Actomyosin contractility drives bile regurgitation as an early response during obstructive cholestasis
Gupta, Kapish Li, Qiushi Fan, Jun Jun Fong, Eliza Li Shan Song, Ziwei Mo, Shupei Tang, Haoyu Pawijit, Pornteera
Fan, Jun Jun
Song, Ziwei
Mo, Shupei
Pawijit, Pornteera
Citations
Altmetric:
Alternative Title
Abstract
Background & Aims A wide range of liver diseases manifest as biliary obstruction, or cholestasis. However, the sequence of molecular events triggered as part of the early hepatocellular homeostatic response in obstructive cholestasis is poorly elucidated. Pericanalicular actin is known to accumulate during obstructive cholestasis. Therefore, we hypothesized that the pericanalicular actin cortex undergoes significant remodeling as a regulatory response to obstructive cholestasis. Methods In vivo investigations were performed in a bile duct-ligated mouse model. Actomyosin contractility was assessed using sandwich-cultured rat hepatocytes transfected with various fluorescently labeled proteins and pharmacological inhibitors of actomyosin contractility. Results Actomyosin contractility induces transient deformations along the canalicular membrane, a process we have termed inward blebbing. We show that these membrane intrusions are initiated by local ruptures in the pericanalicular actin cortex; and they typically retract following repair by actin polymerization and actomyosin contraction. However, above a certain osmotic pressure threshold, these inward blebs pinch away from the canalicular membrane into the hepatocyte cytoplasm as large vesicles (2–8 μm). Importantly, we show that these vesicles aid in the regurgitation of bile from the bile canaliculi. Conclusion Actomyosin contractility induces the formation of bile-regurgitative vesicles, thus serving as an early homeostatic mechanism against increased biliary pressure during cholestasis. Lay summary Bile canaliculi expand and contract in response to the amount of secreted bile, and resistance from the surrounding actin bundles. Further expansion due to bile duct blockade leads to the formation of inward blebs, which carry away excess bile to prevent bile build up in the canaliculi.
Keywords
Science & Technology, Life Sciences & Biomedicine, Gastroenterology & Hepatology, Blebs, Vesicles, Actomyosin cortex, Hepatocytes, Bile canaliculi, Cholestasis, Bile, CANALICULAR CONTRACTION, RAT HEPATOCYTES, ACTIN, VESICLES, TENSION, BLEBS, MECHANISMS, PRESSURE, MOTILITY, POLARITY
Source Title
JOURNAL OF HEPATOLOGY
Publisher
ELSEVIER SCIENCE BV
Series/Report No.
Collections
Rights
Date
2017-06-01
DOI
10.1016/j.jhep.2017.01.026
Type
Article