Bile acid flux is necessary for normal liver regeneration

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background & Aims: Many signals governing liver regeneration (LR) following 2/3 partial hepatectomy (PH) are recognized, but the primary signal(s) remains unknown. The aim of the study was to confirm that the remnant liver after PH lacks capacity to secrete the BA pool returning via the enterohepatic ciruculation (EHC), which may in turn stimulate LR. Methods: After standard PH, BA flux was documented and BA signaling (Fgf15) and synthesis (Cyp7a) determined by qPCR. Rat biliary fistula (BF) and Asbt knockout mouse models interrupted the EHC prior to PH, and standard assays for LR employed along with complete RNA sequencing. CCl4 intoxication after BF tested the hypothesis in an alternate injury model. Results: BA rise in systemic blood immediately following PH, confirming that the remnant liver cannot handle the BA returning via portal circulation. When the BA pool is drained prior to PH in the rat BF model, LR is markedly attenuated, a phenomenon reversed with duodenal BA replacement. Hepatocyte proliferation is similarly attenuated after PH in the Asbt knockout mouse as well as after CCl44 intoxication in rats with BF. Complete RNA sequencing in the rat PH model shows that early c-jun and AP-1 gene expression pathways are down regulated in the absence of BA, coincident with attenuated LR. Conclusions: Absent BA return to the liver after PH or CCl 4 injury markedly attenuates LR, though hepatocyte proliferation still occurs, inferring that BA flux and signaling are not the sole signals governing LR. Transcriptional networks involving c-jun and AP-1 are involved in the BA-specific effects on hepatocyte proliferation.

Original languageEnglish (US)
Article numbere97426
JournalPLoS One
Volume9
Issue number5
DOIs
StatePublished - May 19 2014

Fingerprint

liver regeneration
Liver Regeneration
Hepatectomy
bile acids
Bile Acids and Salts
Liver
Fluxes
fistula
Biliary Fistula
hepatocytes
Rats
rats
RNA Sequence Analysis
Hepatocytes
liver
poisoning
Transcription Factor AP-1
sequence analysis
Knockout Mice
blood circulation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Bile acid flux is necessary for normal liver regeneration. / Naugler, Willscott (Scott).

In: PLoS One, Vol. 9, No. 5, e97426, 19.05.2014.

Research output: Contribution to journalArticle

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