PT  - JOURNAL ARTICLE
AU  - Kapish Gupta
AU  - Qiushi Li
AU  - Jun Jun Fan
AU  - Eliza Li Shan Fong
AU  - Ziwei Song
AU  - Shupei Mo
AU  - Haoyu Tang
AU  - Inn Chuan Ng
AU  - Chan Way Ng
AU  - Pornteera Pawijit
AU  - Shuangmu Zhuo
AU  - Chen-Yuan Dong
AU  - Boon Chuan Low
AU  - Aileen Wee
AU  - Yock Young Dan
AU  - Pakorn Kanchanawong
AU  - Peter So
AU  - Virgile Viasnoff
AU  - Hanry Yu
TI  - Actomyosin Contractility Drives Bile Regurgitation as an Early Homeostatic Response to Increased Biliary Pressure in Obstructive Cholestasis
AID  - 10.1101/077792
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 077792
4099  - http://biorxiv.org/content/early/2016/09/28/077792.short
4100  - http://biorxiv.org/content/early/2016/09/28/077792.full
AB  - 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 to abnormal elevations in biliary pressure remains poorly elucidated. Bile canaliculi are dynamic luminal structures that undergo actomyosin-mediated periodic contractions to propel secreted bile. Additionally, pericanalicular actin is accumulated during obstructive cholestasis. Therefore, we hypothesize that the pericanalicular actin cortex undergoes significant remodeling as a regulatory response against increased biliary pressure. Here, we report that, 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 canalicular system. Conclusion: Actomyosin contractility induces the formation of bile-regurgitative vesicles, thus serving as an early homeostatic mechanism against increased biliary pressure during cholestasis.