foto

PhD K.F.J. van de Graaf

Position
Associate Professor
Main activities
Research, Other
Specialisation
Cholestatic liver diseases, metabolite signalling, Bile acid transport,
Focus of research

Metabolite dynamics and liver-centered organ crosstalk

A plethora of signals comes from the intestine in the form of metabolites produced by the microbiome with food as the source. Different types of food or food components are associated with improved health or with disease. Similarly, dysbiosis, or an aberrant intestinal microbiota composition and function, associates with many diseases. The ultimate goal of my research is to exploit the intestinal-derived signals to prevent or target common metabolic diseases, such as type 2 diabetes, NAFLD and atherosclerosis. Likely, the liver is the key to success as this organ is the first to detect and integrate the signals and plays a dominant role in controlling the spatial and temporal signaling of gut-derived metabolites.

Specifically, we aim to stimulate specific signals by modulating transport and detection pathways in the liver. To this end we generate novel tools to specifically modulate hepatic metabolite uptake/sensing in vivo. We use a variety of techniques, including (live cell) confocal microscopy, FRET imaging, biochemical characterization of transporter trafficking, cellular transport/enzymatic assays and high throughput screens with inhibitors/shRNA/gRNAs pools in combination with in vivo studies using transgenic mice, disease-mimicking cell systems and isolated organ perfusion.

Recent proof-of-concept data was obtained by targeting the bile acid transporter NTCP. Genetic and pharmacological targeting of this liver-specific transporter resulted in prolonged bile acid signaling leading to enhanced release of GLP1, increased energy expenditure, reduced intestinal lipid uptake and dampening of inflammation. Furthermore, shifting bile acids away from the liver into the peripheral circulation dampened hepatic damage due to cholestatic liver diseases (chole-stasis = impaired bile flow). NTCP inhibition dampens cholestatic liver injury by lowering hepatocellular bile salt accumulation and by reducing biliary toxicity. Cholestasis (impaired bile flow) constitutes a major cause of liver failure, since accumulated BSs are cytotoxic. This plays a role in multiple cholestatic liver diseases, including Primary Sclerosing Cholangitis, Primary Biliary Cholangitis and progressive intrahepatic familial cholestasis (PFIC). As a second and related research line we aim to open new areas of diagnosis, research and future treatment of cholestasis.

 

Key publications
  • Roscam Abbing Reinout L. P., Slijepcevic Davor, Donkers Joanne M., Havinga Rick, Duijst Suzanne, Paulusma Coen C., Kuiper Johan, Kuipers Folkert, Groen Albert K., Oude Elferink Ronald P. J., van de Graaf Stan F. J. Blocking Sodium-Taurocholate Cotransporting Polypeptide Stimulates Biliary Cholesterol and Phospholipid Secretion in Mice Hepatology (Baltimore, Md.) 2020;71 (1):247-258 [PubMed]
  • Donkers Joanne M., Kooijman Sander, Slijepcevic Davor, Kunst Roni F., Roscam Abbing Reinout L. P., Haazen Lizette, de Waart Dirk R., Levels Johannes H. M., Schoonjans Kristina, Rensen Patrick C. N., Oude Elferink Ronald P. J., van de Graaf Stan F. J. NTCP deficiency in mice protects against obesity and hepatosteatosis JCI insight 2019;4 (14) [PubMed]
  • Slijepcevic Davor, Roscam Abbing Reinout L. P., Fuchs Claudia D., Haazen Lizette C. M., Beuers Ulrich, Trauner Michael, Oude Elferink Ronald P. J., van de Graaf Stan F. J. Na+-taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice Hepatology (Baltimore, Md.) 2018;68 (3):1057-1069 [PubMed]
  • Hubers Lowiek M., Vos Harmjan, Schuurman Alex R., Erken Robin, Oude Elferink Ronald P., Burgering Boudewijn, van de Graaf Stan F. J., Beuers Ulrich Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease Gut 2018;67 (4):728-735 [PubMed]
  • van der Woerd Wendy L., Mulder Johanna, Pagani Franco, Beuers Ulrich, Houwen Roderick H. J., van de Graaf Stan F. J. Analysis of aberrant pre-messenger RNA splicing resulting from mutations in ATP8B1 and efficient in vitro rescue by adapted U1 small nuclear RNA Hepatology (Baltimore, Md.) 2015;61 (4):1382-1391 [PubMed]
All Publications
Curriculum Vitae
Scientific Awards
2018 United European Gastroenterology Rising Star Award 2018
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

PhD K.F.J. van de Graaf (Bile acid dynamics and metabolic disease)

Postdocs
PhD B. Porteiro

Others
BEng E.W.M. Vogels

Prof. PhD R.P.J. Oude Elferink (Hepatic metabolism and transport processes)

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