• Principal Investigator
  • Male

Dr. K.F.J. van de Graaf

Position: Scientific staff member (UD)
Main activities: Research
Specialisation: Bile acid transport, Cholestatic liver diseases
foto K.F.J. van de Graaf is one of the AMC Principal Investigators
Focus of research:

We aim to elucidate how bile acid dynamics relates to metabolism and generate novel tools to specifically modulate hepatic bile acid uptake in vivo.To this end we use a variety of techniques, including (live cell) confocal microscopy, FRET imaging, biochemical characterization of transporter trafficking, cellular transport assays and high throughput screens with inhibitors/shRNA/gRNAs pools in combination with in vivo studies using transgenic mice or disease-mimicking  cell systems.

 Impaired hepatic bile salt secretion results in cholestasis (impaired bile flow) and constitutes a major cause of liver failure, since accumulated BSs are cytotoxic. Mutations in ATP8B1 lead to familial cholestasis with variable severity from severe pruritus to life-threatening progressive liver damage. We aim to open new areas of diagnosis, research and future treatment of familial intrahepatic cholestasis

 

AMC themes: Metabolic disorders and gastrointestinal diseases
Departments: Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research
Appelman MD, Chakraborty A, Protzer U, McKeating JA, van de Graaf SFJ, N-Glycosylation of the Na+-Taurocholate Cotransporting Polypeptide (NTCP) Determines Its Trafficking and Stability and Is Required for Hepatitis B Virus Infection. PLOS ONE 2017;12 (1):e0170419 [PubMed]
Blank A, Eidam A, Haag M, Hohmann N, Burhenne J, Schwab M, van de Graaf SFJ, Meyer MR, Maurer HH, Meier K, Weiss J, Bruckner T, Alexandrov A, Urban S, Mikus G, Haefeli WE, The NTCP - inhibitor myrcludex B: Effects on bile acid disposition and tenofovir pharmacokinetics. CLIN PHARMACOL THER 2017;ahead of print [PubMed]
Donkers JM, Zehnder B, van Westen GJP, Kwakkenbos MJ, IJzerman AP, Oude Elferink RPJ, Beuers U, Urban S, van de Graaf SFJ, Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. SCI REP-UK 2017;7 (1):15307 [PubMed]
Hubers LM, Vos H, Schuurman AR, Erken R, Oude Elferink RP, Burgering B, van de Graaf SFJ, Beuers U, Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease. GUT 2017;ahead of print [PubMed]
Kersseboom S, van Gucht ALM, van Mullem A, Brigante G, Farina S, Carlsson B, Donkers JM, van de Graaf SFJ, Peeters RP, Visser TJ, Role of the Bile Acid Transporter SLC10A1 in Liver Targeting of the Lipid-Lowering Thyroid Hormone Analog Eprotirome. ENDOCRINOLOGY 2017;158 (10):3307-3318 [PubMed]
Maroni L, Hohenester SD, van de Graaf SFJ, Tolenaars D, van Lienden K, Verheij J, Marzioni M, Karlsen TH, Oude Elferink RPJ, Beuers U, Knockout of the primary sclerosing cholangitis-risk gene Fut2 causes liver disease in mice. HEPATOLOGY 2017;66 (2):542-554 [PubMed]
Slijepcevic D, Roscam Abbing RLP, Katafuchi T, Blank A, Donkers JM, van Hoppe S, de Waart DR, Tolenaars D, van der Meer JHM, Wildenberg M, Beuers U, Oude Elferink RPJ, Schinkel AH, van de Graaf SFJ, Hepatic Uptake of Conjugated Bile Acids Is Mediated by Both Sodium Taurocholate Cotransporting Polypeptide and Organic Anion Transporting Polypeptides and Modulated by Intestinal Sensing of Plasma Bile Acid Levels in Mice. HEPATOLOGY 2017;66 (5):1631-1643 [PubMed]
Slijepcevic D, van de Graaf SFJ, Bile Acid Uptake Transporters as Targets for Therapy. DIGEST DIS 2017;35 (3):251-258 [PubMed]
Trampert DC, Hubers LM, van de Graaf SFJ, Beuers U, On the role of IgG4 in inflammatory conditions: lessons for IgG4-related disease. BBA-BIOENERGETICS 2017;ahead of print [PubMed]
van der Woerd WL, Houwen RH, van de Graaf SF, Current and future therapies for inherited cholestatic liver diseases. WORLD J GASTROENTERO 2017;23 (5):763-775 [PubMed]
van Dijk R, Aronson SJ, de Waart DR, van de Graaf SF, Duijst S, Seppen J, Oude Elferink R, Beuers U, Bosma PJ, Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo. SCI REP-UK 2017;7 (1):1646 [PubMed]
Doorenspleet ME, Hubers LM, Culver EL, Maillette de Buy Wenniger LJ, Klarenbeek PL, Chapman RW, Baas F, van de Graaf SF, Verheij J, van Gulik TM, Barnes E, Beuers U, de Vries N, Immunoglobulin G4(+) B-cell receptor clones distinguish immunoglobulin G 4-related disease from primary sclerosing cholangitis and biliary/pancreatic malignancies. HEPATOLOGY 2016;64 (2):501-507 [PubMed]
Meredith LW, Hu K, Cheng X, Howard CR, Baumert TF, Balfe P, van de Graaf KF, Protzer U, McKeating JA, Lentiviral hepatitis B pseudotype entry requires sodium taurocholate co-transporting polypeptide and additional hepatocyte-specific factors. J GEN VIROL 2016;97 (1):121-127 [PubMed]
