Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.

Details

Original languageEnglish
Article numbere57181
JournalEMBO reports
Volume24
Issue number9
Publication statusPublished - 31 Jul 2023
Peer-reviewedYes

External IDs

WOS 001039881900001
Scopus 85166430458
ORCID /0000-0003-0137-5106/work/142244266

Keywords

Sustainable Development Goals

ASJC Scopus subject areas

Keywords

  • Apical bulkheads, Bile canaliculi, Hepatocyte, Hepatocyte rosettes, Hepatocytes, Primary sclerosing cholangitis