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     Sander Kersten, PhD

Professor, Nutrition Metabolism and Genomics Group, Wageningen University

email: sander.kersten@wur.nl     phone: (+31) 317 485787    fax: (+31) 317 483342

Biography

Sander Kersten received his Masters of Science degree in Human Nutrition from Wageningen University in 1993, and his PhD degree in Nutritional Biochemistry from Cornell University in 1997. From 1997 to 2000 he was a postdoc in the laboratory of Dr. Walter Wahli and Dr. Beatrice Desvergne at the University of Lausanne in Switzerland. In 2000 he joined the Division of Human Nutrition at Wageningen as a fellow of Royal Netherlands Academy of Arts and Sciences. He was promoted to Associate Professor in 2006 and to Full Professor in 2011. Dr. Kersten is also Adjunct Associate Professor in the Division of Nutritional Sciences at Cornell University.

Research Interests

Our primary research interests revolve around the mechanisms, pathways, and functional implications of dietary fatty acid sensing. Fatty acid sensing can be interpreted as the property of fatty acids to influence biological processes by serving as signaling molecules. In the past two decades, a molecular framework underlying fatty acid sensing has slowly evolved. It is well established that one of the mechanisms by which fatty acids alter gene transcription is by serving as agonists for a group of receptors called peroxisome proliferactors-activated receptors (PPARs). PPARs are ligand-activated transcription factors that are members of the nuclear hormone receptor superfamily. Three different PPARs are known: PPARα, PPARβ/δ and PPARγ. Most of our work has been on PPARα. Partly using transcriptomics we have been able to provide a comprehensive picture of the diverse role of PPARα in hepatic metabolism. We have also come up with an unique experimental design by feeding mice individual fatty acids in the form of synthetic triglycerides. Via the use of transcriptomics we showed that the effects of dietary unsaturated fatty acids on gene expression in liver are almost entirely mediated by PPARα. In recent years, our research focus has progressively shifted to specific target genes of PPARs and fatty acids.

One of the genes that is very sensitive to stimulation by fatty acids encodes Angiopoietin-like protein 4 (Angptl4). Angptl4 is a pro-hormone released by a variety of different organs and cells types. Depending on the cell type, expression of Angptl4 is under control of PPARα, PPARβ/δ or PPARγ. Upon secretion Angptl4 is cleaved into at least two fragments. One fragment blocks lipoprotein lipase, the enzyme that catalyzes uptake of circulating lipids into tissues. Through this mechanism, Angptl4 raises serum triglycerides and protects against cellular lipotoxicity. In macrophages inhibition of lipoprotein lipase by Angptl4 protects against lipid-induced macrophage activation. Failure of this mechanism in mesenteric lymph nodes leads to excessive lipolytic release of fatty acids from lymph chylomicrons, macrophage foam cell formation, ER stress, and marked inflammation that becomes systemic. The other Angptl4 fragment interacts with integrins, a family of cell surface receptors that mediate cell-to-cell and cell-to–extracellular matrix interactions, to modulate wound healing and tumor cell behavior. Currently, we are trying to better characterize the role of Angptl4 in a variety of tissues. In addition, we are exploring the regulation of circulating Angptl4 levels in humans. Finally, our research addresses the communication between metabolically active organs in the context of metabolic diseases such as obesity, diabetes and atherosclerosis. Particular attention goes to the role of specific components of the immune system. To meet these research objectives, a functional genomics type of approach is followed that combines detailed in vitro studies in cell lines and primary cells with experiments in (transgenic) animal models and humans.

Selected publications:

Clement LC, Avila-Casado C, Macé C, Soria E, Bakker WW, Kersten S, Chugh SS. (2011) Podocyte secreted Angiopoietin-like 4 mediates proteinuria in glucocorticoid-sensitive minimal change disease. Nat. Med. 17, 117-22.

Stienstra R, Joosten LAB, Koenen T, Fantuzzi G, Hijmans A, Kersten S, Müller M, van den Berg WB, van Rooijen N, Wabitsch M, Kullberg BJ, van der Meer JWM, Kanneganti T, Tack CJ, Netea MG. (2010) The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 12, 593-605.

Lichtenstein L, Mattijssen F, de Wit NJ, Georgiadi A, Hooiveld NJ, van der Meer R, He Y, Qi L, Koster A, Tamsma JT, Tan NS, Müller M, Kersten S. (2010) Angptl4 protects against severe pro-inflammatory effects of dietary saturated fat by inhibiting lipoprotein lipase-dependent uptake of fatty acids in mesenteric lymph node macrophages. Cell Metab. 12, 580-92.

Duval C, Keshtkar S, Accart B, Stienstra R, Boekschoten MV, de Groot PJ, Roskams T, Kersten S, and Müller M. (2010) Adipose tissue dysfunction signals the progression of hepatic steatosis towards nonalcoholic steatohepatitis. Diabetes. 59, 3181-91.

Goh YY, Pal M, Chong HC, Zhu P, Tan MJ, Punugu L, Tan CK, Huang R, Tang MB, Ding JL, Kersten S, Tan NS. (2010) Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing. J. Biol. Chem. 285, 32999-3009.

Goh YY, Pal M, Chong HC, Zhu P, Tan, MJ, Punuga L, Yau YH, Tan CK, Huang R, Tan SM, Tang MB, Ding JL, Kersten S, Tan NS. (2010) Angiopoietin-like 4 interacts with integrins β1 and β5 to modulate keratinocyte migration. Am. J. Pathol. 177, 2791-803.

