Featuring molecular regulation of bile acid homeostasis in pediatric short bowel syndrome - 07/11/23
Highlights |
• | In SBS, enterohepatic circulation is interrupted due massive intestinal resection which associated with transcriptional evidence of increased hepatic synthesis and uptake of bile acids. |
• | In PN dependent SBS patients with frequent hepatic cholestasis and inflammation, mRNA expression of transporters responsible for hepatic bile acid secretion was decreased. |
• | Simultaneously increased hepatic synthesis and conservation of bile acids with impaired bile acid secretion may predispose to intestinal failure associated liver disease due to accumulation of bile acids in hepatocytes. |
Abstract |
Background |
Disturbed bile acid homeostasis may foster development of short bowel syndrome (SBS) associated liver disease during and after weaning off parenteral nutrition (PN). Our aim was to study hepatic molecular regulation of bile acid homeostasis in relation to serum and fecal bile acid profiles in pediatric SBS.
Methods |
Liver histopathology and mRNA expression of genes regulating synthesis, uptake and export of bile acids, and cellular receptors involved in bile acid signaling were measured in SBS patients (n = 33, median age 3.2 years). Simultaneously, serum (n = 24) and fecal (n = 10) bile acid profiles were assessed. Sixteen patients were currently on PN. Results of patients were compared to healthy control subjects.
Results |
Nine of ten (90 %) patients with histological cholestasis received current PN, while portal inflammation was present in 60 % (6/10) of patients with cholestasis compared to 13 % (3/23) without cholestasis (P = 0.01). In all SBS patients, hepatic synthesis and uptake of bile acids was increased. Patients on current PN showed widespread repression of hepatic FXR target genes, including downregulated canalicular (BSEP, MDR3) and basolateral (MRP3) bile acid exporters. Serum and fecal primary bile acids were increased both during and after weaning off PN.
Conclusions |
Bile acid homeostasis in SBS is characterized by interrupted enterohepatic circulation promoting increased hepatic synthesis and conservation of bile acids. In PN dependent SBS patients with hepatic cholestasis and inflammation, the molecular fingerprint of downregulated hepatocyte canalicular and basolateral bile acid export with simultaneously increased synthesis and uptake of bile acids could favor their accumulation in hepatocytes and predispose to liver disease.
Le texte complet de cet article est disponible en PDF.Keywords : Canalicular bile transporter, Cholestasis, Intestinal failure associated liver disease, Parenteral nutrition, Pediatric intestinal failure
List of abbreviations : SBS, PN, IFALD, FXR (NR1H4), BSEP (ABCB11), ASBT (SLC10A2), qPCR, B2M, CA, CDCA, LCA, DCA, UDCA, ICV, GGT, APRI, CYP7A1, NTCP (SLC10A1), MRP3 (ABCC3), OATP1B1 (SLCO1B1), OSTβ (SLC51B), SHP (NR0B2), CYP8B1, CYP27A1, OATP1B3 (SLCO1B3), MDR3 (ABCB4), CYP8B1, FGFR4, KLB, FGF19, VDR (NR1I1), PPRA (NR1C1), NR3C1 (GR), FGF21, C4, MRP2 (ABCC2), MRP4 (ABCC4), OSTα (SLC51A), PXR (NR1I2), GR (NR3C1), TGR5 (GPBAR1)
Plan
Vol 47 - N° 9
Article 102220- novembre 2023 Retour au numéro
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