Sander Kersten, PhD
Associate 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. Dr. Kersten is also
Adjunct Associate Professor in the Division of Nutritional Sciences at Cornell
University.
Research Interests In response to repeated and long-lasting food
shortages during evolution, humans have evolved with an intricate metabolic
control system that allows them to survive prolonged period of food deprivation.
One hallmark of this adaptive system is the ability to store large amounts of
energy in the form of fat in times of plenty and mobilize this energy under
conditions of food shortage. My lab is interested in the molecular mechanisms
that govern energy metabolism during fasting, concentrating on the role of two
factors: the peroxisome proliferator activated receptor alpha, a ligand-activated
transcription factor, and the Angiopoietin-like protein 4, a secreted
protein mainly produced in adipose tissue. To study the function of these two
proteins, a variety of tools are used including transgenics and micro-array
technology PPARa
is one of three different PPAR isotypes that are known to date. The PPARs
are members of the nuclear hormone receptor superfamily and therefore share the
typical structure and molecular mode of action of these type of receptors. They
can be activated by certain ligands and modulate DNA transcription by binding to
specific nucleotide sequences in the promoter region of target genes. The PPARa
isotype is mostly expressed in liver and is the cellular target of fibrate
drugs. Fibrates, which include gemfibrozil, bezafibrate and fenofibrate, are
potent hypolipidemic drugs widely used in the treatment of cardiovascular
disease. It is now evident that one of the main functions of PPARa
is to stimulate the expression of genes involved in fatty acid metabolism in
liver, which includes fatty acid uptake through membranes, fatty acid binding in
cells, fatty acid oxidation (mitochondrial, peroxisomal and microsomal), and
lipoprotein assembly and transport. PPARa is also activated by fatty acids and
likely accounts for the majority of the effects of dietary poly-unsaturated fatty
acids on gene expression in liver. One of my current interests is to further
elucidate the role of PPARa in energy homeostasis in liver and other organs.
In this pursuit we extensively use transcriptomics as a global screening tool
to map PPARa-dependent genes and pathways. By following this approach, we have
been able to show that PPARa is directly involved in the regulation of glucose
metabolism via stimulating the conversion of glycerol into glucose. Recently,
we came up with an unique experimental design by feeding mice individual fatty acids in the form of synthetic triglycerides. Using microarray
analysis we were able to show that the effect of dietary unsaturated fatty acids on gene expression in liver are
almost entirely mediated by PPARa. In the past few years it has become increasingly clear that adipose tissue not
merely serves as a storage site for excess calories but also has an important
endocrine function. The most widely known factor produced by adipose tissue is
leptin, a 16 kD protein which regulates feeding behavior and influences energy
expenditure. Other factors secreted by adipose tissue include Tumor Necrosis
Factor alpha, which has been postulated to act as a link between obesity and
insulin resistance, adipocyte complement related protein 30, adipoQ, angiotensin II,
resistin, and the fasting induced adipose factor/Angiopoietin-like protein 4
(FIAF/Angptl4). Angptl4 is an about 50 kD protein that belongs to the family of
angiopoietin-like proteins. The expression of Angptl4 is markedly increased
during fasting in both liver and adipose tissue. It was discovered by screening
for target genes of the peroxisome proliferators activated receptors alpha and
gamma, which serve as the molecular targets of the hypolipidemic fibrate and the
insulin sensitizing thiazolidinedione drugs, respectively. These data suggests that
Angptl4 represents an endocrine factor involved in the regulation of energy homeostasis.
Research in the lab is focused on further elucidating the function of Angptl4
in mammalian energy metabolism. Studies from our and other groups have indicated that
Angptl4 plays a major role in the regulation of plasma lipoprotein metabolism. Indeed,
upregulation of Angptl4 leads to markedly elevated plasma triglyceride concentrations.
Rather than by affecting the production of very low density lipoproteins, Angptl4
raises plasma TG by impairing the LPL-mediated clearance of plasma triglycerides.
These effects are likely achieved by physical association with plasma lipoproteins.
Angptl4 thus represents a highly interesting candidate for therapeutic targeting of
dyslipidemia. Selected publications: Stienstra R, Saudale F, Duval C, Keshtkar S, Groener C, van Rooijen N, Staels B, Kersten S, Müller M. (2009)
Kupffer cells promote hepatic steatosis via IL-1β dependent suppression of PPARα activity. Hepatology.
In press
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. In press
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. 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. List of publications
last updated April 30, 2009