Eric Kalkhoven

Areas of expertise

Since the start of his PhD project Dr. Kalkhoven has been interested in signalling through nuclear hormone receptors. His research activities have focussed on the structure and function of several members of this transcription factor superfamily (PR, ER, PPAR) and their associated coactivator proteins (SRC1, CBP/p300).

During his PhD project (Hubrecht laboratory, Utrecht) he investigated the mechanism of growth inhibition of human breast cancer cells by the steroid hormone progesterone and the role of TGF-b in this process. In addition, a study on the mechanism of transcriptional interference between the progesterone receptor and the transcription factor NFk-B was performed. After finishing his PhD he went to the ICRF (London) to work in the laboratory of Dr. M.G. Parker on nuclear receptor coactivators, a class of proteins that interacts with hormone-activated receptors and is required to elicit a transcriptional response. Besides studies on various estrogen receptor mutants, he studied the structure-function relationships between two different isoforms of the coactivator SRC1. He was also involved in the discovery of the LXXLL motif in coactivators, which is required for nuclear receptor binding. After that he went to the LUMC (Leiden) to work on the function of the coactivators CBP and p300 in the laboratory of Dr. A. Zantema and Prof. Dr. A.J. van der Eb, who was succeeded by Prof. C.P Verrijzer in that period. In August 2003 Eric Kalkhoven moved to the UMC Utrecht to start a new research group focusing on the molecular mechanisms behind the differentiation of adipocytes and their endocrine function in health and disease, and was appointed associate professor in 2007.

Dr. Kalkhoven is the chairman and co-founder of the Dutch-Belgian Nuclear Receptor Research Network (NRRN; http://www.nuclearreceptorresearchnetwork.org/), which organizes a yearly one-day international meeting in nuclear receptor research.

In addition, he is the coordinator of the PhD programme ‘Cancer, stem cells and developmental biology’, which offers training and education to approximately 200 PhD students from research groups located in the Hubrecht Institute, the Princess Maxima Center, the UMC Utrecht and Utrecht university (http://www.csnd.nl/home/).

Research programme/group

The aim of our group is to determine the molecular mechanisms behind adipocyte (dys)function in obesity, insulin resistance, lipodystrophy and cancer. We focus on adipocyte differentiation, the endocrine and metabolic functions of these cells and their communication with immune cells, cancer cells and muscle cells. we have for example implicated iNKT cells in metabolism and unravelled a novel USP7-Tip60 pathway in adipogenesis. Together with clinicians and geneticists our laboratory has also identified and characterized rare human mutations in the PPARγ gene and other key genes, as a tool to better understand the function of the encoded proteins in adipogenesis and adipocyte function.

Currently, our research builds on these findings. Our main research questions currently are:

• What are the critical molecular pathways that maintain healthy adipocyte function?
• Which molecules and signaling pathways are involved in communication between adipocytes and immune cells (e.g. iNKT cells) and muscle cells?
• Which molecules and signaling pathways are involved in communication between adipocytes and other metabolic tissues?
• What is the role of PPARγ in cancer?

Our research is founded on a deep curiosity into the molecular and cellular mechanisms behind human disease, with the ultimate goal to translate these research findings into improved patient care with our clinical partners. We are embedded in the CMM which focuses on understanding the molecular basis of disease, employing a multidisciplinary approach, including genetics and genomics, metabolomics, bioinformatics, molecular and cell biology, protein chemistry and proteomics.

Group members

Eric Kalkhoven, Group leader

Denise Westland, Technician

Bob van Eijkeren, PhD student

Imogen Morris, PhD student

Miguel Hernandez Quiles, PhD student

Rosalie Baak, PhD student

Former group members

Brenda Hendriks-Stegeman, Technician

Nicole Hamers, Technician

Anouska Borgman, Technician

Olivier van Beekum, PhD student-graduation 10-04-2008

Ellen Jeninga, PhD student-graduation 19-05-2009

Daniel Faber, PhD student-graduation 06-06-2012

Yuan Gao, PhD student-graduation 14-01-2013

Henk Schipper, PhD student-graduation 05-03-2013

Ismayil Tasdelen, PhD student-graduation 25-03-2014

Mariette Kranendonk, PhD student-graduation 19-06-2014

Inkie Evers-van Gogh, PhD student-graduation 28-06-2016

Marjoleine Broekema, PhD student-graduation 03-12-2019

Annemarie Huijbrechts, Post-doc

Arjen Koppen, Post-doc

Maryam Rakhshandehroo, Post-doc

Raquel Saldanha Campello, Post-doc

Key publications

For a complete overview see https://pubmed.ncbi.nlm.nih.gov/?term=kalkhoven+e&sort=date.

