Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Identification and characterization of metabolite quantitative trait loci in tomato leaves and comparison with those reported for fruits and seeds
Nunes-Nesi, Adriano ; Alseekh, Saleh ; Oliveira Silva, Franklin Magnum de; Omranian, Nooshin ; Lichtenstein, Gabriel ; Mirnezhad, Mohammad ; González, Roman R.R. ; y Garcia, Julia Sabio ; Conte, Mariana ; Leiss, Kirsten A. ; Klinkhamer, Peter G.L. ; Nikoloski, Zoran ; Carrari, Fernando ; Fernie, Alisdair R. - \ 2019
Metabolomics 15 (2019)4. - ISSN 1573-3882
Leaf metabolism - Metabolite network - Metabolite QTL - Tomato

Introduction: To date, most studies of natural variation and metabolite quantitative trait loci (mQTL) in tomato have focused on fruit metabolism, leaving aside the identification of genomic regions involved in the regulation of leaf metabolism. Objective: This study was conducted to identify leaf mQTL in tomato and to assess the association of leaf metabolites and physiological traits with the metabolite levels from other tissues. Methods: The analysis of components of leaf metabolism was performed by phenotypying 76 tomato ILs with chromosome segments of the wild species Solanum pennellii in the genetic background of a cultivated tomato (S. lycopersicum) variety M82. The plants were cultivated in two different environments in independent years and samples were harvested from mature leaves of non-flowering plants at the middle of the light period. The non-targeted metabolite profiling was obtained by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). With the data set obtained in this study and already published metabolomics data from seed and fruit, we performed QTL mapping, heritability and correlation analyses. Results: Changes in metabolite contents were evident in the ILs that are potentially important with respect to stress responses and plant physiology. By analyzing the obtained data, we identified 42 positive and 76 negative mQTL involved in carbon and nitrogen metabolism. Conclusions: Overall, these findings allowed the identification of S. lycopersicum genome regions involved in the regulation of leaf primary carbon and nitrogen metabolism, as well as the association of leaf metabolites with metabolites from seeds and fruits.

Priorities for protected area research
Dudley, Nigel ; Hockings, Marc ; Stolton, Sue ; Amend, Thora ; Badola, Ruchi ; Bianco, Mariasole ; Chettri, Nakul ; Cook, Carly ; Day, Jon C. ; Dearden, Phil ; Edwards, Mary ; Ferraro, Paul ; Foden, Wendy ; Gambino, Roberto ; Gaston, Kevin J. ; Hayward, Natalie ; Hickey, Valerie ; Irving, Jason ; Jeffries, Bruce ; Karapetyan, Areg ; Kettunen, Marianne ; Laestadius, Lars ; Laffoley, Dan ; Lham, Dechen ; Lichtenstein, Gabriela ; Makombo, John ; Marshall, Nina ; McGeoch, Melodie ; Nguyen, Dao ; Nogué, Sandra ; Paxton, Midori ; Rao, Madhu ; Reichelt, Russell ; Rivas, Jorge ; Roux, Dirk ; Rutte, Claudia ; Schreckenberg, Kate ; Sovinc, Andrej ; Sutyrina, Svetlana ; Utomo, Agus ; Vallauri, Daniel ; Vedeld, Pål Olav ; Verschuuren, Bas ; Waithaka, John ; Woodley, Stephen ; Wyborn, Carina ; Zhang, Yan - \ 2018
PARKS: the International of Protected Areas and Conservation 24 (2018)1. - ISSN 0960-233X - p. 35 - 50.
Managers - Protected areas - Research priorities - Researchers - Stakeholder assessment

A hundred research priorities of critical importance to protected area management were identified by a targeted survey of conservation professionals; half researchers and half practitioners. Respondents were selected to represent a range of disciplines, every continent except Antarctica and roughly equal numbers of men and women. The results analysed thematically and grouped as potential research topics as by both practitioners and researchers. Priority research gaps reveal a high interest to demonstrate the role of protected areas within a broader discussion about sustainable futures and if and how protected areas can address a range of conservation and socio-economic challenges effectively. The paper lists the hundred priorities structured under broad headings of management, ecology, governance and social (including political and economic issues) and helps contribute to setting future research agendas.