van der Woerd WL, Wichers CGK, Vestergaard AL, Andersen JP, Paulusma CC, Houwen RHJ, van de Graaf SFJ, Rescue of defective ATP8B1 trafficking by CFTR correctors as a therapeutic strategy for familial intrahepatic cholestasis. J HEPATOL 2016;64 (6):1339-1347 [PubMed]
van de Wiel S, Merkx M, van de Graaf S, Real Time Monitoring of Intracellular Bile Acid Dynamics Using a Genetically Encoded FRET-based Bile Acid Sensor. JOVE-J VIS EXP 2016;ahead of print [PubMed]
Bruurs LJM, Donker L, Zwakenberg S, Zwartkruis FJ, Begthel H, Knisely AS, Posthuma G, van de Graaf SFJ, Paulusma CC, Bos JL, ATP8B1-mediated spatial organization of Cdc42 signaling maintains singularity during enterocyte polarization. J CELL BIOL 2015;210 (7):1055-1063 [PubMed]
Hubers LM, Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, Verheij J, Rauws EA, van Gulik TM, Oude Elferink RPJ, van de Graaf SFJ, de Vries N, Beuers U, IgG4-associated cholangitis: a comprehensive review. CLIN REV ALLERG IMMU 2015;48 (2-3):198-206 [PubMed]
Kasteleijn-Nolst Trenité DGA, Volkers L, Strengman E, Schippers HM, Perquin W, de Haan GJ, Gkountidi AO, van't Slot R, van de Graaf SF, de Graaf SF, Jocic-Jakubi B, Capovilla G, Covanis A, Parisi P, Veggiotti P, Brinciotti M, Incorpora G, Piccioli M, Cantonetti L, Berkovic SF, Scheffer IE, Brilstra EH, Sonsma ACM, Bader AJ, de Kovel CGF, Koeleman BPC, Clinical and genetic analysis of a family with two rare reflex epilepsies. SEIZURE-EUR J EPILEP 2015;29:90-96 [PubMed]
Maroni L, van de Graaf SFJ, Hohenester SD, Oude Elferink RPJ, Beuers U, Fucosyltransferase 2: a genetic risk factor for primary sclerosing cholangitis and Crohn's disease--a comprehensive review. CLIN REV ALLERG IMMU 2015;48 (2-3):182-191 [PubMed]
Slijepcevic D, Kaufman C, Wichers CGK, Gilglioni EH, Lempp FA, Duijst S, de Waart DR, Elferink RPJO, Mier W, Stieger B, Beuers U, Urban S, van de Graaf SFJ, Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na(+) -taurocholate cotransporting polypeptide knockout mice. HEPATOLOGY 2015;62 (1):207-219 [PubMed]
Trenite DGAKN, Volkers L, Strengman E, Schippers HM, Perquin W, de Haan GJ, Gkountidi AO, van't Slot R, van de Graaf SF, Jocic-Jakubi B, Capovilla G, Covanis A, Parisi P, Veggiotti P, Brinciotti M, Incorpora G, Piccioli M, Cantonetti L, Berkovic SF, Scheffer IE, Brilstra EH, Sonsma ACM, Bader AJ, de Kovel CGF, Koeleman BPC, Clinical and genetic analysis of a family with two rare reflex epilepsies (vol 29, pg 90, 2015). SEIZURE-EUR J EPILEP 2015;33:104
van der Woerd WL. ATP8B1 deficiency: Steps towards personalized therapy. S.l.: s.n.; 2015. 159p. ISBN 978-94-6259-882-9 [UvA Dissertations Online] Proefschrift Universiteit van Amsterdam. (Promotor(s): Beuers UHW; copromotor(s): Houwen RHJ, van de Graaf KFJ)
van der Woerd WL, Mulder J, Pagani F, Beuers U, Houwen RHJ, van de Graaf SFJ, Analysis of aberrant pre-messenger RNA splicing resulting from mutations in ATP8B1 and efficient in vitro rescue by adapted U1 small nuclear RNA. HEPATOLOGY 2015;61 (4):1382-1391 [PubMed]
Beuers U, Maillette de Buy Wenniger LJ, Doorenspleet M, Hubers L, Verheij J, van Gulik T, van de Graaf SFJ, de Vries N, IgG4-associated cholangitis. DIGEST DIS 2014;32 (5):605-608 [PubMed]
Lindenburg LH, Malisauskas M, Sips T, van Oppen L, Wijnands SPW, van de Graaf SFJ, Merkx M, Quantifying stickiness: thermodynamic characterization of intramolecular domain interactions to guide the design of förster resonance energy transfer sensors. BIOCHEMISTRY-US 2014;53 (40):6370-6381 [PubMed]
van de Graaf S, Beuers U, Autophagy - another piece of the puzzle towards understanding primary biliary cirrhosis?. LIVER INT 2014;34 (4):481-483 [PubMed]
Gao Y, Koppen A, Rakhshandehroo M, Tasdelen I, van de Graaf SF, van Loosdregt J, van Beekum O, Hamers N, van Leenen D, Berkers CR, Berger R, Holstege FCP, Coffer PJ, Brenkman AB, Ovaa H, Kalkhoven E, Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60. NAT COMMUN 2013;4:2656 [PubMed]
van der Velden LM, Golynskiy MV, Bijsmans ITGW, van Mil SWC, Klomp LWJ, Merkx M, van de Graaf SFJ, Monitoring bile acid transport in single living cells using a genetically encoded Förster resonance energy transfer sensor. HEPATOLOGY 2013;57 (2):740-752 [PubMed]
van der Woerd WL, van Haaften-Visser DY, van de Graaf SFJ, Férec C, Masson E, Stapelbroek JM, Bugert P, Witt H, Houwen RHJ, Mutational Analysis of ATP8B1 in Patients with Chronic Pancreatitis. PLOS ONE 2013;8 (11):e80553 [PubMed]
Bijsmans ITGW, Bouwmeester RAM, Geyer J, Faber KN, van de Graaf SFJ, Homo- and hetero-dimeric architecture of the human liver Na⁺-dependent taurocholate co-transporting protein. BIOCHEM J 2012;441 (3):1007-1015 [PubMed]
