two cohorts reflecting the Danish general population: the Copenhagen City Heart Study (CCHS, n = 8589) and the Copenhagen General Population Study (CGPS; n = 93 857). Observational analyses included a subset of participants froM the CCHS with available plasMa apoM (n = 725). Genetic analyses included the coMplete cohorts (n = 102 446). During a Median follow-up of 16 years (CCHS) and 8 years (CGPS), 563 and 2132 participants developed type 2 diabetes. Main outcoMe Measures PlasMa apoM concentration, genetic variants in APOM, and type 2 diabetes. Results First, we identified an inverse correlation between plasMa apoM and risk of type 2 diabetes in a subset of participants froM the CCHS (hazard ratio between highest vs lowest quartile (reference) = 0.32; 95% confidence interval = 0.1-1.01; P for trend = .02). Second, genotyping of specific single nucleotide polyMorphisMs in APOM further revealed a 10.8% (P = 6.2 × 10-5) reduced plasMa apoM concentration in participants with variant rs1266078. Third, a Meta-analysis including data froM 599 451 individuals showed no association between rs1266078 and risk of type 2 diabetes. Conclusions The present study does not appear to support a causal association between plasMa apoM and risk of type 2 diabetes.
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Effect of Menopause and exercise training on plasMa Apolipoprotein M and sphingosine-1-phosphate
Journal of applied physiology (Bethesda Md. : 1985), 2018Co-Authors: Adelina Yafasova, Camilla M. Mandrup, Jon Egelund, Michael Nyberg, Bente Stallknecht, Ylva Hellsten, Lars Nielsen, Christina ChristoffersenAbstract:The Apolipoprotein M/sphingosine-1-phosphate (apoM/S1P) coMplex is involved in Maintaining a healthy endothelial barrier function. Our study is the first, to our knowledge, to show how Menopause af...
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Apolipoprotein M Mediates sphingosine-1-phosphate efflux froM erythrocytes
Scientific reports, 2017Co-Authors: Pernille M. Christensen, Lars Nielsen, Markus H. Bosteen, Stefan Hajny, Christina ChristoffersenAbstract:Sphingosine-1-phosphate (S1P) is a bioactive lipid iMplicated in e.g. angiogenesis, lyMphocyte trafficking, and endothelial barrier function. Erythrocytes are a Main source of plasMa S1P together with platelets and endothelial cells. Apolipoprotein M (apoM) in HDL carries 70% of plasMa S1P, whereas 30% is carried by albuMin. The current aiM was to investigate the role of apoM in export of S1P froM huMan erythrocytes. Erythrocytes exported S1P More efficiently to HDL than to albuMin, particularly when apoM was present in HDL. In contrast, export of sphingosine to HDL was unaffected by the presence of apoM. The specific ability of apoM to proMote export of S1P was independent of apoM being bound in HDL particles. TreatMent with MK-571, an inhibitor of the ABCC1 transporter, effectively reduced export of S1P froM huMan erythrocytes to apoM, whereas the export was unaffected by inhibitors of ABCB1 or ATPase. Thus, ABCC1 could be involved in export of S1P froM erythrocytes to apoM.
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IMpaired endothelial barrier function in Apolipoprotein M–deficient Mice is dependent on sphingosine-1-phosphate receptor 1
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2016Co-Authors: Pernille M. Christensen, Lars Nielsen, Hideru Obinata, Timothy Hla, Catherine H. Liu, Steven L. Swendeman, Klaus Qvortrup, Annarita Di Lorenzo, Christina ChristoffersenAbstract:Apolipoprotein M (ApoM) transports sphingosine-1-phosphate (S1P) in plasMa, and ApoM-deficient Mice (ApoM(-/-)) have ∼50% reduced plasMa S1P levels. There are 5 known S1P receptors, and S1P induces adherens junction forMation between endothelial cells through the S1P1 receptor, which in turn suppresses vascular leak. Increased vascular perMeability is a hallMark of inflaMMation. The purpose of this study was to explore the relationships between vascular leakage in ApoM deficiency and S1P1 function in norMal physiology and in inflaMMation. Vascular perMeability in the lungs was assessed by accuMulation of dextran Molecules (70 kDa) and was increased ∼40% in ApoM(-/-) Mice coMpared to WT (C57Bl6/j) Mice. Reconstitution of plasMa ApoM/S1P or treatMent with an S1P1 receptor agonist (SEW2871) rapidly reversed the vascular leakage to a level siMilar to that in WT Mice, suggesting that it is caused by decreased plasMa levels of S1P and reduced S1P1 stiMulation. In a carrageenan-induced Model of inflaMMation, ApoM(-/-) Mice had increased vascular leakage coMpared with that in WT Mice. Adenoviral overexpression of ApoM in ApoM(-/-) Mice decreased the vascular leakage coMpared to adenoviral overexpression of green fluorescent protein. The study suggests that vascular leakage of albuMin-sized particles in ApoM deficiency is S1P- and S1P1-dependent and this dependency exacerbates the response to inflaMMatory stiMuli.-Christensen, P. M., Liu, C. H., SwendeMan, S. L., Obinata, H., Qvortrup, K., Nielsen, L B., Hla, T., Di Lorenzo, A., Christoffersen, C. IMpaired endothelial barrier function in Apolipoprotein M-deficient Mice is dependent on sphingosine-1-phosphate receptor 1.
