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Henrik Gold,
Mina Mirzaian,
Nick Dekker,
Maria Joao Ferraz,
Johan Lugtenburg,
Jeroen D C Codée,
Gijs A van der Marel,
Herman S Overkleeft,
Gabor E Linthorst,
Johanna E M Groener, Johannes M Aerts,
Ben J H M Poorthuis
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ABSTRACT: BACKGROUND: Biochemical markers that accurately reflect the severity and progression of disease in patients with Fabry disease and their response to treatment are urgently needed. Globotriaosylsphingosine, also called lysoglobotriaosylceramide (lysoGb3), is a promising candidate biomarker.METHODS: We synthesized lysoGb3 and isotope-labeled [5,6,7,8,9] (13)C(5)-lysoGb3 (internal standard). After addition of the internal standard to 25 μL plasma or 400 μL urine from patients with Fabry disease and healthy controls, samples were extracted with organic solvents and the lysoGb3 concentration was quantified by UPLC-ESI-MS/MS (ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry). Calibration curves were constructed with control plasma and urine supplemented with lysoGb3. In addition to lysoGb3, lyso-ene-Gb3 was quantified. Quantification was achieved by multiple reaction monitoring of the transitions m/z 786.4 > 282.3 [M+H](+) for lysoGb3, m/z 791.4 > 287.3 [M+H](+) for [5,6,7,8,9] (13)C(5)-lysoGb3, and 784.4 > 280.3 [M+H](+) for lyso-ene-Gb3.RESULTS: The mean (SD) plasma lysoGb3 concentration from 10 classically affected Fabry hemizygotes was 94.4 (25.8) pmol/mL (range 52.7-136.8 pmol/mL), from 10 classically affected Fabry heterozygotes 9.6 (5.8) pmol/mL (range 4.1-23.5 pmol/mL), and from 20 healthy controls 0.4 (0.1) pmol/mL (range 0.3-0.5 pmol/mL). Lyso-ene-Gb3 concentrations were 10%-25% of total lysoGb3. The urine concentration of lysoGb3 was 40-480 times lower than in corresponding plasma samples. Lyso-ene-Gb3 concentrations in urine were comparable or even higher than the corresponding lysoGb3 concentrations.CONCLUSIONS: This assay for the quantification of lysoGb3 and lyso-ene-Gb3 in human plasma and urine samples will be an important tool in the diagnosis of Fabry disease and for monitoring the effect of enzyme replacement therapy in patients with Fabry disease.
Clinical Chemistry 12/2012; · 7.91 Impact Factor
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Carlos L J Vrins,
Roelof Ottenhoff,
Karin van den Oever,
Dirk R de Waart,
J Kar Kruyt,
Ying Zhao,
Theo J C van Berkel,
Louis M Havekes, Johannes M Aerts,
Miranda van Eck,
Patrick C N Rensen,
Albert K Groen
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ABSTRACT: Transintestinal cholesterol efflux (TICE) provides an attractive target to increase body cholesterol excretion. At present, the cholesterol donor responsible for direct delivery of plasma cholesterol to the intestine is unknown. In this study, we investigated the role of HDL in TICE. ATP-binding cassette protein A1 deficient (Abca1(-/-)) mice that lack HDL and wild-type (WT) mice were intravenously injected with chylomicron-like emulsion particles that contained radiolabeled cholesterol that is liberated in the liver and partly reenters the circulation. Both groups secreted radiolabeled cholesterol from plasma into intestinal lumen and TICE was unaltered between the two mouse models. To further investigate the role of HDL, we injected HDL with radiolabeled cholesterol in WT mice and Abca1(-/-)×Sr-b1(-/-) mice that lack HDL and are also unable to clear HDL via the liver. The intestines of both mice were unable to take up and secrete radiolabeled cholesterol from HDL via TICE. Although a generally accepted major player in the hepatobiliary route-based cholesterol excretion, HDL plays no significant role in TICE in mice.
The Journal of Lipid Research 07/2012; 53(10):2017-23. · 5.56 Impact Factor
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Adriaan G Holleboom,
Helen Karlsson,
Ruei-Shiuan Lin,
Thomas M Beres,
Jeroen A Sierts,
Daniel S Herman,
Erik S G Stroes, Johannes M Aerts,
John J P Kastelein,
Mohammad M Motazacker, [......],
Christine E Seidman,
Stefan Ljunggren,
Dirk J Lefeber,
Eva Morava,
Ron A Wevers,
Timothy A Fritz,
Lawrence A Tabak,
Mats Lindahl,
G Kees Hovingh,
Jan Albert Kuivenhoven
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ABSTRACT: Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.