ANGPTL4 is produced by entero-endocrine cells in the human intestinal tract
Alex, S. ; Lichtenstein, L.L. ; Dijk, W. ; Mensink, R.P. ; Tan, N.S. ; Kersten, A.H. - \ 2014
Histochemistry and Cell Biology 141 (2014)4. - ISSN 0948-6143 - p. 383 - 391.
angiopoietin-like protein-4 - activated receptor-gamma - diet-induced obesity - lipoprotein-lipase - chromogranin-a - fatty-acids - enteroendocrine cells - gut microbiota - target gene - plasma
Gut hormones produced by entero-endocrine cells (EEC) located throughout the gastrointestinal tract play a major role in the regulation of glucose and energy homeostasis. Angiopoietin-like 4 (ANGPTL4, also referred to as fasting induced adipose factor) is a secreted factor involved in regulation of lipid homeostasis and has been proposed as circulating mediator between the gut microbiota and fat storage in adipose tissue, although discordant data exist. Currently, little is known about the site and regulation of ANGPTL4 production in the intestine. Here, we show using immunohistochemistry and immunofluorescence that cells positive for ANGPTL4 are scattered along the epithelial layer in the human small and large intestine. ANGPTL4-positive cells exhibit typical features of EEC characterized by large ANGPTL4-positive secretory granules directed towards the basolateral side. In support, extensive overlap was observed between ANGPTL4-positive cells and cells positive for the entero-endocrine marker chromogranin A. Higher resolution images revealed that ANGPTL4 and chromogranin A are partially present in distinct intracellular vesicles. Using entero-endocrine HuTu-80 cells, ANGPTL4 secretion was shown to be induced by short chain fatty acids and reduced by bile acids. Finally, levels of ANGPTL4 in human plasma were significantly decreased following meal consumption. In conclusion, ANGPTL4 is produced by EEC in human intestine and expression may be regulated by short chain fatty acids and bile acids.
Angptl4 Protects against Severe Proinflammatory Effects of Saturated Fat by Inhibiting Fatty Acid Uptake into Mesenteric Lymph Node Macrophages
Lichtenstein, L.L. ; Mattijssen, F.B.J. ; Wit, N.J.W. de; Georgiadi, A. ; Hooiveld, G.J.E.J. ; Meer, R. van der; He, Y. ; Qi, L. ; Köster, A. ; Tamsma, J.T. ; Tan, N.S. ; Müller, M.R. ; Kersten, A.H. - \ 2010
Cell Metabolism 12 (2010)6. - ISSN 1550-4131 - p. 580 - 592.
endoplasmic-reticulum stress - mouse peritoneal-macrophages - angiopoietin-like protein-4 - low-density lipoproteins - induced adipose factor - insulin-resistance - target gene - lipase - obesity - activation
Dietary saturated fat is linked to numerous chronic diseases, including cardiovascular disease. Here we study the role of the lipoprotein lipase inhibitor Angptl4 in the response to dietary saturated fat. Strikingly, in mice lacking Angptl4, saturated fat induces a severe and lethal phenotype characterized by fibrinopurulent peritonitis, ascites, intestinal fibrosis, and cachexia. These abnormalities are preceded by a massive acute phase response induced by saturated but not unsaturated fat or medium-chain fat, originating in mesenteric lymph nodes (MLNs). MLNs undergo dramatic expansion and contain numerous lipid-laden macrophages. In peritoneal macrophages incubated with chyle, Angptl4 dramatically reduced foam cell formation, inflammatory gene expression, and chyle-induced activation of ER stress. Induction of macrophage Angptl4 by fatty acids is part of a mechanism that serves to reduce postprandial lipid uptake from chyle into MLN-resident macrophages by inhibiting triglyceride hydrolysis, thereby preventing macrophage activation and foam cell formation and protecting against progressive, uncontrolled saturated fat-induced inflammation
Induction of cardiac Angpt14 by dietary fatty acids Is mediated by peroxisome proliferator-activated receptor ß/d and protects against fatty acid-induced oxidative stress
Georgiadi, A. ; Lichtenstein, L.L. ; Degenhardt, T. ; Boekschoten, M.V. ; Bilsen, M. van; Desvergne, B. ; Müller, M.R. ; Kersten, A.H. - \ 2010
Circulation Research 106 (2010). - ISSN 0009-7330 - p. 1712 - 1721.