Schipper HS, Rakhshandehroo M, van de Graaf SFJ, Venken K, Koppen A, Stienstra R, Prop S, Meerding J, Hamers N, Besra G, Boon L, Nieuwenhuis EES, Elewaut D, Prakken B, Kersten S, Boes M, Kalkhoven E, Natural killer T cells in adipose tissue prevent insulin resistance. J CLIN INVEST 2012;122 (9):3343-3354 [PubMed]
van der Velden LM, Stapelbroek JM, Krieger E, van den Berghe PVE, Berger R, Verhulst PM, Holthuis JCM, Houwen RHJ, Klomp LWJ, van de Graaf SFJ, Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate. HEPATOLOGY 2010;51 (1):286-296 [PubMed]
van der Velden LM, van de Graaf SFJ, Klomp LWJ, Biochemical and cellular functions of P4 ATPases. BIOCHEM J 2010;431 (1):1-11 [PubMed]
van der Velden LM, Wichers CGK, van Breevoort AED, Coleman JA, Molday RS, Berger R, Klomp LWJ, van de Graaf SFJ, Heteromeric interactions required for abundance and subcellular localization of human CDC50 proteins and class 1 P4-ATPases. J BIOL CHEM 2010;285 (51):40088-40096 [PubMed]
van der Woerd WL, van Mil SWC, Stapelbroek JM, Klomp LWJ, van de Graaf SFJ, Houwen RHJ, Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. BEST PRACT RES CL GA 2010;24 (5):541-553 [PubMed]
Schoeber JPH, van de Graaf SFJ, Lee KP, Wittgen HGM, Hoenderop JGJ, Bindels RJM, Conditional fast expression and function of multimeric TRPV5 channels using Shield-1. AM J PHYSIOL-RENAL 2009;296 (1):F204-F211 [PubMed]
van den Berghe PVE, Stapelbroek JM, Krieger E, de Bie P , van de Graaf SFJ, de Groot REA, van Beurden E, Spijker E, Houwen RHJ, Berger R, Klomp LWJ, Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. HEPATOLOGY 2009;50 (6):1783-1795 [PubMed]
van de Graaf SFJ, Rescher U, Hoenderop JGJ, Verkaart S, Bindels RJM, Gerke V, TRPV5 is internalized via clathrin-dependent endocytosis to enter a Ca2+-controlled recycling pathway. J BIOL CHEM 2008;283 (7):4077-4086 [PubMed]
van de Graaf SFJ, Bindels RJM, Hoenderop JGJ, Physiology of epithelial Ca2+ and Mg2+ transport. REV PHYSIOL BIOCH P 2007;158:77-160 [PubMed]
van de Graaf SFJ, Chang Q, Mensenkamp AR, Hoenderop JGJ, Bindels RJM, Direct interaction with Rab11a targets the epithelial Ca2+ channels TRPV5 and TRPV6 to the plasma membrane. MOL CELL BIOL 2006;26 (1):303-312 [PubMed]
van de Graaf SFJ, Hoenderop JGJ, Bindels RJM, Regulation of TRPV5 and TRPV6 by associated proteins. AM J PHYSIOL-RENAL 2006;290 (6):F1295-F1302 [PubMed]
van de Graaf SFJ, Hoenderop JGJ, van der Kemp AWCM, Gisler SM, Bindels RJM, Interaction of the epithelial Ca2+ channels TRPV5 and TRPV6 with the intestine- and kidney-enriched PDZ protein NHERF4. PFLUG ARCH EUR J PHY 2006;452 (4):407-417 [PubMed]
van de Graaf SFJ, van der Kemp AWCM, van den Berg D, van Oorschot M, Hoenderop JGJ, Bindels RJM, Identification of BSPRY as a novel auxiliary protein inhibiting TRPV5 activity. J AM SOC NEPHROL 2006;17 (1):26-30 [PubMed]
den Dekker E, Schoeber J, Topala CN, van de Graaf SFJ, Hoenderop JGJ, Bindels RJM, Characterization of a Madin-Darby canine kidney cell line stably expressing TRPV5. PFLUG ARCH EUR J PHY 2005;450 (4):236-244 [PubMed]
Palmada M, Poppendieck S, Embark HM, van de Graaf SFJ, Boehmer C, Bindels RJM, Lang F, Requirement of PDZ domains for the stimulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase SGK1. CELL PHYSIOL BIOCHEM 2005;15 (1-4):175-182 [PubMed]
Chang Q, Gyftogianni E, van de Graaf SFJ, Hoefs S, Weidema FA, Bindels RJM, Hoenderop JGJ, Molecular determinants in TRPV5 channel assembly. J BIOL CHEM 2004;279 (52):54304-54311 [PubMed]
Embark HM, Setiawan I, Poppendieck S, van de Graaf SFJ, Boehmer C, Palmada M, Wieder T, Gerstberger R, Cohen P, Yun CC, Bindels RJM, Lang F, Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes. CELL PHYSIOL BIOCHEM 2004;14 (4-6):203-212 [PubMed]
van de Graaf SFJ, Boullart I, Hoenderop JGJ, Bindels RJM, Regulation of the epithelial Ca2+ channels TRPV5 and TRPV6 by 1alpha,25-dihydroxy Vitamin D3 and dietary Ca2+. J STEROID BIOCHEM 2004;89-90 (1-5):303-308 [PubMed]
van de Graaf SFJ, Hoenderop JGJ, Gkika D, Lamers D, Prenen J, Rescher U, Gerke V, Staub O, Nilius B, Bindels RJM, Functional expression of the epithelial Ca2+ channels (TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex. EMBO J 2003;22 (7):1478-1487 [PubMed]
Danahay H, Withey L, Poll CT, van de Graaf SF, Bridges RJ, Protease-activated receptor-2-mediated inhibition of ion transport in human bronchial epithelial cells. AM J PHYSIOL-CELL PH 2001;280 (6):C1455-C1464 [PubMed]
Hoenderop JG, van der Kemp AW, Hartog A, van de Graaf SF, van Os CH, Willems PH, Bindels RJ, Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D-3-responsive epithelia. J BIOL CHEM 1999;274 (13):8375-8378 [PubMed]
Key publications

