title: Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway.
abstract: This study describes a unique function of taurocholate in bile canalicular formation involving signaling through a cAMP-Epac-MEK-Rap1-LKB1-AMPK pathway. In rat hepatocyte sandwich cultures, polarization was manifested by sequential progression of bile canaliculi from small structures to a fully branched network. Taurocholate accelerated canalicular network formation and concomitantly increased cAMP, which were prevented by adenyl cyclase inhibitor. The cAMP-dependent PKA inhibitor did not prevent the taurocholate effect. In contrast, activation of Epac, another cAMP downstream kinase, accelerated canalicular network formation similar to the effect of taurocholate. Inhibition of Epac downstream targets, Rap1 and MEK, blocked the taurocholate effect. Taurocholate rapidly activated MEK, LKB1, and AMPK, which were prevented by inhibition of adenyl cyclase or MEK. Our previous study showed that activated-LKB1 and AMPK participate in canalicular network formation. Linkage between bile acid synthesis, hepatocyte polarization, and regulation of energy metabolism is likely important in normal hepatocyte development and disease.
authors.affiliation: Cell Biology and Metabolism Program, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Fu
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Wakabayashi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lippincott-Schwartz
authors.forename: Irwin M
authors.initials: IM
authors.lastname: Arias
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000263:Adenylate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D015153:Blotting, Western; D016764:Cell Polarity / Q000187:drug effects*; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007097:Imines / Q000494:pharmacology; D018613:Microscopy, Confocal; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013656:Taurocholic Acid / Q000494:pharmacology; D014580:Ursodeoxycholic Acid / Q000494:pharmacology; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D020662:Guanine Nucleotide Exchange Factors; D007097:Imines; D002635:Chenodeoxycholic Acid; D049452:Green Fluorescent Proteins; D013656:Taurocholic Acid; D014580:Ursodeoxycholic Acid; C014925:RMI 12330A; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000263:Adenylate Kinase; D020827:rap1 GTP-Binding Proteins