angiopoietin-like protein-4 - lipoprotein-lipase - gene-expression - ppar-gamma - lipotoxic cardiomyopathy - triglyceride-metabolism - target genes - mouse heart - plasma - alpha
Rationale: Although dietary fatty acids are a major fuel for the heart, little is known about the direct effects of dietary fatty acids on gene regulation in the intact heart. Objective: To study the effect of dietary fatty acids on cardiac gene expression and explore the functional consequences. Methods and Results: Oral administration of synthetic triglycerides composed of one single fatty acid altered cardiac expression of numerous genes, many of which are involved in the oxidative stress response. The gene most significantly and consistently upregulated by dietary fatty acids encoded Angiopoietin-like protein (Angptl)4, a circulating inhibitor of lipoprotein lipase expressed by cardiomyocytes. Induction of Angptl4 by the fatty acid linolenic acid was specifically abolished in peroxisome proliferator-activated receptor (PPAR)beta/delta(-/-) and not PPAR alpha(-/-) mice and was blunted on siRNA-mediated PPAR beta/delta knockdown in cultured cardiomyocytes. Consistent with these data, linolenic acid stimulated binding of PPAR beta/delta but not PPAR alpha to the Angptl4 gene. Upregulation of Angptl4 resulted in decreased cardiac uptake of plasma triglyceride-derived fatty acids and decreased fatty acid-induced oxidative stress and lipid peroxidation. In contrast, Angptl4 deletion led to enhanced oxidative stress in the heart, both after an acute oral fat load and after prolonged high fat feeding. Conclusions: Stimulation of cardiac Angptl4 gene expression by dietary fatty acids and via PPAR beta/delta is part of a feedback mechanism aimed at protecting the heart against lipid overload and consequently fatty acid-induced oxidative stress. (Circ Res. 2010; 106: 1712-1721.)
Modulation of plasma TG lipolysis by Angiopoietin-like proteins and GPIHBP1
Lichtenstein, L.L. ; Kersten, A.H. - \ 2010
Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1801 (2010)4. - ISSN 1388-1981 - p. 415 - 420.
induced adipose factor - lipoprotein-lipase activity - endothelial-cell adhesion - activated receptor-alpha - ppar-gamma activators - coiled-coil domain - in-vivo - lipid concentrations - genetic-variation - target gene
There is evidence that elevated plasma triglycerides (TG) serve as an independent risk factor for coronary heart disease. Plasma TG levels are determined by the balance between the rate of production of chylomicrons and VLDL in intestine and liver, respectively, and their rate of clearance in peripheral tissues. Lipolytic processing of TG-rich lipoproteins is mediated by the enzyme lipoprotein lipase (LPL), which is tethered to the capillary endothelium via heparin sulphate proteoglycans. In recent years the Angiopoietin-like proteins ANGPTL3 and ANGPTL4 have emerged as novel modulators of LPL activity. Studies in transgenic animals supported by in vitro experiments have demonstrated that ANGPTL3 and ANGPTL4 impair plasma TG clearance by inhibiting LPL activity. In humans, genetic variation within the ANGPTL3 and ANGPTL4 genes contributes to variation in plasma TG and HDL levels, thereby validating the importance of ANGPTLs in the regulation of lipoprotein metabolism in humans. Combined with the discovery of GPIHBP1 as a likely LPL anchor, these findings have led to a readjustment of the mechanism of LPL function. This review provides an overview of our current understanding of the role and regulation of ANGPTL3, ANGPTL4 and GPIHBP1, and places the newly acquired knowledge in the context of the established function and mechanism of LPL-mediated lipolysis
Functional characterization of Angptl4 protein
Lichtenstein, L.L. - \ 2009
Wageningen University. Promotor(en): Michael Muller, co-promotor(en): Sander Kersten. - [S.l. : S.n. - ISBN 9789085855033 - 118
vetzuren - genexpressie - lipidenmetabolisme - vasten - nutrigenomica - fatty acids - gene expression - lipid metabolism - fasting - nutrigenomics
Background: Elevated plasma triglycerides (TG) are increasingly recognized as a risk factor for atherosclerosis. A new adipocytokine was discovered by several groups which is referred to as Angptl4 (Angiopoietin-like protein 4). Angptl4 was recently identified as a major determinant of plasma TG levels in mice. Angptl4 is a 50 KDa secreted protein belonging to the family of fibrinogen/angiopoietin-like proteins.

Objective/Design: In order to characterize the metabolic function of Angptl4, we explored dietary modulation effects on transgenic mice overexpressing Angptl4.

