α₅β₁ integrins in hepatocytes act as receptors for bile acids with a (nor)ursodeoxycholane scaffold

Excerpt

Ursodeoxycholic acid (UDCA) is a standard treatment in several cholestatic liver diseases (Figure 1A) [1]. In vivo, conjugation with taurine occurs rapidly and yields tauroursodeoxycholic acid (TUDC), which has been shown to promote choleresis by triggering the insertion of ATP-dependent transport proteins (e.g., the bile salt export pump (Bsep) and the multidrug resistance protein-2 (Mrp2)) into the canalicular membrane [2]. TUDC-induced recruitment of Bsep results from activation of focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3 kinase), and c-Src, which leads to downstream activation of extracellular signal-regulated kinases (Erks) and p38 mitogen-activated protein kinase (p38^MAPK). Upon hepatocyte swelling, either induced by exposure to a hypoosmotic environment or insulin, α₅β₁ integrins become activated and trigger similar signaling events towards choleresis. α₅β₁ Integrins may also become activated by a swelling-independent way as previously shown by exposing hepatocytes to pathophysiological concentrations of urea [3]. Both TUDC-induced and swelling-dependent signaling were abolished in the presence of an antagonistic, RGD-motif containing hexapeptide (GRGD SP).

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