Prof. R.P.J. Oude Elferink PhD

Prof. PhD R.P.J. Oude Elferink

Position

Full Professor

Main activities

Education, Research, Other

Specialisation

Experimental Hepatology

Focus of research

Hepatic transport processes

Many cholestatic patients suffer from itch (pruritus) and this can develop into an enormous burden to the patient. Nevertheless, the mechanism of cholestatic itch is unresolved and therapy therefore remains problematic. We have initiated a study into the fundamental basis of this clinical problem and discovered that autotaxin, the serum levels of this enzyme, which produces the signaling molecule LPA, closely correlate with the extent of itch in patients with any form of cholestasis. However, this cannot be the only factor contributing to itch as the enzyme is also increased in other disease states that are not associated with itch. We are currently unravelling which other factors in plasma of patients can further contribute to itch perception.
Primary biliary cirrhosis is a relatively frequent liver disease that occurs mainly in middle aged women. It is regarded as an autoimmune disease, but the mechanism by which it develops remains obscure. Most likely it involves a combination of dysregulation of the immune ssystem and dysfunction of bile duct epithelial cells. It has been reported that bile duct epithelial cells in PBC patients have reduced expression of the chloride bicarbonate exchanger, SLC4A2. We have found that SLC4A2 deficiency causes bicarbonate accumulation and increased expression of soluble adenylyl cyclase which makes the cells more vulnerable to apoptosis. We are currently investigating the various signaling roles of soluble adenylyl cyclase.
Focus of research is the role of transporter proteins in the canalicular membrane, which are involved in the formation of bile, particularly the mechanism of bile salt and lipid excretion across the canalicular membrane. This process is unique in the sense that bile salt (=detergent) concentrations are reached which are high enough to dissolve any biological membrane. Hence, the canalicular membrane needs to harness itself against this highly toxic fluid. We study inherited liver diseases in which this mechanism of self defense is compromised.
The plasma membrane of hepatocytes harbors several drug extrusion pumps, such as MRP2 (ABCC2), ABCG2 and MDR1 (ABCB1) in the canalicular membrane and MRP3 (ABCC3) and MRP4 (ABCC4) in the basolateral membrane. These ATP-dependent transporters are expressed both in liver and in the intestine; therefore they determine to a large extent the pharmacokinetic behaviour of drugs. In mouse strains with disruptions of the various transporter genes (as well as combined gene disruptions) we determine the role of these transporters in pharmacokinetics of various classes of drugs. These issues will become increasingly important for drug development as well as the elucidation of drug-drug interactions.

Amsterdam UMC Research Institutes

AMC departments

Tytgat Institute for Liver and Intestinal Research

Key publications

Chang Jung-Chin, Go Simei, de Waart Dirk R., Munoz-Garrido Patricia, Beuers Ulrich, Paulusma Coen C., Oude Elferink Ronald Soluble Adenylyl Cyclase Regulates Bile Salt-Induced Apoptosis in Human Cholangiocytes Hepatology (Baltimore, Md.) 2016;64 (2):522-534 [PubMed]
Kremer Andreas E., Bolier Ruth, Dixon Peter H., Geenes Victoria, Chambers Jenny, Tolenaars Dagmar, Ris-Stalpers Carrie, Kaess Bernhard M., Rust Christian, van der Post Joris A., Williamson Catherine, Beuers Ulrich, Oude Elferink Ronald P. J. Autotaxin activity has a high accuracy to diagnose intrahepatic cholestasis of pregnancy Journal of hepatology 2015;62 (4):897-904 [PubMed]
Kunne Cindy, Acco Alexandra, Hohenester Simon, Duijst Suzanne, de Waart Dirk R., Zamanbin Alaleh, Oude Elferink Ronald P. J. Defective bile salt biosynthesis and hydroxylation in mice with reduced cytochrome P450 activity Hepatology (Baltimore, Md.) 2013;57 (4):1509-1517 [PubMed]
Groen Annemiek, Romero Marta Rodriguez, Kunne Cindy, Hoosdally Sarah J., Dixon Peter H., Wooding Carol, Williamson Catherine, Seppen Jurgen, van den Oever Karin, Mok Kam S., Paulusma Coen C., Linton Kenneth J., Oude Elferink Ronald P. J. Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity Gastroenterology 2011;141 (5):1927-37.e1-4 [PubMed]
Kremer Andreas E., Martens Job J. W. W., Kulik Wim, Ruëff Franziska, Kuiper Edith M. M., van Buuren Henk R., van Erpecum Karel J., Kondrackiene Jurate, Prieto Jesus, Rust Christian, Geenes Victoria L., Williamson Catherine, Moolenaar Wouter H., Beuers Ulrich, Elferink Ronald P. J. Oude Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus Gastroenterology 2010;139 (3):1008-U399 [PubMed]

