@article {47674,
	title = {Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway.},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {108},
	year = {2011},
	month = {2011 Jan 25},
	pages = {1403-8},
	abstract = {<p>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.</p>
},
	keywords = {Adenylate Kinase, Animals, Bile Acids and Salts, Blotting, Western, Cell Polarity, Cells, Cultured, Chenodeoxycholic Acid, Cholagogues and Choleretics, Cyclic AMP, Dose-Response Relationship, Drug, Green Fluorescent Proteins, Guanine Nucleotide Exchange Factors, Hepatocytes, Imines, Microscopy, Confocal, Mitogen-Activated Protein Kinase Kinases, Models, Biological, Protein-Serine-Threonine Kinases, rap1 GTP-Binding Proteins, Rats, Rats, Sprague-Dawley, Signal Transduction, Taurocholic Acid, Ursodeoxycholic Acid},
	issn = {1091-6490},
	doi = {10.1073/pnas.1018376108},
	author = {Fu, Dong and Wakabayashi, Yoshiyuki and Lippincott-Schwartz, Jennifer and Arias, Irwin M}
}
@article {47679,
	title = {Regulation of bile canalicular network formation and maintenance by AMP-activated protein kinase and LKB1.},
	journal = {Journal of cell science},
	volume = {123},
	year = {2010},
	month = {2010 Oct 1},
	pages = {3294-302},
	abstract = {<p>AMP-activated protein kinase (AMPK), a cellular metabolic sensor, is essential in energy regulation and metabolism. Hepatocyte polarization during liver development and regeneration parallels increased metabolism. The current study investigates the effects of AMPK and its upstream activator LKB1 on polarity and bile canalicular network formation and maintenance in collagen sandwich cultures of rat hepatocytes. Immunostaining for the apical protein ABCB1 and the tight junction marker occludin demonstrated that canalicular network formation is sequential and is associated with activation of AMPK and LKB1. AMPK and LKB1 activators accelerated canalicular network formation. Inhibition of AMPK or LKB1 by dominant-negative AMPK or kinase-dead LKB1 constructs blocked canalicular network formation. AICAR and 2-deoxyglucose, which activate AMPK, circumvented the inhibitory effect of kinase-dead LKB1 on canalicular formation, indicating that AMPK directly affects canalicular network formation. After the canalicular network was formed, inhibition of AMPK and LKB1 by dominant-negative AMPK or kinase-dead LKB1 constructs resulted in loss of canalicular network, indicating that AMPK and LKB1 also participate in network maintenance. In addition, activation of AMPK and LKB1 prevented low-Ca(2+)-mediated disruption of the canalicular network and tight junctions. These studies reveal that AMPK and its upstream kinase, LKB1, regulate canalicular network formation and maintenance.</p>
},
	keywords = {Animals, Bile Canaliculi, Cell Polarity, Cells, Cultured, Cloning, Molecular, Enzyme Activation, Hepatocytes, Male, Mutant Proteins, Organ Culture Techniques, Organogenesis, Protein Kinases, Protein-Serine-Threonine Kinases, Rats, Rats, Sprague-Dawley},
	issn = {1477-9137},
	doi = {10.1242/jcs.068098},
	author = {Fu, Dong and Wakabayashi, Yoshiyuki and Ido, Yasuo and Lippincott-Schwartz, Jennifer and Arias, Irwin M}
}
