Function and regulation of the human bile salt export pumpPlass, J. R. M., 2005, Groningen: s.n.. 128 p.
Research output: Thesis › Thesis fully internal (DIV) › Academic
During the past decade, important progress has been made in our understanding of the pathophysiology of cholestasis. Inherited disorders have been explained at the molecular level and were shown to be the result of mutations in enzymes involved in bile salt biosynthesis or transmembrane transporters involved in bile formation. Acquired cholestasis, for instance due to inflammation, is linked to disregulation of these proteins. The challenge of future research is to use this knowledge to develop successful therapies for cholestatic patients. The studies described in this thesis initiate such studies. We showed that a mutation in BSEP may cause PFIC-2 even though the protein product is a normally active bile salt export pump. The cause of the disease is due to a specific mutation in the BSEP gene that strongly reduces the BSEP protein level, most likely due to increased protein degradation. This phenomenon has also been described for several other inherited diseases. An important focus of esearch is therefore to define conditions or drug therapies that will maintain or increase the protein level of the mutant, but active protein in these patients. Novel targets to treat cholestasis are the transcription factors that regulate the levels of enzymes and transporters involved in the synthesis and enterohepatic circulation of bile salts. RXR and FXR are key players in this process. Endogenous and synthetic ligands for these transcription factors have been identified. Recent research, however, shows that the activation of FXR-target genes is ligand-dependent. In other words, a specific target gene may be activated by the endogenous ligand, CDCA, but not by the synthetic ligand GW4064. In addition, our own research shows that the ligand for RXR, 9-cis retinoic acid, in combination with bile salt-activated FXR, may simultaneously stimulate and inhibit expression of a subset of FXR-target genes. Therapies to treat cholestatic disease aimed at modulating the activity of these transcription factors therefore requires an in depth study of the effect of the (combination of the) individual ligands on human gene transcription. In the meantime, it should be noted that in a significant number of PFIC patients the genetic defect still has not been elucidated. Therefore, novel genes/proteins that are essential for bile salt homeostasis may be identified in the near future. Altogether, many challenges await us still to further understand the (molecular) causes of cholestasis and to develop successful therapies for this disease.
|Qualification||Doctor of Philosophy|
|Place of Publication||Groningen|
|Publication status||Published - 2005|
- Proefschriften (vorm), Galzouten Transporteiwitten, gastro-enterologie
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