Cell metabolism 12/2011; 14(6):811-8. · 17.35 Impact Factor
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Nick Dekker,
Laura van Dussen,
Carla E M Hollak,
Herman Overkleeft,
Saskia Scheij,
Karen Ghauharali,
Mariëlle J van Breemen,
Maria J Ferraz,
Johanna E M Groener,
Mario Maas,
Frits A Wijburg,
Dave Speijer,
Anna Tylki-Szymanska,
Pramod K Mistry,
Rolf G Boot, Johannes M Aerts
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ABSTRACT: Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leads to prominent glucosylceramide accumulation in lysosomes of tissue macrophages (Gaucher cells). Here we show glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of symptomatic nonneuronopathic (type 1) Gaucher patients (n = 64, median = 230.7 nM, range 15.6-1035.2 nM; normal (n = 28): median 1.3 nM, range 0.8-2.7 nM). The method developed for mass spectrometric quantification of plasma glucosylsphingosine is sensitive and robust. Plasma glucosylsphingosine levels correlate with established plasma markers of Gaucher cells, chitotriosidase (ρ = 0.66) and CCL18 (ρ = 0.40). Treatment of Gaucher disease patients by supplementing macrophages with mannose-receptor targeted recombinant glucocerebrosidase results in glucosylsphingosine reduction, similar to protein markers of Gaucher cells. Since macrophages prominently accumulate the lysoglycosphingolipid on glucocerebrosidase inactivation, Gaucher cells seem a major source of the elevated plasma glucosylsphingosine. Our findings show that plasma glucosylsphingosine can qualify as a biomarker for type 1 Gaucher disease, but that further investigations are warranted regarding its relationship with clinical manifestations of Gaucher disease.
Blood 08/2011; 118(16):e118-27. · 9.90 Impact Factor
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Mirjam Langeveld,
Sjoerd A A van den Berg,
Nora Bijl,
Silvia Bijland,
Cindy P van Roomen,
Judith H Houben-Weerts,
Roelof Ottenhoff,
Sander M Houten,
Ko Willems van Dijk,
Johannes A Romijn,
Albert K Groen, Johannes M Aerts,
Peter J Voshol
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ABSTRACT: Obesity and its associated conditions such as type 2 diabetes mellitus are major causes of morbidity and mortality. The iminosugar N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin (AMP-DNM) improves insulin sensitivity in rodent models of insulin resistance and type 2 diabetes mellitus. In the current study, we characterized the impact of AMP-DNM on substrate oxidation patterns, food intake, and body weight gain in obese mice. Eight ob/ob mice treated with 100 mg/(kg d) AMP-DNM mixed in the food and 8 control ob/ob mice were placed in metabolic cages during the first, third, and fifth week of the experiment for measurement of substrate oxidation rates, energy expenditure, activity, and food intake. Mice were killed after 6 weeks of treatment. Initiation of treatment with AMP-DNM resulted in a rapid increase in fat oxidation by 129% (P = .05), a decrease in carbohydrate oxidation by 35% (P = .01), and a reduction in food intake by approximately 26% (P < .01) compared with control mice. Treatment with AMP-DNM decreased hepatic triglyceride content by 66% (P < .01) and, in line with the elevated fat oxidation rates, increased hepatic carnitine palmitoyl transferase 1a expression. Treatment with AMP-DNM increased plasma levels of the appetite-regulating peptide YY compared with control mice. Treatment with AMP-DNM rapidly reduces food intake and increases fat oxidation, resulting in improvement of the obese phenotype. These features of AMP-DNM, together with its insulin-sensitizing capacity, make it an attractive candidate drug for the treatment of obesity and its associated metabolic derangements.