1. Hernandez-Quiles, M., Broekema, M.F. and Kalkhoven, E. (2021) PPARgamma in metabolism, immunity and cancer: unified and diverse mechanisms of action. Frontiers Endocrinol. 12, 624112.
2. Ramos Pittol J.M., Milona A., Morris I., Willemsen E.C.L., van der Veen S.W., Kalkhoven E, van Mil S.W.C. (2020) FXR Isoforms Control Different Metabolic Functions in Liver Cells via Binding to Specific DNA Motifs. Gastroenterology 159, 1853-1865.
3. Rakhshandehroo, M., van Eijkeren, R.J., Gabriel, T.L., de Haar, C., Gijzel, S.M.W., Hamers, N., Ferraz, M.J., Aerts, J.M.F.G., Schipper, H.S., van Eijk, M., Boes, M. and Kalkhoven, E. (2019) Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation. BBA - Molecular and Cell Biology of Lipids., 1864, 1157-1167.
4. Koenis, D.S. Medzikovic, L., van Loenen, P.B., van Weeghel, M., Huveneers, S., Vos,I., Evers-van Gogh, I.J.A., van den Bossche, J., Speijer, D.,  Kim, Y., Wessels, L., Zelcer, N., Zwart, W.,  Kalkhoven, E. and de Vries, C.J.M. (2018) Nuclear receptor Nur77 limits the macrophage inflammatory response through transcriptional reprogramming of mitochondrial metabolism. Cell Rep. 24, 2127-2140.
5. Majithia, A.R., Tsuda, B., Agostini, M., Gnanapradeepan, K., Rice, R., Peloso, G., Patel, K.A., Zhang, X., Broekema, M.F., Patterson, N., Duby, M., Sharpe, T., Kalkhoven, E., Rosen, E.D., Barroso, I., Ellard, S.,  for the UK Monogenic Diabetes Consortium, Kathiresan, S.,  for the Myocardial Infarction Genetics Consortium, O’Rahilly, S.,  for the UK Congenital Lipodystrophy Consortium, Chatterjee, K., Florez, J.C., Mikkelsen, T., Savage, D., and Altshuler, D. (2016) Prospective functional classification of all possible missense variants in PPARG. Nat. Genet. 48, 157-1575.
6. Rakhshandehroo, M., Gijzel, S.M.W., Siersbæk, R., Broekema, M.F., de Haar, C., Schipper, H.S., Boes, M., Mandrup, S. and Kalkhoven, E. (2014) CD1d-mediated presentation of endogenous lipid antigens by adipocytes requires microsomal triglyceride transfer protein (MTP). J. Biol. Chem. 289, 22128-22139.
7. Catoire, M., Alex, S., Paraskevopulos, N., Mattijssen, F., Schaart, G., Kneppers, A., Evers-van Gogh, I., Mensink, M., Voshol, P., Olivecrona, G., Müller, M., Tan, N.S., Hesselink, M., Berbée, J., Rensen, P., Kalkhoven, E., Schrauwen, P. and Kersten, S. The fatty acid inducible myokine ANGPTL4 directs lipid fuels from non-exercising to exercising muscle. Proc. Natl. Acad. Sci. USA 111, E1043-52.
8. Farin, H.F., Karthaus, W.R., Kujala, P., Rakhshandehroo, M., Schwank, G., Vries, R., Kalkhoven, E., Nieuwenhuis, E.E.S. and Clevers, H. (2014) Paneth cell extrusion and release of antimicrobial products is directly controlled by immune cell-derived IFN-γ. J. Exp. Med. 211, 1393-1405.
9. Gao, Y., Koppen, A., Rakhshandehroo, M., Tasdelen, I., van de Graaf, S.F., van Loosdregt J.,van Beekum, O., Hamers, N., van Leenen, D., Berkers, C.R., Berger, R., Holstege, F.C.P., Coffer, P.J., Brenkman A.B., Ovaa, H. and Kalkhoven, E. (2013) Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase Tip60. Nature Comm. 4, 2656.
10. Schipper, H.S., Rakhshandehroo, M., van de Graaf, S.F.J., Venken, K., Koppen, A., Steinstra, R., Prop, S., Meerding, J., Hamers, N., Besra, G., Boon, L., Nieuwenhuis, E.E.A., Elewaut, D., Prakken, B.J., Kersten, S., Boes, M and Kalkhoven, E. (2012) Natural killer T cells in adipose tissue prevent insulin resistance. J. Clin. Invest. 122, 3343-54.
11. Roodhart, J.M.L.,  Daenen, L.G.M., Stigter, E.C.A., Prins, H.-J., Gerrits, J., Houthuijzen, J.M., Gerritsen, M.G., Schipper, H.S., Backer, M.J.G., van Amersfoort, M., Vermaat, J.S.P., Moerer, P., Ishihara, K., Kalkhoven, E., Beijnen, J.H., Derksen, P.W.B., Medema, R.H., Martens, A.C., Brenkman, A.B., and Voest, E.E. (2011) Mesenchymal Stem Cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 20, 370-383.
12. Jeninga, E.H., Bugge, A., Nielsen, R., Kersten, S., Hamers, N., Dani, C., Wabitsch, M., Berger, R., Stunnenberg, H.G., Mandrup, S. and Kalkhoven, E. (2009) PPARγ regulates expression of the anti-lipolytic G-protein-coupled receptor 81 (GPR81/Gpr81). J. Biol. Chem. 284, 26385-26393.
13. Kalkhoven, E., Roelfsema, J.H., Teunissen, H., den Boer, A., Zantema, A.,  Breuning,M.H., Hennekam, R.C.M., and Peters, D.J. (2003) Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome. Hum Mol. Genet. 12, 441-450.
14. Kalkhoven, E., Valentine, J.E., Heery, D.M. and Parker, M.G. (1998) Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor. EMBO J. 17, 232-243.
15. Heery, D.M., Kalkhoven, E., Hoare, S. and Parker, M.G. (1997) A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733-736.

Contact details

Telephone number: +31 (0)88 7554258

E-mail address: e.kalkhoven@umcutrecht.nl

Visiting address

Stratenum, room number 3.149

Universiteitsweg 100

3584 CG Utrecht

The Netherlands

Secretariat

Cristina Arpesella

m.c.arpesella@umcutrecht.nl

+31 88 75 68988

See here the link to the research group's website: https://www.umcutrecht.nl/en/group-eric-kalkhoven