Results: Taking advantage of the induction of Angptl4 by fasting, we showed that Angptl4 strongly inhibits LPL and HL activities. Later, we reported the development, validation and utilization of an ELISA assay to quantitatively assess Angptl4 levels in human plasma. Within an individual, Angptl4 levels rise in response to elevation of plasma free fatty acids. Furthermore, we address the function of Angptl4 in the heart. Dietary unsaturated fatty acids have a major impact on human health, which is likely achieved via changes in gene expression. Fatty acids regulate gene expression mainly via nuclear receptors, including the PPARs. Angptl4 appears to be regulated by dietary fat in a PPARb/d dependent, but in a PPARa independent way. Upregulation of Angptl4 resulted in decreased cardiac uptake of plasma TG-derived fatty acids and decreased fatty acid-induced oxidative stress and lipid peroxidation. Finally we investigated the function of Angptl4 in the intestine. Elevated saturated fat consumption is associated with increased risk for numerous chronic diseases, including inflammatory bowel disease, and obesity. Besides carrying out nutrient digestion and absorption, the GI-tract also produces a variety of hormones that play pivotal roles in nutrient handling and energy homeostasis. We report that Angptl4 is fat sensitive hormone produced by enteroendocrines cells. Noticeably, chronic saturated fat feeding led to complex and dramatic phenotype in Angptl4-/- mice. Angptl4-/- fed saturated fat developed a severe pathology leading to death. This lethal phenotype is preceded by excessive inflammation as shown by a dramatic hepatic acute phase response.

Conclusion: The data show that Angptl4 protects against the pro-inflammatory and ultimately lethal effects of chronic overconsumption of saturated fat.

Caloric Restriction and Exercise Increase Plasma ANGPTL4 Levels in Humans via Elevated Free Fatty Acids
Kersten, A.H. ; Lichtenstein, L.L. ; Steenbergen, E. ; Mudde, C.M. ; Hendriks, H.F.J. ; Hesselink, M.K. ; Schrauwen, P. ; Müller, M.R. - \ 2009
Arteriosclerosis Thrombosis and Vascular Biology 29 (2009). - ISSN 1079-5642 - p. 969 - 974.
angiopoietin-like protein-4 - lipoprotein-lipase - adipose-tissue - target gene - inhibition - expression - metabolism - hyperlipidemia - overexpression - triglycerides
Objective - Plasma lipoprotein levels are determined by the balance between lipoprotein production and clearance. Recently, angiopoietin-like protein 4 (ANGPTL4) was uncovered as a novel endocrine factor that potently raises plasma triglyceride levels by inhibiting triglyceride clearance. However, very little is known about ANGPTL4 in human. Here we set out to identify physiological determinants of plasma ANGPTL4 levels in humans, focusing on the effect of energy restriction and plasma FFAs. Methods and Results¿We developed an ELISA for quantitative measurement of ANGPTL4 in human plasma. Using this assay we found major variations in baseline plasma ANGPTL4 levels between individuals. Within an individual, plasma ANGPTL4 levels remain stable throughout the day but increase significantly in response to long-term fasting, chronic caloric restriction, and endurance exercise. Intralipid injection as well as treatment with a -adrenergic agonist, both of which lead to elevated plasma FFA levels, increased plasma ANGPTL4 levels compared to control treatment. Fatty acids markedly induced ANGPTL4 gene expression in rat hepatoma FAO cells, human primary myocytes, and mouse intestinal MSIE cells. Conclusion - In conclusion, our results show that plasma ANGPTL4 levels are increased by fasting, caloric restriction, and exercise, which is likely mediated by elevated plasma FFAs
Angptl4 Upregulates Cholesterol Synthesis in Liver via Inhibition of LPL- and HL- Dependent Hepatic Cholesterol Uptake
Lichtenstein, L.L. ; Berbee, J.F.P. ; Dijk, S.J. ; Willems van Dijk, K. ; Bensadoun, A. ; Kema, I.P. ; Voshol, P.J. ; Müller, M.R. ; Rensen, P.C.N. ; Kersten, A.H. - \ 2007
Arteriosclerosis Thrombosis and Vascular Biology 27 (2007). - ISSN 1079-5642 - p. 2420 - 2427.