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iMpaired endothelial barrier function in Apolipoprotein M deficient Mice is dependent on sphingosine 1 phosphate receptor 1
The FASEB Journal, 2016Co-Authors: Pernille M. Christensen, Lars Nielsen, Hideru Obinata, Timothy Hla, Catherine H. Liu, Steven L. Swendeman, Klaus Qvortrup, Annarita Di Lorenzo, Christina ChristoffersenAbstract:Apolipoprotein M (ApoM) transports sphingosine-1-phosphate (S1P) in plasMa, and ApoM-deficient Mice (ApoM(-/-)) have ∼50% reduced plasMa S1P levels. There are 5 known S1P receptors, and S1P induces adherens junction forMation between endothelial cells through the S1P1 receptor, which in turn suppresses vascular leak. Increased vascular perMeability is a hallMark of inflaMMation. The purpose of this study was to explore the relationships between vascular leakage in ApoM deficiency and S1P1 function in norMal physiology and in inflaMMation. Vascular perMeability in the lungs was assessed by accuMulation of dextran Molecules (70 kDa) and was increased ∼40% in ApoM(-/-) Mice coMpared to WT (C57Bl6/j) Mice. Reconstitution of plasMa ApoM/S1P or treatMent with an S1P1 receptor agonist (SEW2871) rapidly reversed the vascular leakage to a level siMilar to that in WT Mice, suggesting that it is caused by decreased plasMa levels of S1P and reduced S1P1 stiMulation. In a carrageenan-induced Model of inflaMMation, ApoM(-/-) Mice had increased vascular leakage coMpared with that in WT Mice. Adenoviral overexpression of ApoM in ApoM(-/-) Mice decreased the vascular leakage coMpared to adenoviral overexpression of green fluorescent protein. The study suggests that vascular leakage of albuMin-sized particles in ApoM deficiency is S1P- and S1P1-dependent and this dependency exacerbates the response to inflaMMatory stiMuli.-Christensen, P. M., Liu, C. H., SwendeMan, S. L., Obinata, H., Qvortrup, K., Nielsen, L B., Hla, T., Di Lorenzo, A., Christoffersen, C. IMpaired endothelial barrier function in Apolipoprotein M-deficient Mice is dependent on sphingosine-1-phosphate receptor 1.
Yutaka Yatomi - One of the best experts on this subject based on the ideXlab platform.
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Protection Against Insulin Resistance by Apolipoprotein M/Sphingosine 1-Phosphate.
Diabetes, 2020Co-Authors: Makoto Kurano, Kazuhisa Tsukamoto, Tomo Shimizu, Hidetoshi Kassai, Kazuki Nakao, Atsu Aiba, Masumi Hara, Yutaka YatomiAbstract:Subjects with low seruM HDL cholesterol levels are reported to be susceptible to diabetes, with insulin resistance believed to be the underlying pathological MechanisM. Apolipoprotein M (apoM) is a carrier of sphingosine-1-phosphate (S1P), a Multifunctional lipid Mediator, on HDL, and the pleiotropic effects of HDL are believed to be Mediated by S1P. In the current study, we atteMpted to investigate the potential association between apoM/S1P and insulin resistance. We observed that the seruM levels of apoM were lower in patients with type 2 diabetes and that they were negatively correlated with BMI and the insulin resistance index. While deletion of apoM in Mice was associated with worsening of insulin resistance, overexpression of apoM was associated with iMproveMent of insulin resistance. PresuMably, apoM/S1P exerts its protective effect against insulin resistance by activating insulin signaling pathways, such as the AKT and AMPK pathways, and also by iMproving the Mitochondrial functions through upregulation of SIRT1 protein levels. These actions of apoM/S1P appear to be Mediated via activation of S1P1 and/or S1P3. These results suggest that apoM/S1P exerts protective roles against the developMent of insulin resistance.
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Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper-IgA Mice
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2019Co-Authors: Makoto Kurano, Koichi Tsuneyama, Yuki Morimoto, Masako Nishikawa, Yutaka YatomiAbstract:Because the association between sphingosine 1-phosphate (S1P)/Apolipoprotein M (ApoM) and chronic kidney diseases has not been established, we investigated the involveMent of S1P/ApoM in the phenot...
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Apolipoprotein M Protects Lipopolysaccharide-Treated Mice froM Death and Organ Injury.
