@article {Gupta077792, author = {Kapish Gupta and Qiushi Li and Jun Jun Fan and Eliza Li Shan Fong and Ziwei Song and Shupei Mo and Haoyu Tang and Inn Chuan Ng and Chan Way Ng and Pornteera Pawijit and Shuangmu Zhuo and Chen-Yuan Dong and Boon Chuan Low and Aileen Wee and Yock Young Dan and Pakorn Kanchanawong and Peter So and Virgile Viasnoff and Hanry Yu}, title = {Actomyosin Contractility Drives Bile Regurgitation as an Early Homeostatic Response to Increased Biliary Pressure in Obstructive Cholestasis}, elocation-id = {077792}, year = {2016}, doi = {10.1101/077792}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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 {\textmu}m). 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.}, URL = {https://www.biorxiv.org/content/early/2016/09/28/077792}, eprint = {https://www.biorxiv.org/content/early/2016/09/28/077792.full.pdf}, journal = {bioRxiv} }