Osmosensing And Osmosignaling Pathways

Toward Canalicular Secretion

Osmoregulation of canalicular secretion requires structures that pick up changes in hepatocyte hydration (osmosensing) and transmit this information toward effector sites (osmosignaling). Studies have identified the integrin system as one major osmosensor in hepatocytes (Haussinger et al., 2003; Schliess et al., 2004; vom Dahl et al., 2003). Integrins are a family of extracellular matrix (ECM) adhesion molecules involved in ''mechano-transduction'' and growth factor signaling (Aplin et al., 1998; Hynes, 2002; Ingber, 1997; Miranti and Brugge, 2002). In liver the most important integrins are a1b1, a5b1, and a9b1 (Carloni et al., 2001; Hsu et al., 2001; Torimura et al., 2001). As shown by immunohistochemistry, hypoosmotic exposure of rat hepatocytes leads to the rapid appearance of the active conformation of the b1subunit in the plasma membrane, indicating integrin activation in response to hepatocyte swelling (Haussinger et al., 2003; Schliess et al., 2004; vom Dahl et al., 2003). Downstream consequences of hypoosmotic integrin activation are the activation of Src kinases and of mitogen-activated protein kinases Erks and p38MAPK (Haussinger et al., 2003; vom Dahl et al., 2003). Dual activation of both Erks and p38MAPK is required for the choleretic effect of cell swelling, and choleresis induced by hypoosmotic cell swelling is abolished in the presence of inhibitors of either the integrin system or Src or one of the two MAP kinases (Haussinger et al., 2003; Kurz et al., 2001; Noe et al., 1996; Schmitt et al., 2001). Interestingly, TC also induces swelling and it was suggested that an increased load of this physiological bile acid to the liver may stimulate canalicular bile acid excretion via a feedforward regulation as a consequence of a swelling-induced recruitment of Bsep to the canalicular membrane (Haussinger et al., 1992; Noe et al., 1996). Such a response would accelerate enterohepatic circulation of bile acids after ingestion of a meal, which by itself also triggers nutrient-driven hepatocyte swelling, for example, by the concentrative uptake of amino acids into hepatocytes. The role of integrins as osmosensors is underlined by the fact that integrin-inhibitory peptides exhibiting a RGD motif fully abolish osmosignaling toward MAP kinases and the stimulation of bile formation, which is otherwise triggered by hypoosmotic swelling. Such peptides prevent integrin binding to the RGD attachment sites of ECM proteins such as fbronectin, thereby impairing the dynamics of integrin/matrix interactions, which are essential for effective mechanotransduction (Ruoslahti, 1996). Interestingly, tauroursodeoxycho-late also activates nonosmotically integrin-dependent osmosensing and osmo-signaling pathways, which may explain the choleretic action of this bile acid (Haussinger et al., 2003; Kurz et al., 2001).

Endosomes have been identified as an osmosensing compartment, which is activated in response to hyperosmotic hepatocyte shrinkage (Reinehr et al., 2006). Here, a hyperosmolarity-induced endosomal acidification was shown to trigger ceramide formation within seconds, which in turn activates protein kinase CZ, which results in an activation of NADPH oxidase isoforms because of an activating phosphorylation ofp47phox. As a consequence, hyperosmotic hepatocyte shrinkage produces oxidative stress. It is not yet clear to what extent this oxidative stress response is involved in the hyperosmotic retrieval of canalicular transport systems; however, exog-enously added hydroperoxides were shown to induce the retrieval of Mrp2 from the canalicular membrane (Schmitt et al., 2000). In line with the suggestion that oxidative stress may contribute to the cholestatic action of hyperosmotic hepatocyte shrinkage is also the finding that toxic, hydrophobic bile acids, which are known to be cholestatic, also induce oxidative stress via NADPH oxidase activation (Becker et al., 2007; Reinehr et al., 2005).

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