Actomyosin contractility drives bile regurgitation as an early response during obstructive cholestasis

JOURNAL OF HEPATOLOGY

卷:66

Article

Gupta, Kapish¹  Li, Qiushi^1,2  Fan, Jun Jun^3,4,5  Fong, Eliza Li Shan^6,7  Song, Ziwei³  Mo, Shupei³  Tang, Haoyu¹  Ng, Inn Chuan⁶  Ng, Chan Way⁶  Pawijit, Pornteera^6,8  Zhuo, Shuangmu^4,9  Dong, Chen-Yuan¹⁰  Low, Boon Chuan^1,11  Wee, Aileen¹²  Dan, Yock Young¹³  Kanchanawong, Pakorn^1,7  So, Peter⁴  Viasnoff, Virgile^1,14  Yu, Hanry^1,3,4,6,15 

[1] Natl Univ Singapore, Mechanobiol Inst, Singapore, Singapore

[2] Natl Univ Singapore, Res Inst, Singapore, Singapore

[3] ASTAR, Inst Bioengn & Nanotechnol, Singapore, Singapore

[4] Singapore MIT Alliance Res & Technol, BioSyM, Singapore, Singapore

[5] Fourth Mil Med Univ, Dept Orthopaed, Xijing Hosp, Xian, Peoples R China

[6] Natl Univ Singapore, Dept Physiol, Singapore, Singapore

[7] Natl Univ Singapore, Dept Biomed Engn, Singapore, Singapore

[8] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore, Singapore

[9] Fujian Normal Univ, Fuzhou, Fujian, Peoples R China

[10] Natl Taiwan Univ, Dept Phys, Taipei, Taiwan

[11] Natl Univ Singapore, Dept Biol Sci, Singapore, Singapore

[12] Natl Univ Singapore, Dept Pathol, Singapore, Singapore

[13] Natl Univ Singapore Hosp, Div Gastroenterol & Hepatol, Singapore, Singapore

[14] CNRS, UMI3639, Singapore, Singapore

[15] Southern Med Univ, Dept Gastroenterol, Nanfang Hosp, Guangzhou, Guangdong, Peoples R China

关键词: Blebs;    Vesicles;    Actomyosin cortex;    Hepatocytes;    Bile canaliculi;    Cholestasis;    Bile;   

DOI  :  10.1016/j.jhep.2017.01.026

来源: Elsevier

【 摘 要 】

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 ductligated 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 mu m). 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. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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