5G). Furthermore, the outward movement of α7 is overlaid with a downward movement of the helix (see arrows in Fig. 5D). In contrast, no T-junction formation is observed for Ruxolitinib order TC- and GRGDSP-bound integrins (Fig. 6) as is no outward and downward movement of helix α7 (Fig. 5D). TUDC is known for its choleretic and hepatoprotective effects. As shown previously, TUDC-induced choleresis is triggered by a p38MAPK and Erk-dependent insertion of intracellularly stored Bsep and Mrp2 into the canalicular membrane of the hepatocyte.6, 12 TUDC-induced choleresis and signal transduction towards MAP kinases was recently shown to involve integrins12 and to resemble strongly osmosignaling events, which

are initiated by hypoosmotic hepatocyte swelling.12 In line with this, TUDC also induced EGFR activation (Fig. 2), as does hypoosmotic hepatocyte swelling.30 As shown here, TUDC directly, i.e., nonosmotically,

interacts with α5β1 integrins, resulting in an integrin activation and initiation of integrin signaling involving c-Src, FAK, EGFR, PI3 kinase, and MAP-kinases.6, 12 In line with this, β1 integrin knockdown abolished TUDC signaling towards Erks. These data suggest that β1 integrins are selleck chemicals llc a long-searched sensor for TUDC in the liver. Integrin activation by TUDC was not only found in rat liver, but also in human HepG2 cells and was not mimicked by other bile acids (TC, GCDC, TCDC, TLCS). This may explain at least in part the unique hepatoprotective and choleretic properties of TUDC compared to other bile acids. Nevertheless, as the experiments reported herein have been performed in noncholestatic livers and hepatocytes, it remains unclear to what extent other mechanisms come into play in the cholestatic

learn more liver, such as Ca2+/type II InsP3 receptor-33, 34 or cPKCα/PKA-dependent pathways.35 In order to effectively trigger integrin activation, TUDC has to be taken up by and/or to be concentrated inside the hepatocyte. In line with this, TUDC-induced integrin activation was most pronounced in the cytosol and only found in HepG2 cells that express Ntcp. This requirement for concentrative TUDC uptake and the liver-specificity of Ntcp-expression may explain why TUDC acts primarily in the liver. Higher TUDC concentrations were required for β1 integrin activation when TC was simultaneously present. This is probably not explained by a competition of TUDC with TC for entry into the hepatocyte by way of Ntcp. This view is supported by the previous finding5 that TUDC at concentrations of 10-50 μmol/L stimulates TC excretion into bile by up to 30% in perfused rat liver when TC is present at a concentration of 100 μmol/L in the perfusate. This would not be expected if bile acid entry into the hepatocyte would become rate-controlling. An alternative explanation for the TC-mediated inhibition of TUDC-induced β1 integrin activation is offered by the results obtained from MD simulations of TUDC, TC, and GRGDSP bound to a 3D model of the ectodomain of α5β1.