Metabolism: clinical and experimental 08/2011; 61(1):99-107. · 2.59 Impact Factor
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ABSTRACT: Fabry disease is treated by two-weekly infusions with α-galactosidase A, which is deficient in this X-linked globotriaosylceramide (Gb3) storage disorder. Elevated plasma globotriaosylsphingosine (lysoGb3) is a hallmark of classical Fabry disease. We investigated effects of enzyme replacement therapy (ERT) on plasma levels of lysoGb3 and Gb3 in patients with classical Fabry disease treated with agalsidase alfa at 0.2mg/kg, agalsidase beta at 0.2mg/kg or at 1.0mg/kg bodyweight. Each treatment regimen led to prominent reductions of plasma lysoGb3 in Fabry males within 3 months (P=0.0313), followed by relative stability later on. Many males developed antibodies against α-galactosidase A, particularly those treated with agalsidase beta. Patients with antibodies tended towards smaller correction in plasma lysoGb3 concentration, whereas treatment with high dose agalsidase beta allowed a reduction comparable to patients without antibodies. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low. In all females and with each treatment regimen, ERT gave reduction or stabilisation of plasma lysoGb3. Our investigation revealed that ERT of Fabry patients reduces plasma lysoGb3, regardless of the recombinant enzyme used. This finding shows that ERT can correct a characteristic biochemical abnormality in Fabry patients.
Biochimica et Biophysica Acta 01/2011; 1812(1):70-6. · 4.66 Impact Factor
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Johannes M Aerts,
Rolf G Boot,
Marco van Eijk,
Johanna Groener,
Nora Bijl,
Elisa Lombardo,
Florence M Bietrix,
Nick Dekker,
Albert K Groen,
Roelof Ottenhoff,
Cindy van Roomen,
Jan Aten,
Mireille Serlie,
Mirjam Langeveld,
Tom Wennekes,
Hermen S Overkleeft
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ABSTRACT: Glycosphingolipids are structural membrane components, residing largely in the plasma membrane with their sugar-moieties exposed at the cell's surface. In recent times a crucial role for glycosphingolipids in insulin resistance has been proposed. A chronic state of insulin resistance is a rapidly increasing disease condition in Western and developing countries. It is considered to be the major underlying cause of the metabolic syndrome, a combination of metabolic abnormalities that increases the risk for an individual to develop Type 2 diabetes, obesity, cardiovascular disease, polycystic ovary syndrome and nonalcoholic fatty liver disease. As discussed in this chapter, the evidence for a direct regulatory interaction of glycosphingolipids with insulin signaling is still largely indirect. However, the recent finding in animal models that pharmacological reduction of glycosphingolipid biosynthesis ameliorates insulin resistance and prevents some manifestations of metabolic syndrome, supports the view that somehow glycosphingolipids act as critical regulators, Importantly, since reductions in glycosphingolipid biosynthesis have been found to be well tolerated, such approaches may have a therapeutic potential.
Advances in experimental medicine and biology 01/2011; 721:99-119. · 1.09 Impact Factor
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ABSTRACT: The chemoenzymatic synthesis of three 1-deoxynojirimycin-type iminosugars is reported. Key steps in the synthetic scheme include a Dibal reduction-transimination-sodium borohydride reduction cascade of reactions on an enantiomerically pure cyanohydrin, itself prepared employing almond hydroxynitrile lyase (paHNL) as the common precursor. Ensuing ring-closing metathesis and Upjohn dihydroxylation afford the target compounds.
Organic Letters 09/2010; 12(17):3957-9. · 5.86 Impact Factor
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Richard Jennemann,
Ulrike Rothermel,
Shijun Wang,
Roger Sandhoff,
Sylvia Kaden,
Ruud Out,
Theo J van Berkel, Johannes M Aerts,
Karen Ghauharali,
Carsten Sticht,
Hermann-Josef Gröne
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ABSTRACT: Recent studies have reported that glycosphingolipids (GSLs) might be involved in obesity-induced insulin resistance. Those reports suggested that inhibition of GSL biosynthesis in animals ameliorated insulin resistance accompanied by improved glycemic control and decreased liver steatosis in obese mice. In addition, pharmacologic GSL depletion altered hepatic secretory function. In those studies, ubiquitously acting inhibitors for GSL biosynthesis have been used to inhibit the enzyme Ugcg (UDP-glucose:ceramide glucosyltransferase), catalyzing the first step of the glucosylceramide-based GSL-synthesis pathway. In the present study a genetic approach for selective GSL deletion in hepatocytes was chosen to achieve complete inhibition of GSL synthesis and to avoid possible adverse effects caused by Ugcg inhibitors. Using the Cre/loxP system under control of the albumin promoter, GSL biosynthesis in hepatocytes and their release into the plasma could be effectively blocked. Deletion of GSL in hepatocytes did not change the quantity of bile excretion through the biliary duct. Total bile salt content in bile, feces, and plasma from mutant mice showed no difference as compared to control animals. Cholesterol concentration in liver, bile, feces, and plasma samples remained unaffected. Lipoprotein concentrations in plasma samples in mutant animals reached similar levels as in their control littermates. No alteration in glucose tolerance after intraperitoneal application of glucose and insulin appeared in mutant animals. A preventive effect of GSL deficiency on development of liver steatosis after a high-fat diet was not observed. CONCLUSION: The data suggest that GSL in hepatocytes are not essential for sterol, glucose, or lipoprotein metabolism and do not prevent high-fat diet-induced liver steatosis, indicating that Ugcg inhibitors exert their effect on hepatocytes either independently of GSL or mediated by other (liver) cell types.
