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Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin–sensitive mechanism in murine and human hepatocytes
Author(s) -
Dent Paul,
Fang Youwen,
Gupta Seema,
Studer Elaine,
Mitchell Clint,
Spiegel Sarah,
Hylemon Philip B.
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20942
Subject(s) - tauroursodeoxycholic acid , glycocholic acid , chenodeoxycholic acid , taurocholic acid , pertussis toxin , protein kinase b , deoxycholic acid , bile acid , tyrosine phosphorylation , receptor tyrosine kinase , biochemistry , biology , kinase , tyrosine kinase , signal transduction , chemistry , g protein , cholic acid , endoplasmic reticulum , unfolded protein response
Several studies have argued that G‐protein–coupled receptors (GPCR) have the capacity to promote activation of receptor tyrosine kinases. The current studies were performed to examine the regulation of the extracellular regulated kinase (ERK)1/2 and AKT pathways by conjugated and unconjugated bile acids in primary hepatocytes. Deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), taurodeoxycholic acid (TDCA), glycodeoxycholic acid (GDCA), taurochenodeoxycholic acid (TCDCA), glycochenodeoxycholic acid (GCDCA), taurocholic acid (TCA), glycocholic acid (GCA), and tauroursodeoxycholic acid (TUDCA) all activated ERK1/2 in primary rat hepatocytes that was abolished by inhibition of ERBB1, and significantly reduced by ROS quenching agents. Bile acid–induced AKT activation was blunted by preventing ERBB1 activation and ROS generation. Treatment of rat hepatocytes with pertussis toxin (PTX) did not alter ERK1/2 and AKT activation induced by DCA or CDCA but abolished pathway activations by conjugated bile acids. Similar data to those with PTX were obtained when a dominant negative form of G i 1α was overexpressed. Treatment of rat hepatocytes with TDCA and TCA promoted guanosine triphosphate (GTP) loading of G i 1α , G i 2α , and G i 3α in vitro . Treatment of rat hepatocytes with PTX abolished TDCA‐induced tyrosine phosphorylation of ERBB1. Similar findings to those in rat hepatocytes were also obtained in primary mouse and human hepatocytes, but not in established rodent or human hepatoma cell lines. In conclusion , collectively our findings demonstrate that unconjugated bile acids activate hepatocyte receptor tyrosine kinases and intracellular signaling pathways in a ROS‐dependent manner. In contrast, conjugated bile acids primarily activate receptor tyrosine kinases and intracellular signaling pathways in a GPCR (G i α ) –dependent and ROS‐dependent manner. (H EPATOLOGY 2005;42:1291–1299.)