Regulation of hepatocellular bile salt secretion: Who shoots the messengers

eds. The metabolic and molecular bases of inherited diseases. Vol 2, Ed 7. hepatocyte is highly regulated by the insertion of vesiNew York: McGraw-Hill, 1995:1841-1885, 1981-2030. cles into this domain and that this process involves both 3. Powell LM, Wallis SC, Pease RJ, Edwards YH, Knott TJ, Scott J. A novel microtubule-dependent and microtubule-independent form of tissue-specific RNA processing produces apo B-48 in the intestine. Cell 1987;50:831-840. mechanisms. 4. Scott J, Navaratnam N, Bhattacharya S, Morrison JR. The apolipoprotein messenger RNA editing enzyme. Curr Opin Lipidol 1994;5:87-93. 5. Teng BB, Burand CF, Davidson NO. Molecular cloning of an apolipoprotein Noé B, Schliess F, Wettstein M, Heinrich S, Häussinger D. B messenger RNA editing protein. Science 1993;260:1816-1819. Regulation of taurocholate excretion by a hypo-osmolarity6. Navaratnam N, Bhattacharya S, Fufino T, Patel D, Jaumuz AL, Scott activated signal transduction pathway in rat liver. GastroenJ. Evolutionary origins of apo B mRNA editing: catalysis by a cytidine terology 1996;110:858-865. deaminase that has acquired a novel RNA-binding motif as its active site. Cell 1995;81:187-195. 7. Giannoni F, Bonen DK, Funahashi T, Hadjiagapiou C, Burant CF, DavidABSTRACT son NO. Complementation of apolipoprotein B mRNA editing by human liver accompanied by secretion of apolipoprotein B-48. J Biol Chem 1994; Background and Aims. Hypo-osmotic cell swelling in269:5932-5936. 8. Greeve J, Altkemper I, Dieterich JH, Greten H, Windler E. Apolipoprotein creases the capacity of taurocholate excretion into bile B mRNA editing in 12 different mammalian species: hepatic expression in the perfused rat liver. The aim of this study was to is reflected in low concentrations of apo B-containing plasma lipoproteins. clarify the mechanisms linking cell swelling to bile acid J Lipid Res 1993;34:1367-1382. secretion. Methods. The influence of hypo-osmotic cell 9. Li X, Catalina F, Grundy SM, Patel S. Method to measure apolipoprotein B-48 and B-100 secretion rates in an individual mouse: evidence for a very swelling on intracellular signal transduction and bile rapid turnover of VLDL and preferential removal of B-48 relative to Bacid secretion was studied in isolated rat hepatocytes 100-containing lipoproteins. J Lipid Res 1996;37:210-220. and the perfused rat liver. Results. In rat livers perfused 10. Nakamuta M, Oka K, Krushkal J, Kobayashi K, Yamamoto M, Li WH, with hypo-osmotic buffer (225 mOsm/L), the maximum Chan L. Alternative mRNA splicing and differential promoter utilization determine tissue-specific of the apolipoprotein B mRNA-editing protein velocity of taurocholate excretion into bile is increased (APOBEC-1) gene in mice. Structure and evolution of APOBEC-1 and by 135% within 10 to 20 minutes. To unravel the signaling related nucleoside/nucleotide deaminases. J Biol Chem 1995;270:13042events mediating this effect, the activities of the mito13056. gen-activated protein kinases, extracellular signal-regu11. Greeve J, Jona VK, Roy Chowdhury N, Horwitz MS, Roy Chowdhury J. Hepatic gene transfer of the catalytic subunit of the apolipoprotein B lated kinases (Erk)-1 and Erk-2, were measured after mRNA editing enzyme, APOBEC-1, leads to reduction of LDL in normal hypo-osmotic treatment in cultured rat hepatocytes. A and Watanabe heritable hyperlipidemic rabbits. J Lipid Res 1996;37:2001rapid parallel activation of Erk-1 and Erk-2 was ob2017. served within 1 minute, which became maximal after 10 12. Giannoni F, Chow S-C, Skarosi SF, Verp MS, Field FH, Coleman RA, Davidson NO. Developmental regulation of the catalytic subunit of the minutes and returned to the basal level within 60 minapolipoprotein B