Hepatology 05/2010; 51(5):1799-809. · 11.66 Impact Factor
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ABSTRACT: The iminosugar N-(5'-adamantane-1'-yl-methoxy)-pentyl-1-deoxynoijirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase catalyzing glycosphingolipid (GSL) biosynthesis, ameliorates diabetes and reduces liver steatosis in ob/ob mice. Because an accumulation of sphingolipids, including sphingomyelin and GSLs, has been reported in atherosclerotic lesions in animal models and in humans, the objective of this study was to determine whether AMP-DNM also exerts beneficial effects on the development of atherosclerosis.
APOE*3 Leiden mice, maintained on a high-cholesterol diet, were treated for up to 18 weeks with AMP-DNM. The iminosugar prevented hyperlipidemia, generated a less atherogenic lipid profile, and induced a dramatic reduction in the development of atherosclerotic lesions. At the highest dose, no lesions were detectable. The effect of AMP-DNM was associated with a decrease in liver cholesterol, an increase in bile secretion, and enhanced excretion of cholesterol in the feces. Similar effects of AMP-DNM were observed in mice deficient for the low-density lipoprotein receptor.
By lowering plasma cholesterol, the iminosugar AMP-DNM dramatically reduces the development of atherosclerosis in APOE*3 Leiden and low-density lipoprotein receptor -/- mice. Thus, targeting GSL synthesis may be a new treatment modality to prevent cardiovascular disease.
Arteriosclerosis Thrombosis and Vascular Biology 02/2010; 30(5):931-7. · 6.37 Impact Factor
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Tom Wennekes,
Alfred J. Meijer,
Albert K. Groen,
Rolf G. Boot,
Johanna E. Groener,
Marco van Eijk,
Roelof Ottenhoff,
Nora Bijl,
Karen Ghauharali,
Hang Song,
Tom J. O’Shea,
Hanlan Liu,
Nelson Yew,
Diane Copeland,
Richard J. van den Berg,
Gijsbert A. van der Marel,
Herman S. Overkleeft, Johannes M. Aerts
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ABSTRACT: The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action of 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the l-ido derivative of 2, l-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbA1c. We conclude that the combination of reduction of glycosphingolipids in tissue and buffering of carbohydrate assimilation by 2 produces a superior glucose homeostasis.
Journal of Medicinal Chemistry 12/2009; 53(2). · 4.80 Impact Factor
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ABSTRACT: Accumulation of macrophages in multiple organs is a common feature of sarcoidosis and Gaucher disease. The vast number of storage macrophages in Gaucher patients has facilitated the discovery of suitable plasma markers like chitotriosidase and CCL18.
Plasma specimens of patients with sarcoidosis were examined on chitotriosidase activity and CCL18 protein levels.
Chitotriosidase was markedly increased, being on average 13.7-fold elevated (range: 1.1-43.3). The sensitivity of demonstrating sarcoidosis using plasma chitotriosidase values exceeded that using serum angiotensin-converting enzyme values. A 3.5-fold (range: 1-15) increase in CCL18 was also observed. The relative changes in chitotriosidase and CCL18 during the course of disease closely mimicked each other, suggesting an identical cellular source. In situ hybridization analysis confirmed massive production of chitotriosidase by sarcoid macrophages. The increase in plasma chitotriosidase correlated with the stage of disease, being highest in active sarcoidosis with extrapulmonary involvement. Therapy with steroids resulted in clear reduction of plasma chitotriosidase and CCL18 and relapse of disease activity was preceded by increases in these parameters.