angiopoietin-like protein-4 - triglyceride-rich lipoproteins - insulin-resistance - lipid-metabolism - target gene - lipase - mice - receptor - plasma - hyperlipidemia
Background¿ Dysregulation of plasma lipoprotein levels may increase the risk for atherosclerosis. Recently, angiopoietin-like protein 4, also known as fasting-induced adipose factor Fiaf, was uncovered as a novel modulator of plasma lipoprotein metabolism. Here we take advantage of the fasting-dependent phenotype of Angptl4-transgenic (Angptl4-Tg) mice to better characterize the metabolic function of Angptl4. Methods and Results¿ In 24-hour fasted mice, Angptl4 overexpression increased plasma triglycerides (TG) by 24-fold, which was attributable to elevated VLDL-, IDL/LDL- and HDL-TG content. Angptl4 overexpression decreased post-heparin LPL activity by stimulating conversion of endothelial-bound LPL dimers to circulating LPL monomers. In fasted but not fed state, Angptl4 overexpression severely impaired LPL-dependent plasma TG and cholesteryl ester clearance and subsequent uptake of fatty acids and cholesterol into tissues. Consequently, hepatic cholesterol content was significantly decreased, leading to universal upregulation of cholesterol and fatty acid synthesis pathways and increased rate of cholesterol synthesis. Conclusions¿ The hypertriglyceridemic effect of Angptl4 is attributable to inhibition of LPL-dependent VLDL lipolysis by converting LPL dimers to monomers, and Angptl4 upregulates cholesterol synthesis in liver secondary to inhibition of LPL- and HL-dependent hepatic cholesterol uptake. The present study exploits the fasting-dependent phenotype of Angptl4-transgenic mice to characterize the function of Angptl4. We conclude that: (1) Angptl4 causes hypertriglyceridemia by inhibiting LPL-dependent VLDL lipolysis by converting LPL dimers to monomers, and (2) Angptl4 upregulates hepatic cholesterol synthesis secondary to inhibition of LPL- and HL-dependent hepatic cholesterol uptake.
AHA scientific statement: Summary of the scientific conference on dietary fatty acids and cardiovascular health
Kris-Etherton, P. ; Daniels, S.R. ; Eckel, R.H. ; Engler, M. ; Howard, B.V. ; Krauss, R.M. ; Lichtenstein, A.H. ; Sacks, F. ; St. Jeor, S. ; Stampfer, M. ; Grundy, S.M. ; Zock, P.L. - \ 2001
The Journal of Nutrition 131 (2001)4. - ISSN 0022-3166 - p. 1322 - 1326.
Conference Planning and Writing Committee:Penny Kris-Etherton, PhD, Stephen R. Daniels, MD, PhD, Robert H. Eckel, MD, Marguerite Engler, PhD, RN, Barbara V. Howard, PhD, Ronald M. Krauss, MD, Alice H. Lichtenstein, DSc, Frank Sacks, MD, Sachiko St. Jeor, PhD, Meir Stampfer, MD, DrPH, For the American Heart Association Nutrition Committee Speakers and Discussants:, Robert H. Eckel, MD, Scott M. Grundy, MD, PhD, Lawrence J. Appel, MD, MPH, Tim Byers, MD, Hannia Campos, PhD, Greg Cooney, PhD, Margo A. Denke, MD, Barbara V. Howard, PhD, Eileen Kennedy, DSc, Ronald M. Krauss, MD, Penny Kris-Etherton, PhD, Alice H. Lichtenstein, DSc, Peter Marckmann, MD, DSc, Thomas A. Pearson, MD, PhD, Gabriele Riccardi, MD, Lawrence L. Rudel, PhD, Mike Rudrum, PhD, Frank Sacks, MD, Daniel T. Stein, MD, Russell P. Tracy, PhD, Virginia Ursin, PhD, Robert A. Vogel, MD, Peter L. Zock, PhD, AHA Members:, Terry L. Bazzarre, PhD and Julie Clark, AHA Staff
Summary of the scientific conference on dietary fatty acids and cardiovascular health: conference summary from the nutrition committee of the American Heart Association
Kris-Etherton, P. ; Daniels, S.R. ; Eckel, R.H. ; Engler, M. ; Howard, B.V. ; Krauss, R.M. ; Lichtenstein, A.H. ; Sacks, F. ; St. Jeor, S. ; Stampfer, M. ; Grundy, S.M. ; Appel, L.J. - \ 2001
Circulation 103 (2001). - ISSN 0009-7322 - p. 1034 - 1039.
Applications of antisense technology in plants.
Kuipers, A.G.J. ; Jacobsen, E. ; Visser, R.G.F. - \ 1997
In: 'Antisense Technology: a practical approach' / Nellen, W., Lichtenstein, C., Oxford : Oxford University Press - p. 191 - 219.
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