Exploring a role for Cyp17a1 in the pathogenesis of cholestasis.
Alexandra Milona1, Bryn M Owen2, Ellen CL Willemsen1, Catherine Williamson3, Saskia
WC van Mil1
1
Department of Molecular Cancer Research, section Metabolic DiseasesMetabolic and
Endocrine Diseases, University Medical Centre Utrecht and Netherlands Metabolomics
Centre, The Netherlands, 2 Department of Pharmacology, University of Texas Southwestern
Medical Center, Dallas, TX, USA, 3 Department of Surgery and Cancer, Institute of
Reproductive and Developmental Biology, Imperial College London, London, United
Kingdom
Introduction: Cholesterol serves as a pre-cursor of steroid hormones and bile acids. In the
liver, cholesterol escapes the body via bile acid formation and secretion into bile. However,
the liver is not considered a steroidogenic tissue, although it expresses several steroidogenic
genes under normal conditions. Bile acids (BAs) are intrinsically toxic, therefore their
intrahepatic concentrations are tightly controlled. Pregnancy can expose cholestatic disease in
genetically predisposed individuals. The nuclear receptor FXR controls BA synthesis by
transcriptional activation of SHP, which in turn represses transcription of the rate-limiting
enzyme in BA-synthesis (CYP7A1). We previously showed that estrogens interfere with FXR
function and may perturb BA homeostasis during pregnancy. Here, we present a novel
hepatic target-gene of FXR/SHP that is estrogen-modulated and may contribute to the
pathology of intrahepatic cholestasis of pregnancy.
Methods: In vivo experiments were conducted on age-matched wild-type and FXR-KO mice.
Gene and protein expression was determined by qPCR and western blotting respectively. In
vitro experiments including ChIP, EMSA, luciferase assays were conducted according to
standard protocols.
Results: We find that BAs robustly repress the expression of the steroidogenic enzyme,
Cyp17a1, in mouse liver. The effect of BAs on Cyp17a1 are FXR-dependent and liverspecific. Extensive in vitro experiments demonstrate that Cyp17a1 is regulated by a nuclear
receptor cascade involving LRH-1, FXR and SHP. As such, the regulation of hepatic
Cyp17a1 is strikingly similar to that of the bile acid synthesis enzyme, Cyp7a1. Intriguingly,
hepatic Cyp17a1 expression is significantly higher in females than in males, is up-regulated
during pregnancy and is induced upon estrogen treatment.
Discussion: 17-hydroxyprogesterone (a product of Cyp17a1) was recently shown to cause
cholestatic liver injury in mice. Our findings raise the possibility that estrogen-mediated
dysregulation of FXR during pregnancy may induce hepatic Cyp17a1 and expose cholestatic
disease in pre-disposed individuals.
The function of Cyp17a1 in liver, and the relevance of its regulation by FXR, is currently
under investigation.