van der Woerd WL, Wichers CGK, Vestergaard AL, Andersen JP, Paulusma CC, Houwen RHJ, van de Graaf SFJ, Rescue of defective ATP8B1 trafficking by CFTR correctors as a therapeutic strategy for familial intrahepatic cholestasis. J HEPATOL 2016;64 (6):1339-1347 [PubMed]
Slijepcevic D, Kaufman C, Wichers CGK, Gilglioni EH, Lempp FA, Duijst S, de Waart DR, Elferink RPJO, Mier W, Stieger B, Beuers U, Urban S, van de Graaf SFJ, Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na(+) -taurocholate cotransporting polypeptide knockout mice. HEPATOLOGY 2015;62 (1):207-219 [PubMed]
van der Woerd WL, Mulder J, Pagani F, Beuers U, Houwen RHJ, van de Graaf SFJ, Analysis of aberrant pre-messenger RNA splicing resulting from mutations in ATP8B1 and efficient in vitro rescue by adapted U1 small nuclear RNA. HEPATOLOGY 2015;61 (4):1382-1391 [PubMed]
van der Velden LM, Golynskiy MV, Bijsmans ITGW, van Mil SWC, Klomp LWJ, Merkx M, van de Graaf SFJ, Monitoring bile acid transport in single living cells using a genetically encoded Förster resonance energy transfer sensor. HEPATOLOGY 2013;57 (2):740-752 [PubMed]
Schipper HS, Rakhshandehroo M, van de Graaf SFJ, Venken K, Koppen A, Stienstra R, Prop S, Meerding J, Hamers N, Besra G, Boon L, Nieuwenhuis EES, Elewaut D, Prakken B, Kersten S, Boes M, Kalkhoven E, Natural killer T cells in adipose tissue prevent insulin resistance. J CLIN INVEST 2012;122 (9):3343-3354 [PubMed]


