Utrecht research group
By Dr Saskia van Mil
Each day, approximately 500 mg of bile acids are synthesized from cholesterol in the adult human liver. Newly synthesized bile acids are conjugated with either glycine or taurine and subsequently secreted into bile and stored in the gallbladder. Biliary secretion of bile salts against a concentration gradient requires the hydrolysis of ATP and this process provides the driving force for bile flow. Because of detergent properties, bile acids are inherently cytotoxic, and hence it is important that intracellular levels of bile acids are tightly regulated. This is largely accomplished by transcriptional regulation of genes encoding proteins involved in bile acid synthesis and transport. Cholestasis, or impaired bile flow, is one of the most common and devastating manifestations of liver disease. Cholestasis is clinically characterized by elevated plasma concentrations of biliary constituents, resulting in jaundice, malabsorption of fats and fat-soluble vitamins and, in many cases, progressive liver damage. Both acquired and hereditary forms of cholestasis have been described.
I am a Dutch scientist who worked in Catherine Williamson’s group at Imperial College London. Over the course of my BSc project, PhD and post-doc position, I have cultivated a strong research interest in bile acid-related physiology, with particular reference to cholestasis. During my PhD programme in the University Medical Center in Utrecht, The Netherlands, I focussed on elucidating the genetic defect in two cholestatic disorders occurring in young childhood, BRIC and PFIC. I was involved in the study that demonstrated that mutations in FIC1, an aminophospholipid transporter, were causative for a subgroup of these patients. Following up from this study, we identified a second form of BRIC associated with mutations in the bile salt export pump (BSEP). Furthermore, I investigated the subcellular expression pattern of FIC1 in the liver. We revealed FIC1 localisation at apical membranes of cholangiocytes and hepatocytes and demonstrated that FIC1 is expressed in a tissue specific and developmentally-regulated fashion at the apical membranes of epithelial cells of the gastrointestinal tract. During my PhD project I became interested in the regulation of bile acid homeostasis by nuclear hormone receptors, and therefore approached Catherine Williamson to explore new ideas about the role of nuclear receptors and endocrine regulation of transporters in bile homeostasis.
Functional FXR variants associated with ICP
Because of the intrinsic toxicity of bile acids, bile acid synthesis and transport are tightly regulated. It has recently become apparent that members of the nuclear receptor family of transcription factors are key regulators of these physiological processes1. The transcription factor FXR (farnesoid X receptor) functions as a critical sensor of bile acid levels in the enterohepatic circulation and modulates bile homeostasis by binding to DNA response elements in promoter regions of target genes. Thus, FXR protects the body from the deleterious effect of bile acid overload by decreasing their endogenous synthesis and by accelerating bile acid biotransformation and excretion into bile, thereby preventing the occurrence of cholestasis. Synthetic FXR ligands may therefore represent a promising therapy for cholestasis. During my post-doc at Imperial College with Catherine Williamson, I hypothesised that FXR mutations cause ICP. Indeed, we identified four heterozygous variants in FXR in 92 women with ICP. Case-control studies of these variants in two independent cohorts of ICP patients and controls, demonstrated that three occur more commonly in ICP patients than controls. We subsequently demonstrated functional defects for three variants. This study showed for the first time that functional variants in FXR are associated with human disease and it provided pivotal pilot data for this proposal.
Role of reproductive hormones in ICP
Reproductive hormones also have important roles in the pathogenesis of ICP. The disease starts usually in the last trimester of pregnancy, when hormone concentrations are high, and resolves after delivery2, 3. Twin pregnancies display both a higher incidence of ICP and more pronounced rises in hormone levels. Additionally, ICP patients often present with cholestasis outside pregnancy when taking oral contraceptives. The molecular mechanisms through which reproductive hormones influence bile homeostasis are currently poorly understood. Further studies to elucidate the role of reproductive hormones in bile homeostasis will be essential to unravel the pathogenesis of ICP. Such studies will also have a general impact on our understanding of the molecular mechanisms of bile formation and may therefore improve clinical management of both hereditary and acquired forms of cholestasis.
In January 2007 I started my own group at the University Medical Center Utrecht, The Netherlands, investigating the role of reproductive hormones in bile homeostasis. We collaborate with Catherine Williamson’s group.
1. Chiang JY. Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr Rev 2002;23:443–463.
2. Kreek MJ. Female sex steroids and cholestasis. Semin Liver Dis 1987;7:8–23.
3. Reyes H, Sjovall J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann Med 2000;32:94–106.