A modular analysis of bile canalicular function and its implications for cholestasis

Hepatocytes produce bile components and secrete them into a lumen, known as a bile canaliculus, that is formed by the apical membranes of adjoining hepatocytes. Bile canaliculi merge to form tubular structures that subsequently connect to the canal of Hering and larger intra-and extrahepatic bile ducts formed by cholangiocytes, which modify bile and enable flow through the small intestine. The major functional requirements for bile canaliculi are the maintenance of canalicular shape to preserve the blood-bile barrier and regulation of bile flow. These functional requirements are mediated by functional modules, primarily trans-porters, the cytoskeleton, cell-cell junctions, and mechanosensing proteins. I propose here that bile canaliculi behave as robust machines whereby the functional modules act in a coordinated manner to perform the multistep task of maintaining canalicular shape and bile flow. Cholestasis, the general term for aberrant bile flow, stems from drug/toxin-induced or genetic dysregulation of one or more of the protein components in the functional modules. Here, I discuss the interactions between components of the various functional modules in bile canaliculi and describe how these functional modules regulate canalicular morphology and function. I use this framework to provide a perspective on recent studies of bile canalicular dynamics.

Automated summary

Hepatocytes produce and secrete bile components into bile canaliculi, which are formed by the apical membranes of hepatocytes. Bile canaliculi merge to form tubular structures that connect to bile ducts and enable bile flow through the small intestine. Functional requirements of bile canaliculi include maintaining canalicular shape and regulating bile flow, which are mediated by functional modules such as transporters, cytoskeleton, cell-cell junctions, and mechanosensing proteins. Cholestasis, abnormal bile flow, can occur due to dysregulation of these functional modules. This article discusses the interactions and regulation of these modules in bile canaliculi and provides a perspective on recent studies of bile canalicular dynamics.