Unconjugated hyperbilirubinemia, a feature of neonatal jaundice or Crigler–Najjar syndrome, can lead to neurotoxicity and even death. We previously demonstrated that unconjugated bilirubin (UCB) can be eliminated via transintestinal excretion in Gunn rats, a model of unconjugated hyperbilirubinemia, and that this is stimulated by enhancing fecal fatty acid excretion. Since transintestinal excretion also occurs for cholesterol (TICE), we hypothesized that increasing fecal cholesterol excretion and/or TICE could also enhance fecal UCB disposal and subsequently lower plasma UCB concentrations.
To determine whether increasing fecal cholesterol excretion could ameliorate unconjugated hyperbilirubinemia, we treated hyperbilirubinemic Gunn rats with ezetimibe (EZE), an intestinal cholesterol absorption inhibitor, and/or a liver X receptor (LXR) and farnesoid X receptor (FXR) agonist (T0901317 (T09) and obeticholic acid (OCA), respectively), known to stimulate TICE.
We found that EZE treatment alone or in combination with T09 or OCA increased fecal cholesterol disposal but did not lower plasma UCB levels.
These findings do not support a link between the regulation of transintestinal excretion of cholesterol and bilirubin. Furthermore, induction of fecal cholesterol excretion is not a potential therapy for unconjugated hyperbilirubinemia.
Increasing fecal cholesterol excretion is not effective to treat unconjugated hyperbilirubinemia.
This is the first time a potential relation between transintestinal excretion of cholesterol and unconjugated bilirubin is investigated.
Transintestinal excretion of cholesterol and unconjugated bilirubin do not seem to be quantitatively linked.
Unlike intestinal fatty acids, cholesterol cannot “capture” unconjugated bilirubin to increase its excretion.
These results add to our understanding of ways to improve and factors regulating unconjugated bilirubin disposal in hyperbilirubinemic conditions.
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The authors gratefully acknowledge the excellent technical contributions to this study by Rick Havinga, Renze Boverhof, Martijn Koehorst, and Anouk Bos. We thank Folkert Kuipers for helpful discussions and advice. This study was funded by a grant from De Cock Hadders stichting. L.V. received a grant from the Czech Ministry of Health (RVO-VFN64165).
The authors declare no competing interests.
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Blankestijn, M., van de Peppel, I.P., Dvorak, A. et al. Induction of fecal cholesterol excretion is not effective for the treatment of hyperbilirubinemia in Gunn rats. Pediatr Res 89, 510–517 (2021). https://doi.org/10.1038/s41390-020-0926-2