Sarcoid macrophages secrete high quantities of chitotriosidase and CCL18. Determination of plasma chitotriosidase and CCL18 may be useful to monitor changes in granulomatous macrophages during the course of sarcoidosis.
Clinica chimica acta; international journal of clinical chemistry 10/2009; 411(1-2):31-6. · 2.54 Impact Factor
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ABSTRACT: Intermittent fasting (IF) was shown to increase whole-body insulin sensitivity, but it is uncertain whether IF selectively influences intermediary metabolism. Such selectivity might be advantageous when adapting to periods of food abundance and food shortage.
The objective was to assess effects of IF on intermediary metabolism and energy expenditure.
Glucose, glycerol, and valine fluxes were measured after 2 wk of IF and a standard diet (SD) in 8 lean healthy volunteers in a crossover design, in the basal state and during a 2-step hyperinsulinemic euglycemic clamp, with assessment of energy expenditure and phosphorylation of muscle protein kinase B (AKT), glycogen synthase kinase (GSK), and mammalian target of rapamycine (mTOR). We hypothesized that IF selectively increases peripheral glucose uptake and lowers proteolysis, thereby protecting protein stores.
No differences in body weight were observed between the IF and SD groups. Peripheral glucose uptake and hepatic insulin sensitivity during the clamp did not significantly differ between the IF and SD groups. Likewise, lipolysis and proteolysis were not different between the IF and SD groups. IF decreased resting energy expenditure. IF had no effect on the phosphorylation of AKT but significantly increased the phosphorylation of glycogen synthase kinase. Phosphorylation of mTOR was significantly lower after IF than after the SD.
IF does not affect whole-body glucose, lipid, or protein metabolism in healthy lean men despite changes in muscle phosphorylation of GSK and mTOR. The decrease in resting energy expenditure after IF indicates the possibility of an increase in weight during IF when caloric intake is not adjusted. This study was registered at www.trialregister.nl as NTR1841.
American Journal of Clinical Nutrition 09/2009; 90(5):1244-51. · 6.67 Impact Factor
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Hongmei Zhao,
Malgorzata Przybylska,
I-Huan Wu,
Jinhua Zhang,
Panagiotis Maniatis,
Joshua Pacheco,
Peter Piepenhagen,
Diane Copeland,
Cynthia Arbeeny,
James A Shayman, Johannes M Aerts,
Canwen Jiang,
Seng H Cheng,
Nelson S Yew
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ABSTRACT: Steatosis in the liver is a common feature of obesity and type 2 diabetes and the precursor to the development of nonalcoholic steatohepatitis (NASH), cirrhosis, and liver failure. It has been shown previously that inhibiting glycosphingolipid (GSL) synthesis increases insulin sensitivity and lowers glucose levels in diabetic rodent models. Here we demonstrate that inhibiting GSL synthesis in ob/ob mice not only improved glucose homeostasis but also markedly reduced the development of hepatic steatosis. The ob/ob mice were treated for 7 weeks with a specific inhibitor of glucosylceramide synthase, the initial enzyme involved in the synthesis of GSLs. Besides lowering glucose and hemoglobin A1c (HbA1c) levels, drug treatment also significantly reduced the liver/body weight ratio, decreased the accumulation of triglycerides, and improved several markers of liver pathology. Drug treatment reduced liver glucosylceramide (GL1) levels in the ob/ob mouse. Treatment also reduced the expression of several genes associated with hepatic steatosis, including those involved in lipogenesis, gluconeogenesis, and inflammation. In addition, inhibiting GSL synthesis in diet-induced obese mice both prevented the development of steatosis and partially reversed preexisting steatosis. CONCLUSION: These data indicate that inhibiting GSL synthesis ameliorates the liver pathology associated with obesity and diabetes, and may represent a novel strategy for treating fatty liver disease and NASH.
