Bile canaliculi contract autonomously by releasing calcium into hepatocytes via mechanosensitive calcium channel. (November 2020)

• Record Type: Journal Article
• Authors: Gupta, Kapish; Ng, Inn Chuan; Balachander, Gowri Manohari; Nguyen, Binh P.; Tucker-Kellogg, Lisa; Low, Boon Chuan; Yu, Hanry
• Is Part Of: Biomaterials. Volume 259(2020)
• Publication Date: 2020-11
• Subjects: Piezo -- Canalicular pressure -- Bile canaliculi derived vesicles -- Hepatocellular cholestasis -- Mechanosensitive ion channels -- Liver disease; BA Bile acid -- BC Bile canaliculi -- BCV Bile canaliculi derived vesicles -- Ca2+ Calcium -- ER endoplasmic reticulum -- ICP intra-canalicular pressure -- MCC mechanosensitive Calcium channel -- PAC peri-canalicular actin cortex -- tbuHBQ 2, 5-di-(ter-butyl)-1, 4-benzohydroquinone -- GB glyburide -- KTZ Ketoconazole; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2020.120283
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Drug-induced hepatocellular cholestasis leads to altered bile flow. Bile is propelled along the bile canaliculi (BC) by actomyosin contractility, triggered by increased intracellular calcium (Ca 2+ ). However, the source of increased intracellular Ca 2+ and its relationship to transporter activity remains elusive. We identify the source of the intracellular Ca 2+ involved in triggering BC contractions, and we elucidate how biliary pressure regulates Ca 2+ homeostasis and associated BC contractions. Primary rat hepatocytes were cultured in collagen sandwich. Intra-canalicular Ca 2+ was measured with fluo-8; and intra-cellular Ca 2+ was measured with GCaMP. Pharmacological modulators of canonical Ca 2+ -channels were used to study the Ca 2+ -mediated regulation of BC contraction. BC contraction correlates with cyclic transfer of Ca 2+ from BC to adjacent hepatocytes, and not with endoplasmic reticulum Ca 2+ . A mechanosensitive Ca 2+ channel (MCC), Piezo-1, is preferentially localized at BC membranes. The Piezo-1 inhibitor GsMTx-4 blocks the Ca 2+ transfer, resulting in cholestatic generation of BC-derived vesicles whereas Piezo-1 hyper-activation by Yoda1 increases the frequency of Ca 2+ transfer and BC contraction cycles. Yoda1 can recover normal BC contractility in drug-induced hepatocellular cholestasis, supporting that Piezo-1 regulates BC contraction cycles. Finally, we show that hyper-activating Piezo-1 can be exploited to normalize bile flow in drug-induced hepatocellular cholestasis.