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

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.

SEEK ID: https://seek.lisym.org/publications/372

PubMed ID: 37522754

Projects: DEEP-HCC network, Forschungsnetzwerk LiSyM-Krebs

Publication type: Journal

Journal: EMBO Rep

Citation: EMBO Rep. 2023 Jul 31:e57181. doi: 10.15252/embr.202357181.

Date Published: 31st Jul 2023

Registered Mode: by PubMed ID

Authors: C. Mayer, S. Nehring, M. Kucken, U. Repnik, S. Seifert, A. Sljukic, J. Delpierre, H. Morales-Navarrete, S. Hinz, M. Brosch, B. Chung, T. Karlsen, M. Huch, Y. Kalaidzidis, L. Brusch, J. Hampe, C. Schafmayer, M. Zerial

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Created: 2nd Aug 2023 at 16:20

Last updated: 8th Mar 2024 at 07:44

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