Georgiadi A, Lichtenstein L, Degenhardt T, Boekschoten MV, van Bilsen M, Desvergne B, Müller M, Kersten S. (2010) Induction of cardiac Angptl4 by dietary fatty acids is mediated by PPARβ/δ and protects against fatty acid- induced oxidative stress. Circ. Res. 106, 1712-21.

Lichtenstein L, Kersten S. (2010) Modulation of plasma TG lipolysis by Angiopoietin-like proteins and GPIHBP1. Biochim Biophys Acta. 1801, 415-20.

van der Meer DL, Degenhardt T, de Groot PJ, Heinäniemi M, de Vries SC, Müller M, Carlberg C, Kersten S. (2010) Profiling of promoter occupancy by PPARα in human hepatoma cells via ChIP-chip analysis. Nucl. Acids Res. 38, 2839-50

Stienstra R, Saudale F, Duval C, Keshtkar S, Groener C, van Rooijen N, Staels B, Kersten S, Müller M. (2010) Kupffer cells promote hepatic steatosis via IL-1β dependent suppression of PPARα activity. Hepatology. 51, 511-522.

Sanderson L, Degerhardt T, Desvergne B, Koppen A, Kalkhoven E, Müller M, Kersten S. (2009) PPARβ/δ but not PPARα serves as plasma free fatty acid sensor in liver. Mol. Cell. Biol. 29,6257-67.

Kersten S, Lichtenstein L, Steenbergen E, Mudde K, Hendriks HFJ, Hesselink MK, Schrauwen P, Muller M. (2009) Caloric restriction and exercise increase plasma ANGPTL4 levels in humans via elevated free fatty acids. Arterioscler. Thromb. Vasc. Biol. 29, 969-74.

Lemke U, Krones-Herzig A, Diaz MB, Narvekar P, Ziegler A, Vegiopoulos A, Cato AC, Bohl S, Klingmüller U, Screaton RA, Müller-Decker K, Kersten S, Herzig S. (2008) The glucocorticoid receptor controls hepatic dyslipidemia through Hes1. Cell Metab. 8, 212-23.

Stienstra R, Duval C, Keshtkar S, van der Laak J, Kersten S, Müller M. (2008) Peroxisome Proliferator- Activated Receptor gamma activation promotes infiltration of alternatively activated macrophages into adipose tissue. J. Biol. Chem. 283, 22620-22627.

Sanderson LM, de Groot PJ, Koppen A, Kalkhoven E, Hooiveld GJEJ, Müller M, Kersten S. (2008) Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics. Plos ONE, 3, e1681.

Lichtenstein L, Berbee JFP, van Dijk SJ, Willems van Dijk K, Bensadoun A, Kema, IP,Voshol PJ, Müller M, Rensen PCN, Kersten S. (2007) Angptl4 upregulates cholesterol synthesis in liver by inhibiting LPL- and HL- dependent remnant uptake. Arterioscler. Thromb. Vasc. Biol. 27, 2420-2427.

Mandard S, Zandbergen F, van Straten E, Wahli W, Kuipers F, Muller M, Kersten S. (2006) The fasting- induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J. Biol. Chem., 281, 34411-34420.

Patsouris D, Reddy JK, Muller M, Kersten S. (2006) PPARalpha mediates the effects of high fat diet on hepatic gene expression. Endocrinology, 147, 1508-1516.

Zandbergen F, Mandard S, Escher P, Tan NS, Patsouris D, Jatkoe T, Rojas-Caro S, Madore S, Wahli W, Tafuri S, Müller M, Kersten S. (2005) The G0/G1 switch gene 2 is a novel PPAR target gene. Biochem J. 392, 313-24.

Mandard S, Zandbergen F, Tan NS, Escher P, Patsouris D, Koenig W, Kleemann R, Bakker A, Veenman F, Wahli W, Muller M, Kersten S. (2004) The direct PPAR target FIAF/PGAR/ANGPTL4 is present in blood plasma as a truncated protein that is increased by fenofibrate treatment. J. Biol. Chem., 279, 934-944.

Patsouris D, Mandard S, Voshol PJ, Escher P, Tan NS, Havekes LM, Koenig W, März W, Tafuri S, Wahli W, Müller M, Kersten S. (2004) The Peroxisome Proliferator Activated Receptor alpha governs glycerol metabolism. J. Clin. Invest., 114, 94-103.

Müller M, Kersten S. (2003) Nutrigenomics: goals and strategies. Nat. Rev. Genet. 4, 315-22.

Kersten S, Mandard S, Escher P, Gonzalez FJ, Tafuri S, Desvergne BD, and Wahli W. (2001) The peroxisome proliferator activated receptor alpha regulates amino acid metabolism. FASEB J., 15, 1971-1978.

Kersten S, Desvergne B, and Wahli W. (2000) Roles of PPARs in health and disease. Nature, 405, 421-424.

Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, Gonzalez FJ, Desvergne B, and Wahli W. (2000) Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J. Biol. Chem., 275, 28488-28493.

Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, and Wahli W. (1999). Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J. Clin. Invest., 103, 1489-1498.

Kersten S, Gronemeyer H, Noy N. (1997) The DNA binding pattern of the retinoid X receptor is regulated by ligand-dependent modulation of its oligomeric state. J.Biol. Chem., 272, 12771-12777.

Kersten S, Dawson MI, Lewis BA, Noy N. (1996). Individual subunits of heterodimers comprised of retinoic acid and retinoid X receptors interact with their ligands independently. Biochemistry, 35, 3816-3824.

Kersten S, Kelleher D, Chambon P, Gronemeyer H, Noy N. (1995). Retinoid X receptor alpha forms tetramers in solution. Proc. Natl. Acad. Sci. U. S. A., 92, 8645-8649.