Skip to Main content Skip to Navigation
Journal articles

Rho-kinase/myosin light chain kinase pathway plays a key role in the impairment of bile canaliculi dynamics induced by cholestatic drugs

Abstract : Intrahepatic cholestasis represents a frequent manifestation of drug-induced liver injury; however, the mechanisms underlying such injuries are poorly understood. In this study of human HepaRG and primary hepatocytes, we found that bile canaliculi (BC) underwent spontaneous contractions, which are essential for bile acid (BA) efflux and require alternations in myosin light chain (MLC2) phosphorylation/dephosphorylation. Short exposure to 6 cholestatic compounds revealed that BC constriction and dilation were associated with disruptions in the ROCK/MLCK/myosin pathway. At the studied concentrations, cyclosporine A and chlorpromazine induced early ROCK activity, resulting in permanent MLC2 phosphorylation and BC constriction. However, fasudil reduced ROCK activity and caused rapid, substantial and permanent MLC2 dephosphorylation, leading to BC dilation. The remaining compounds (1-naphthyl isothiocyanate, deoxycholic acid and bosentan) caused BC dilation without modulating ROCK activity, although they were associated with a steady decrease in MLC2 phosphorylation via MLCK. These changes were associated with a common loss of BC contractions and failure of BA clearance. These results provide the first demonstration that cholestatic drugs alter BC dynamics by targeting the ROCK/MLCK pathway; in addition, they highlight new insights into the mechanisms underlying bile flow failure and can be used to identify new predictive biomarkers of drug-induced cholestasis
Complete list of metadatas

https://hal-univ-rennes1.archives-ouvertes.fr/hal-01326368
Contributor : Laurent Jonchère <>
Submitted on : Tuesday, October 11, 2016 - 12:00:30 PM
Last modification on : Friday, January 31, 2020 - 9:54:49 AM

Identifiers

Citation

Ahmad Sharanek, Audrey Burban, Matthew Burbank, Rémy Le Guevel, Ruoya Li, et al.. Rho-kinase/myosin light chain kinase pathway plays a key role in the impairment of bile canaliculi dynamics induced by cholestatic drugs. Scientific Reports, Nature Publishing Group, 2016, 6 (1), pp.24709. ⟨10.1038/srep24709⟩. ⟨hal-01326368⟩

Share

Metrics

Record views

239

Files downloads

260