mRNA editing enzyme (APOBEC-1) in human small inutes. The hypo-osmolarity-induced Erk activation and testine. J Lipid Res 1995;36:1664-1675. the increase in bile flow after hypo-osmotic liver perfu13. Schock D, Kuo S-R, Steinburg MF, Bolognino M, Sparks JD, Sparks CE, sion were completely abolished by inhibitors of signal Smith HC. An auxiliary factor containing a 240 kDa protein complex is involved in apolipoprotein B RNA editing. Proc Natl Acad Sci U S A 1996; transduction at the level of G proteins and tyrosine ki93:1097-1102. nases but remained unaffected by the inhibition of the protein kinase C. Conclusions. A G protein and tyrosine kinase-dependent but protein kinase C-independent acREGULATION OF HEPATOCELLULAR BILE SALT tivation of mitogen-activated protein kinases is involved SECRETION: WHO SHOOTS THE MESSENGERS? in the regulation of taurocholate excretion by liver cell Boyer JL, Soroka CJ. Vesicle targeting to the apical domain hydration changes. regulates bile excretory function in isolated rat hepatocyte couplets. Gastroenterology 1995;109:1600-1611. Beuers U, Throckmorton DC, Anderson MS, Isales CM, Thasler W, Kullak-Ublick G-A, Sauter G, et al. TauroursoABSTRACT deoxycholic acid activates protein kinase C in isolated rat hepatocytes. Gastroenterology 1996;110:1553-1563. Background and Aims. Plasma membrane solute transport may be regulated in many epithelial cells by vesicle traffic to and from the site of residence of the ABSTRACT transporter. The aim of this study is to determine if this phenomenon may also play a role in the regulation of Background and Aims. Ursodeoxycholic acid improves liver function in patients with chronic cholestatic liver the canalicular transport of bile acids. Methods. Confocal microscopy and image analysis were performed to diseases by an unknown mechanism. Ursodeoxycholic acid is conjugated to taurine in vivo, and tauroursodeoxyquantitatively assess changes in secretory capacity and vesicle targeting in isolated rat hepatocyte couplets that cholic acid (TUDCA) is a potent hepatocellular Ca2/ agonist and stimulates biliary exocytosis and hepatocelhad been exposed to fluorescent bile acid after pretreatment with dibutyryl adenosine 3*,5*-cyclic monophoslular Ca influx, both of which are defective in experimental cholestasis. Protein kinase C (PKC) mediates the phate (DBcAMP) and/or nocodazole. Results. DBcAMP stimulated bile acid secretion by 240% while signifistimulation of exocytosis in the liver. The aim of this study was to determine the effects of TUDCA on PKC in cantly increasing canalicular circumference. Nocodazole decreased secretion by 410% and significantly deisolated hepatocytes. Methods. The effect of TUDCA on the distribution of PKC isoenzymes within the hepatocreased canalicular circumference. When DBcAMP was added to nocodazole-treated couplets, a slight but signifcyte was studied using immunoblotting and immunofluorescence techniques. In addition, the effect of TUDCA icant increase was found in both fluorescent bile acid secretion and canalicular circumference as compared on the accumulation of sn-1,2-diacylglycerol, the intracellular activator of PKC, and hepatocellular PKC activwith nocodazole alone. Finally, DBcAMP stimulated the translocation of vesicles to the canalicular membrane ity was studied using radioenzymatic techniques. Results. Immunoblotting studies showed the presence of as determined by immunocytochemical localization of a putative bile acid transporter, Ca, Mg-ecto-adenosine four isoenzymes (a, d, e, and z). The phorbol ester phorbol 12-myristate 13-acetate (1mmol/L) induced translocation triphosphatases. Conclusions. The findings support the view that apical membrane transport activity in the rat ofa-PKC, d-PKC, and e-PKC from cytosol to a particulate