Induction of fecal cholesterol excretion is not effective for the treatment of hyperbilirubinemia in Gunn rats

• Published in: Pediatric research 2021-02, Vol.89 (3), p.510-517
• Main Authors: Blankestijn, Maaike, van de Peppel, Ivo P., Dvorak, Ales, Capkova, Nikola, Vitek, Libor, Jonker, Johan W., Verkade, Henkjan J.
• Format: Article
• Language: English
• Subjects: Animals; Basic Science Article; Bile - chemistry; Bile Acids and Salts - metabolism; Bilirubin - chemistry; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - pharmacology; Chenodeoxycholic Acid - therapeutic use; Cholesterol; Cholesterol - metabolism; Crigler-Najjar Syndrome - metabolism; Crigler-Najjar Syndrome - therapy; Dietary Fats - pharmacokinetics; Ezetimibe - pharmacology; Ezetimibe - therapeutic use; Feces; Feces - chemistry; Haptoglobins - analysis; Hydrocarbons, Fluorinated - pharmacology; Hydrocarbons, Fluorinated - therapeutic use; Hyperbilirubinemia - therapy; Intestines - drug effects; Intestines - metabolism; Lipids - blood; Liver X Receptors - metabolism; Male; Medicine; Medicine & Public Health; Pediatric Surgery; Pediatrics; PPAR delta - metabolism; Random Allocation; Rats; Rats, Gunn; Receptors, Cytoplasmic and Nuclear - metabolism; Sulfonamides - pharmacology; Sulfonamides - therapeutic use
• ISSN: 0031-3998; 1530-0447
• DOI: 10.1038/s41390-020-0926-2

Background 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. Methods 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. Results We found that EZE treatment alone or in combination with T09 or OCA increased fecal cholesterol disposal but did not lower plasma UCB levels. Conclusions 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. Impact 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.