All Publications

Curriculum Vitae

Training
'74 - '81 Study Biochemistry at the University of Amsterdam (graduation cum laude)

'81 - '85 PhD-student at the Dept. of Biochemistry University of Amsterdam (PhD. thesis: "Biosynthesis, transport and processing of lysosomal α-glucosidase" (promotor: prof. J.M. Tager)

'85 - '86 post-doc at the Biotechnological Center, University of Amsterdam (project: In vitro immunisation of B-cells for production of monoclonal antibodies)

Position
'86 - '99 staff member (biochemist) of the Dept. of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam

'99 - '00 Associate professor and head of the Laboratory for Experimental Hepatology, Academic Medical Center, Amsterdam

2000-present Professor of Experimental Hepatology, Academic Medical Center Amsterdam

2002-present Head of the Tytgat Institute for Liver and Intestinal Research.

Research programmes

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

1. Cholestatic pruritus. Patients with various forms of cholestasis often suffer from chronic itch (pruritus). This can be a very heavy burden to the patient. The mechanism of cholestatic itch is unknown. Bile salts and endogenous opioids have been implicated but we have found no evidence to support this contetnion. We have set up assays to analyze the effect of cholestatic factors on neuronal signalling. Currently, we are analyzing the factors that we have identified and we are trying to elucidate the mechanism by which they cause itch. This will provide means to implement existing drugs or develop new drugs against this agonizing problem (collaboration with prof. Ulrich Beuers).

2. The (patho)physiological function of soluble adenylyl cyclase (sAC). Soluble adenyl cyclase is an enzyme that synthesizes the potent signaling molecule cyclic AMP. sAC is the evolutionary oldest adenylyl cyclase but it has hardly been studied so far. We are investigating its role in regulation of apoptosis, the Warburg effect (in relation to cancer and immune cell metabolism), and barrier function of epithelial cells.It appears that sAC has a regulatory role in various important cell-autonomous functions

2. Hepatic transport functions. Many aspects of bile formation have been elucidated in the past decades. However, several aspects of normal bile formation and especially of biliary dyfunction and cholestasis are not well understood. We are improving animal models for cholestatic diseases; not only with respect to defects in transport function but also with respect to the role of bile salt signalling and the role of biliary bicarbonate secretion. In addition, we are trying to unravel the factors that contribute to the development of autoimmunitiy against bile duct epithelial cells as occurs in primary biliary cirrhosis (collaboration with prof. Ulrich Beuers)

This research group participates in the Amsterdam UMC Research Institutes: Amsterdam Gastroenterology & Metabolism as well as Cancer Center Amsterdam

Faculty
PhD D.R. de Waart
PhD I.C. Gaemers
PhD C.C. Paulusma
PhD K.F.J. van de Graaf

Postdocs
PhD R. Hoekstra

PhD Students
L.M. Hubers

Others
MD PhD R.A.F.M. Chamuleau
PhD H. de Jonge
BSc S. Duijst
K.S. Ho-Mok
W.D. Tolenaars