β1 integrin is a long‐sought sensor for tauroursodeoxycholic acid

M ore than a thousand years ago at the time of the gleaming Tang dynasty in China (618-907 A.C.), a golden age of Chinese poetry, dried black bear’s bile was recommended for treatment of jaundice (but also of intractable diarrhea in the summer and heart complaints) as documented in the Tang Materia Medica, the first state pharmacopoeia. The major organic constituent of black bear’s bile is ursodeoxycholic acid (UDC), which may form up to 60% of black bear’s total bile acids. UDC has potent anticholestatic and antiapoptotic properties and is today regarded as the standard treatment of primary biliary cirrhosis (PBC) and intrahepatic cholestasis of pregnancy (ICP). It exerts anticholestatic effects in numerous other conditions of hepatocellular (as in ICP) or cholangiocellular cholestasis (as in early PBC). Of note, UDC is enriched from 1%2% to 40% of total bile acids in bile of patients with PBC and healthy volunteers treated with therapeutic doses of UDC (15 mg/kg daily). How does UDC exert its choleretic and anticholestatic properties at the level of the hepatocyte? In contrast to hydrophobic bile acids such as chenodeoxycholic (CDC) or lithocholic acid (LC), UDC does not markedly affect transport protein expression in vivo at the transcriptional level to modulate transport capacity. The impact of limited posttranscriptional modification of carrier expression for the choleretic and anticholestatic effects of UDC, possibly by way of modulation of expression of specific microRNAs, is yet unclear. The first hints that UDC may act as a potent intracellular signaling molecule come from the early 1990s when UDC was unraveled as a Caþþ agonist and an activator of protein kinase C (cPKCa), mitogen-activated protein kinases (MAPK: Erk1/2, p38), and a5b1 integrins 16 in hepatocytes (later confirmed in cholangiocytes). The concept that UDC conjugates, by activating intracellular signaling cascades, might enhance the secretory capacity of hepatocytes (and cholangiocytes) by stimulating vesicular exocytosis and, thereby, insertion of key transport proteins into their target membrane was independently developed by H€aussinger et al. (then in the context of bile acid-induced cell swelling) and Beuers et al. (as a Caþþ-/cPKCa-dependent vesicle fusion process). These groups and others were subsequently able to show in experimental models that UDC conjugates exert choleretic effects by apical carrier insertion by way of a dual MAPKand integrin-dependent mechanism in healthy liver and anticholestatic effects by stimulation of impaired apical carrier insertion by way of Caþþ-/type II inositol-1,4,5triphosphate (InsP3R) receptor/cPKCa/PKA-dependent mechanisms in cholestatic liver. The intracellular effects of UDC appear to be dependent on taurine (T) or glycine (G) conjugation of the bile acid. Thus, TUDC and GUDC appear to be the secretory saviors under (patho-) physiological conditions in liver. UDC conjugates exert their intracellular signaling in liver cells after cell entry, but not by extracellular membrane/receptor interactions. This explains why hepatocytes equipped with the bile acid membrane carrier Naþ/taurocholate cotransporting peptide (NTCP) are more than any other cell type sensitive to the effects of UDC conjugates at low micromolar concentrations. Still, an intracellular receptor/sensor specifically for UDC conjugates which might initiate one or the other signaling cascade had so far not been identified. In the present issue of HEPATOLOGY, Gohlke et al. present in an elegant series of experiments the landmark finding that low micromolar TUDC, but not taurocholic acid (TC), TCDC, GCDC, and TLC-sulfate within a minute after cell entry transfers the b1 unit of mainly cytosolic a5b1 integrins into its active conformation in perfused rat liver and human Ntcp-transfected HepG2 hepatoma cells. This leads to rapid phosphorylation and Abbreviations: CDC, chenodeoxycholic; cPKCa, activator of protein kinase C; EGFR, epidermal growth factor receptor; ICP, intrahepatic cholestasis of pregnancy; LC, lithocholic acid; MAPK, mitogen-activated protein kinase; NTCP, Naþ/taurocholate cotransporting peptide; PBC, primary biliary cirrhosis; TC, taurocholic acid; UDC, ursodeoxycholic acid. The author is supported by research grants ‘‘Primary sclerosing cholangitis’’ from the Deutsche Crohn-Colitis-Vereinigung and the Norwegian Primary Sclerosing Cholangitis Foundation. Potential conflict of interest: Dr. Beuers consults for Intercept and Novartis. He lectures Falk Foundation, Gilead, Roche, and Zambon. Address reprint requests to: Ulrich Beuers, M.D., Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, G4-216, University of Amsterdam, Meibergdreef 9, 1100 DE Amsterdam, The Netherlands. E-mail: u.h. beuers@ amc.uva. nl. Copyright VC 2012 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26228