All Publications

Curriculum Vitae

Research experience
2013-present Group leader at the Tytgat Institute for Liver and Intestinal Research

2009-2013 Assistant-professor at the Section of Metabolic Diseases,
Department Molecular Cancer Research, University Medical
Center Utrecht
2007-2009 Post-doc at the Department of Metabolic and Endocrine
diseases, University Medical Center Utrecht,
2005-2007 Long-term EMBO Fellowship University of Muenster, Germany
2000-2004 PhD student at the Department of Physiology, University Medical
Centre Nijmegen, the Netherlands
 

Scientific Awards
2012 Best Presentation (first prize), XXII International Bile Acid Meeting
2011 Dutch Liver Retreat 2011 networking prize
2006 Best Ph.D. thesis of 2005, Dutch Nephrology Society and Dutch Kidney
Foundation
2005 Recipient of the "Jacob Hamburger" prize for the best thesis in 2005, Dutch
Physiology Society
2004 Best Lecture Award of the Nijmegen Center for Molecular Life Science
2004 Best Debater Award of the Nijmegen Center for Molecular Life Science
2002 Best Poster Award of the Institute of Cellular Signaling, Nijmegen
 

Grants
2013 AMC Fellowship
2013 ERC starting grant
2013 Vidi grant from the Netherlands Organization for Scientific Research
2010 Wilhelmina Childrens Hospital Fund
2008 Veni grant from the Netherlands Organization for Scientific
Research
2005 Long-term EMBO fellowship
2005 “Talent“ stipendium Netherlands Organization for Scientific
Research
 

Research programmes

Bile acid dynamics and metabolic disease

Faculty
Dr. K.F.J. van de Graaf

Postdocs
Dr. M. Robin

PhD Students
M.D. Appelman
H.W. Chen
J.M. Donkers MSc
T. Herta
Drs. L.M. Hubers
Drs. J.B. van Niekerk
Drs. R.L.P. Roscam Abbing
Drs. D. Slijepcevic
S.M.W. van de Wiel MSc

Others
Ing. C.C. Croes
Ing. L. Haazen
Ing. E.W.M. Vogels

Prof. dr. R.P.J. Oude Elferink PhD (Hepatic transport processes and Bioartificial Liver Support)

Prof. dr. U.H.W. Beuers (Pathogenetic and therapeutic aspects of chronic cholestatic liver diseases)

Other research related activities
  • Membership of editorial board / Editorship, JOURNAL OF HEPATOLOGY
  • Membership of medical or scientific committee, Dutch Organization for the Study of the Liver (NVH), Board member (secretary)
Current research funding
  • AMC
  • AMC (Vrijgesteld)
  • Europese Unie
  • Stichting AMC Foundation (Vrijgesteld)
  • ZonMw