Osmosensing by integrins in rat liver.

Changes in hepatocyte hydration are induced not only by ambient hypo- or hyperosmolarity, but also under isosmotic condition by hormones, substrates, and oxidative stress. The perfused rat liver is a well-established intact organ model with preservation of the three-dimensional hepatocyte anchoring to the extracellular matrix and/or adjacent cells, parenchymal cell polarity, liver cell heterogeneity, acinar construction, and gene expression gradients. Originally, data from the perfused rat liver indicated that changes of cell hydration independent of their origin critically contribute to the control of autophagic proteolysis and canalicular bile acid excretion. Meanwhile, the concept that cell hydration changes trigger signal transduction processes that control metabolism, gene expression, transport, and the susceptibility to stress is well accepted. This chapter summarizes evidence obtained from experiments with the perfused rat liver that integrins are osmosensors in the liver and thereby critically contribute to the Src- and MAP-kinase-dependent inhibition of autophagic proteolysis, stimulation of canalicular taurocholate excretion, and regulatory volume decrease as induced by hypoosmotic swelling. Moreover, integrin-dependent sensing of hepatocyte swelling is essential for signaling and proteolysis inhibition by insulin and glutamine. These findings define a novel role of integrins in insulin and glutamine signaling and set an example for mechanotransduction as an integral part of overall growth factor and nutrient signaling.