| Bile salts play an essential role in cholesterol homeostasis. Furthermore, they are needed for the intestinal solubilization of dietary fats and elimination of toxic hydrophobic compounds via the bile. Detailed information is available about bile salt biosynthesis enzymes and transmembrane transporters that are active in the enterohepatic circulation of bile salts. Mutations in these proteins are known causes of inherited cholestatic liver disease. Acute, chronic and drug induced cholestasis are characterized by disturbed regulation and/or function of these proteins. Bile salts have been shown to be important signaling molecules. They control their own biosynthesis and enterohepatic circulation through regulation of gene transcription and post-translational processes. De novo synthesis of bile salts from cholesterol in the liver involves enzymes present in the endoplasmic reticulum, mitochondria, peroxisomes and cytosol. Hence, efficient transport of these compounds and biosynthetic intermediates between these cellular compartments is required. Surprisingly, little attention has been paid to the organellar bile salt transporters (orgBSTs). Consequently, orgBSTs and their role in bile salt/cholesterol homeostasis have not been characterized to date. In recent years, mutations in BSEP, FIC1 or MDR3 have been shown to cause cholestatic syndromes. Still, various unexplained inheritable and/or acquired cholestatic diseases remain that may result from organellar transporter defects. This program aims to characterize organellar bile salt transporters and their importance in cholesterol and bile salt homeostasis in animal/human physiology. In preliminary studies, we have identified 3 putative orgBSTs. In this program, two PhD projects are proposed. Both projects have the collective aim to further characterize these and possibly other orgBSTs by independent approaches. Subsequently, one research line will focus on the functional characterization of the orgBSTs. The second line will focus on their importance in animal/human health and cholastatic disease. State of the art technology (DNA-microarrays, MALDI- and SELDI-TOF mass spectrometry, confocal laser scanning microscopy; available in our institute) and a novel method for gene inactivation (RNA interference, recently established in our laboratory) will be applied. |
