Abstract
The regulation of glycogen synthase activity by bile acids in primary hepatocytes and in the intact liver was investigated. Bile acids (deoxycholic acid, DCA; taurocholic acid, TCA) activated AKT and glycogen synthase (GS) in primary rat hepatocytes. Incubation with a phosphatidyl inositol-3 kinase inhibitor or expression of dominant-negative AKT in primary rat hepatocytes abolished activation of AKT and GS by DCA and TCA. TCA, but not DCA, activated Gαi proteins in primary rat hepatocytes. Treatment of cells with pertussis toxin or expression of dominant-negative Gαi blocked TCA-induced activation of AKT and of GS but did not alter AKT or GS activation caused by DCA. TCA caused activation of AKT and GS in intact rat liver. Expression of dominant-negative Gαi reduced TCA-induced activation of AKT and of GS in intact rat liver. Together, our findings demonstrate that bile acids are physiological regulators of glycogen synthase in rat liver and that conjugated bile acids use a Gαi-coupled G protein-coupled receptor to regulate GS activity in vitro and in vivo.
Footnotes
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This work was funded by Public Health Service (PHS) grants R01-DK52825, P01-DK38030, P01-CA72955, and R01-CA88906, Department of Defense Awards BC980148 and BC020338, and a fellowship from the V Foundation (to P.D.); PHS grant P01-DK38030 (to P.B.H.); and PHS grants P01-CA72955, R01-CA63753, and R01-CA77141 and Leukemia Society of America grant 6405-97 (to S.G.). P.D. is the holder of the Universal Inc. Professorship in Signal Transduction Research.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.032060.
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ABBREVIATIONS: ERK, extracellular signal-regulated kinase; PI3K, phosphatidyl inositol-3 kinase; GS, glycogen synthase; DCA, deoxycholic acid; TCA, taurocholic acid; GPCR, G protein-coupled receptor; HRP, horseradish peroxidase; ECL, enhanced chemiluminescence; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; CDCA, chenodeoxycholic acid; TUDCA, tauroursodeoxycholic acid; TDCA, taurodeoxycholic acid; GDCA, glycodeoxycholic acid; GSK3, glycogen synthase kinase 3.
- Received October 20, 2006.
- Accepted January 2, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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