Hepatology 04/2009; 50(1):85-93. · 11.66 Impact Factor
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Barbara C van Munster,
Marielle J van Breemen,
Perry D Moerland,
Dave Speijer,
Sophia E De Rooij,
Christel J Pfrommer,
Marcel Levi,
Markus W Hollmann, Johannes M Aerts,
Aeilko H Zwinderman,
Johanna C Korevaar
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ABSTRACT: The aim of this study was to compare plasma and serum protein profiles in elderly acute hip fracture patients with and without delirium. The spectra from surface-enhanced laser desorption ionization (SELDI) using time-of-flight (TOF) mass spectrometry of 16 patients without and 16 patients with delirium (two groups of eight and eight) scored using the Confusion Assessment Method were compared. The most discriminating peak of 15.9 kDa in plasma in a testing group of eight patients with delirium to eight patients without delirium was confirmed in an independent validation group. Taking both groups together, three discriminating peaks of 7.97, 15.9, and 16.0 kDa were found in delirious patients. These peaks presumably correspond to hemoglobin-beta, its doubly charged ion, and its glycosylated form.
The Journal of neuropsychiatry and clinical neurosciences 01/2009; 21(3):284-91. · 2.34 Impact Factor
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ABSTRACT: Recent reports indicate that glycosphingolipids play an important role in regulation of carbohydrate metabolism. We have shown that the iminosugar N-(5'-adamantane-1'-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase, is a potent enhancer of insulin signaling in rodent models for insulin resistance and type 2 diabetes. In this study, we determined whether AMP-DNM also affects lipid homeostasis and, in particular, the reverse cholesterol transport pathway. Treatment of C57BL/6J mice with AMP-DNM for 5 weeks decreased plasma levels of triglycerides and cholesterol by 35%, whereas neutral sterol excretion increased twofold. Secretion of biliary lipid also increased twofold, which resulted in a similar rise in bile flow. This effect was not due to altered expression levels or kinetics of the various export pumps involved in bile formation. However, the bile salt pool size increased and the expression of Cyp7A1 was up-regulated. In vitro experiments using HepG2 hepatoma cell line revealed this to be due to inhibition of fibroblast growth factor-19 (FGF19)-mediated suppression of Cyp7A1 via the FGF receptor. Conclusion: Pharmacological modulation of glycosphingolipid metabolism showed surprising effects on lipid homeostasis in C57BL/6J mice. Upon administration of 100 mg AMP-DNM/kg body weight/day, plasma cholesterol and triglyceride levels decreased, biliary lipid secretion doubled and also the endpoint of reverse cholesterol transport, neutral sterol excretion, doubled.
Hepatology 12/2008; 49(2):637-45. · 11.66 Impact Factor
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ABSTRACT: It has been demonstrated repeatedly that short-term fasting induces insulin resistance, although the exact mechanism in humans is unknown to date. Intramyocellular sphingolipids (i.e. ceramide) have been suggested to induce insulin resistance by interfering with the insulin signaling cascade in obesity.
Our objective was to study peripheral insulin sensitivity together with muscle ceramide concentrations and protein kinase B/AKT phosphorylation after short-term fasting. MAIN OUTCOME MEASURES AND DESIGN: After 14- and 62-h fasting, glucose fluxes were measured before and after a hyperinsulinemic euglycemic clamp. Muscle biopsies were performed in the basal state and during the clamp to assess muscle ceramide and protein kinase B/AKT.
Insulin-mediated peripheral glucose uptake was significantly lower after 62-h fasting compared with 14-h fasting. Intramuscular ceramide concentrations tended to increase during fasting. During the clamp the phosphorylation of protein kinase B/AKT at serine(473) in proportion to the total amount of protein kinase B/AKT was significantly lower. Muscle ceramide did not correlate with plasma free fatty acids.
Fasting for 62 h decreases insulin-mediated peripheral glucose uptake with lower phosphorylation of AKT at serine(473). AKT may play a regulatory role in fasting-induced insulin resistance. Whether the decrease in AKT can be attributed to the trend to higher muscle ceramide remains unanswered.
