Oude Elferink R.P.J.: Hepatic transport processes and Bioartificial Liver Support

1. The physiological function of ATP8B1 and other members of the P4 ATPase subfamily. We have discovered that this lipid flippase (which is deficient in an inherited form of cholestasis) needs at least one accessory protein from the small family of CDC50 proteins to be properly targeted to the plasma membrane. In the presence of this protein flippase activity can be assayed enabling us to screen the effect of mutations. Also the CDC50 genes are now candidates as causative genes for cholestatic disorders. The human genome harbours 14 P4 ATPases, all of which are thought to be phospholipid flippases. However, most of these gene products have not been studied yet. We are currently exploring the function of these flippases and their CDC50 partners.

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)

3. 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).
4. Development of a liver function test. In collaboration with a pharmaceutical company we have analyzed the mechanism of clearance of a fluorescent bile salt analog that is under development as a liver function test.

5. Bioartificial liver support; hardware: The AMC bioartificial liver has been evaluated by 3D numerical modeling and computational simulation: resulting in improved oxygenation capacity by increased oxygen capillaries and thinner matrix. Comparable function of AMC-BAL and Berlin BAL (MELSS); cells: Immortalised human fetal liver cell line (cBAL111), patent pending. Improvement of differentiation grade

This research group participates in the AMC Liver Center and the Amsterdam Center for Metabolism