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.