Journal of Clinical Endocrinology & Metabolism 08/2008; 93(7):2900-3. · 6.50 Impact Factor
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Johannes M Aerts,
Marielle J van Breemen,
Anton P Bussink,
Karen Ghauharali,
Richard Sprenger,
Rolf G Boot,
Johanna E Groener,
Carla E Hollak,
Mario Maas,
Suzanne Smit,
Huub C Hoefsloot,
Age K Smilde,
Johannes Pc Vissers,
Sheryas de Jong,
Dave Speijer,
Chris G de Koster
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ABSTRACT: A biomarker is an analyte that indicates the presence of a biological process linked to the clinical manifestations and outcome of a particular disease. An ideal biomarker provides indirect but ongoing determinations of disease activity. In the case of lysosomal storage disorders (LSDs), metabolites or proteins specifically secreted by storage cells are good candidates for biomarkers. Potential clinical applications of biomarkers are found in improved diagnosis, monitoring of disease progression and assessment of therapeutic correction. These applications are illustrated by reviewing the use of plasma chitotriosidase in the clinical management of patients with Gaucher disease, the most common LSD. The ongoing debate on the value of biomarkers in patient management is addressed. Novel analytical methods have revolutionized the identification and measurement of biomarkers at the protein and metabolite level. Recent developments in biomarker discovery by proteomics are described and the future for biomarkers of LSDs is discussed. CONCLUSION: Besides direct applications for biomarkers in patient management, biomarker searches are likely to render new insights into pathophysiological mechanisms and metabolic adaptations, and may provide new targets for therapeutic intervention.
Acta paediatrica (Oslo, Norway: 1992). Supplement 05/2008; 97(457):7-14.
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ABSTRACT: Complex glycosphingolipids, in majority the ganglioside GM3, surround the insulin receptor in a special membrane compartment (raft) and modulate signaling through this receptor. Increased levels of GM3 in rafts impair insulin signaling, resulting in insulin resistance. Gaucher disease is a lysosomal storage disorder in which impaired breakdown of glucosylceramide leads to its accumulation in macrophages. Secondary to this defect, GM3 concentrations, for which glucosylceramide is the precursor, in plasma and several cell types are elevated.
We studied the influence of glycosphingolipid storage on whole body glucose and fat metabolism by measuring insulin-mediated (IMGU) and noninsulin-mediated glucose uptake (NIMGU) and suppression of free fatty acids by insulin.
We studied six Gaucher patients, either naive to treatment or with considerable remaining burden of disease, and six matched healthy control subjects in the basal state, during an euglycemic and a hyperglycemic clamp with somatostatin measuring NIMGU and during an euglycemic hyperinsulinemic clamp measuring IMGU, using stable isotopes.
NIMGU (both during euglycemia and hyperglycemia) did not differ between patients and control subjects. IMGU was lower in Gaucher patients, compared with controls. Suppression of lipolysis by insulin tended to be less effective in Gaucher patients.
Gaucher disease, a lysosomal glycosphingolipid storage disorder, is associated with (peripheral) insulin resistance, possibly through the influence of glycosphingolipids on insulin receptor functioning.
Journal of Clinical Endocrinology & Metabolism 04/2008; 93(3):845-51. · 6.50 Impact Factor
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ABSTRACT: Patients with Gaucher disease show signs of insulin resistance. The ganglioside GM3 has recently shown to be a negative regulator of insulin sensitivity. In fibroblasts of Gaucher patients, deficient in degradation of glucosylceramide, an increased anabolism of this lipid to gangliosides occurs. The goal of the current study was to establish whether GM3 is elevated in plasma of type I Gaucher disease patients, and is related to disease manifestations.
Plasma GM3, glucosylceramide, and ceramide were determined and compared to overall severity of disease, hepatomegaly, and plasma chitotriosidase activity.
The ceramide concentration in plasma of untreated Gaucher patients was slightly but not significantly lower than in controls (median: 9.8 micromol/L, range: 5.7-14.7 micromol/L, (n=40) vs. median: 11.0 micromol/L, range: 5.1-18.0 micromol/L, (n=30)). Glucosylceramide was significantly (p<0.0001) elevated. GM3 was also significantly (p<0.0001) increased (median: 10.2 micromol/L, range: 4.3-19.1 micromol/L, (n=40) vs. median: 3.6 micromol/L, range: 2.7-5.4 micromol/L, (n=30)). Plasma GM3 concentrations correlated with those of plasma chitotriosidase activity (rho=0.45, p=0.0036), overall severity of disease (rho=0.39, p=0.012), and hepatomegaly (rho=0.49, p=0.0015).
GM3 is strikingly elevated in plasma of most Gaucher patients. The increase is comparable to that of glucosylceramide, the primary storage lipid. The marked elevations in GM3 may play a role in the insulin resistance of Gaucher patients.
Clinica Chimica Acta 03/2008; 389(1-2):109-13. · 2.54 Impact Factor
