Goals 1. To analyze the proteins that are involved in the transport of compounds from the blood-to-bile and gut-to-blood and how these transport processes are effected in health and disease. 2. To determine the protective role of ABC-transporters for hepatic and intestinal cells. Background Important functions of the liver are the production of bile and detoxification of the body. Crucial components of bile are bile salts and phospholipids. They act as detergents to keep hydrophobic compounds in solution. This is an essential process for uptake of dietary fats and vitamins in the gut and removal of cholesterol and other "waste products" from the body. To maintain proper concentrations of these compounds in blood, bile and gut, the liver and intestinal epithelial cells are equipped with many different proteins that transport these compounds across specialized domains in the plasmamembrane (see figure). The transporters in the liver that transport these compounds from the cell s cytoplasm to the bile are all members of one superfamily, the ATP-binding cassette or ABC-transporters. These proteins transport their substrates at the expense of ATP against a steep concentration gradient to bile. They protect the liver cell (hepatocyte) for the toxic effects of high concentration of their substrates. The best characterized ABC transporters in the liver are: the multidrug resistance protein (MDR1, transports a great variety of drugs), MDR3 (phospholipds), the bile salt export pump (BSEP, bile salts) and the multi drug resistance related protein 2 (MRP2, bilirubin). Conditions that inactivate or reduce the activity of these proteins results in cholestasis. Mutations in these transporters result in inherited disorders including progressive familial intrahepatic cholestasis type 2 (BSEP) and type 3 (MDR3) and Dubin-Johnson syndrome (MRP2).
Research lines Our research is aimed at understanding the role of the transport proteins in inherited and acquired disease of the liver and intestine. We make use of molecular cell biology techniques to analyze these proteins in various research lines: 1. Determination of the effect on disease-causing mutations in ABC-transporters on the activity, subcellular sorting and stability of the protein. 2. Identification and characterization of novel transporters in liver and/or intestinal cells. Exploring the complete human DNA sequence to. 3. Transcriptional regulation of ABC-transporters, with emphasis on nuclear hormone receptors. Proteins that belong to this superfamily include FXR, LXR, PXR and PPAR. They are ligand-activated transcription factors. Remarkably, they are activated by ligands that are transported by the ABC-transporters and as an intrinsic control mechanism, they regulate the mRNA expression of the corresponding ABC-transporter(s). 4. Analyzing the relationship between acquired and/or chronic liver and intestinal disease and ABC-transporters. 5. The role of ABC-transporters in cell survival in liver and intestine. |
