Cholestatis is a serious medical condition in which bile cannot freely flow from the liver to the duodenum. Liver diseases associated with cholestasis account for significant morbidity and mortality in both children and adults. While diverse in etiology, all cholestatic disorders converge on a final common pathway characterized by a decrease in bile flow.
Mechanotransduction is the process by which cells translate external mechanical force into internal signals. The senses of touch and hearing depend on mechanotransduction to convert pressure and/or movement to nerve signals.
Our laboratory investigates the role of mechanotransduction in regulating liver function. We have found that biliary epithelial cells, known as cholangiocytes, respond to the mechanical force of bile flow over their apical surfaces. The cells translate the mechanical stimulus into intracellular signals that regulate membrane transport of ions.
Our research evaluates the role of these newly identified mechanosensitive pathways in bile formation.
We have found that increased fluid flow, or shear, at the apical membrane of cholangiocytes is a potent stimulus for:
- ATP release
- Increases in [Ca2+]
- Regulation of Cl– and Na+ transport
Collectively these observations support the hypothesis that mechanosensitive signaling serves as a powerful mechanism for autocrine/paracrine regulation of cholangiocyte transport and bile formation. Indeed, this signaling pathway may represent the dominant mechanism for dynamic regulation of cholangiocyte Cl– and HCO3– secretion to meet rapidly changing physiologic demands. Mechanosensitive signaling, therefore, may be a key regulator of bile formation.