Thrombosis and haemostasis, 2018Co-Authors: Makoto Kurano, Koichi Tsuneyama, Yuki Morimoto, Tomo Shimizu, Hidetoshi Kassai, Kazuki Nakao, Atsu Aiba, Masahiro Jona, Yutaka YatomiAbstract:High-density lipoprotein (HDL) has been epideMiologically shown to be associated with the outcoMe of sepsis. One potential MechanisM is that HDL possesses pleiotropic effects, such as anti-apoptosis, soMe of which can be ascribed to sphingosine 1-phosphate (S1P) carried on HDL via Apolipoprotein M (apoM). Therefore, the aiM of this study was to elucidate the roles of apoM/S1P in the consequent lethal conditions of sepsis, such as Multiple organ failure caused by severe inflaMMation and/or disseMinated intravascular coagulation. In Mice treated with lipopolysaccharide (LPS), both plasMa apoM levels and the expression of apoM in the liver and kidney were suppressed. The overexpression of apoM iMproved the survival rate and aMeliorated the elevated plasMa alanine aMinotransferase (ALT) and creatinine levels, while the knockout or knockdown of apoM deteriorated these paraMeters in Mice treated with LPS. TreatMent with VPC23019, an antagonist against S1P receptor 1 and 3, or LY294002, a PI3K inhibitor, partially reversed these protective properties arising froM the overexpression of apoM. The overexpression of apoM inhibited the elevation of plasMa plasMinogen activator inhibitor-1, restored the phosphorylation of Akt, and induced anti-apoptotic changes in the liver, kidney and heart. These results suggest that apoM possesses protective properties against LPS-induced organ injuries and could potentially be introduced as a novel therapy for the severe conditions that are consequent to sepsis. Schattauer GMbH Stuttgart.
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Apolipoprotein M Protects Lipopolysaccharide-Treated Mice froM Death and Organ Injury.
Thrombosis and Haemostasis, 2018Co-Authors: Makoto Kurano, Koichi Tsuneyama, Yuki Morimoto, Tomo Shimizu, Hidetoshi Kassai, Kazuki Nakao, Atsu Aiba, Masahiro Jona, Yutaka YatomiAbstract:Objective High-density lipoprotein (HDL) has been epideMiologically shown to be associated with the outcoMe of sepsis. One potential MechanisM is that HDL possesses pleiotropic effects, such as anti-apoptosis, soMe of which can be ascribed to sphingosine 1-phosphate (S1P) carried on HDL via Apolipoprotein M (apoM). Therefore, the aiM of this study was to elucidate the roles of apoM/S1P in the consequent lethal conditions of sepsis, such as Multiple organ failure caused by severe inflaMMation and/or disseMinated intravascular coagulation. Methods and Results In Mice treated with lipopolysaccharide (LPS), both plasMa apoM levels and the expression of apoM in the liver and kidney were suppressed. The overexpression of apoM iMproved the survival rate and aMeliorated the elevated plasMa alanine aMinotransferase (ALT) and creatinine levels, while the knockout or knockdown of apoM deteriorated these paraMeters in Mice treated with LPS. TreatMent with VPC23019, an antagonist against S1P receptor 1 and 3, or LY294002, a PI3K inhibitor, partially reversed these protective properties arising froM the overexpression of apoM. The overexpression of apoM inhibited the elevation of plasMa plasMinogen activator inhibitor-1, restored the phosphorylation of Akt, and induced anti-apoptotic changes in the liver, kidney and heart. Conclusion These results suggest that apoM possesses protective properties against LPS-induced organ injuries and could potentially be introduced as a novel therapy for the severe conditions that are consequent to sepsis.
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Resveratrol exerts a biphasic effect on Apolipoprotein M
British journal of pharmacology, 2015Co-Authors: Makoto Kurano, Kazuhisa Tsukamoto, Masumi Hara, Takahiro Nojiri, Hitoshi Ikeda, Yutaka YatomiAbstract:Background and Purpose Resveratrol exerts a range of beneficial actions in several areas of pathophysiology, including vascular biology. Here, we have investigated the effects of resveratrol on Apolipoprotein M (apoM), a carrier and Modulator of sphingosine 1-phosphate (S1P), a vasoactive lipid Mediator. ExperiMental Approach We used a hepatoMa cell line (HepG2), huMan priMary hepatocytes and C57BL/6 Mice. We Measured apoM, S1P and related enzyMes, LDL receptors and sirtuin1 activity, using Western blotting, RT-PCR and enzyMe assays. We also used si-RNA to knock-down sirtuin1 in HepG2 cells. Key Results In cultures of HepG2 cells, resveratrol (1-10 μM) increased intracellular apoM and S1P. High concentrations of resveratrol (100 μM) decreased extracellular (in the culture MediuM) apoM, whereas Moderate concentrations of resveratrol (1–10 μM) increased extracellular apoM. High concentrations of resveratrol also increased LDL receptor expression, while all concentrations of resveratrol activated the histone deacetylase sirtuin1. In cultures of huMan priMary hepatocytes, resveratrol, at all concentrations, increased both intra- and extracellular apoM. When wild-type Mice were fed a resveratrol-containing chow (0.3% w/w) for 2 weeks, both the plasMa and hepatic apoM and S1P levels were increased. However, the resveratrol diet did not affect hepatic LDL receptor levels in this in vivo study. Conclusions and IMplications Resveratrol increased intra- and extracellular levels of apoM, along with intracellular S1P levels, while a high concentration of resveratrol reduced extracellular apoM. The present findings suggest that resveratrol has novel effects on the Metabolic kinetics of S1P, a Multi-functional bioactive phospholipid.