Document Detail


Diacylglycerol kinase θ couples farnesoid X receptor-dependent bile acid signalling to Akt activation and glucose homoeostasis in hepatocytes.
MedLine Citation:
PMID:  23767959     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
DGKs (diacylglycerol kinases) catalyse the conversion of diacylglycerol into PA (phosphatidic acid), a positive modulator of mTOR (mammalian target of rapamycin). We have found that chenodeoxycholic acid and the synthetic FXR (farnesoid X receptor) ligand GW4064 induce the mRNA and protein expression of DGKθ in the HepG2 cell line and in primary human hepatocytes. Reporter gene studies using 1.5 kB of the DGKθ promoter fused to the luciferase gene revealed that bile acids increase DGKθ transcriptional activity. Mutation of putative FXR-binding sites attenuated the ability of GW4046 to increase DGKθ luciferase activity. Consistent with this finding, ChIP (chromatin immunoprecipitation) assays demonstrated that bile acid signalling increased the recruitment of FXR to the DGKθ promoter. Furthermore, GW4064 evoked a time-dependent increase in the cellular concentration of PA. We also found that GW4064 and PA promote the phosphorylation of mTOR, Akt and FoxO1 (forkhead box O1), and that silencing DGKθ expression significantly abrogated the ability of GW4046 to promote the phosphorylation of these PA-regulated targets. DGKθ was also required for bile-acid-dependent decreased glucose production. Taken together, our results establish DGKθ as a key mediator of bile-acid-stimulated modulation of mTORC2 (mTOR complex 2), the Akt pathway and glucose homoeostasis.
Authors:
Kai Cai; Marion B Sewer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Biochemical journal     Volume:  454     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-08-12     Completed Date:  2013-11-04     Revised Date:  2014-04-09    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  267-74     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Cells, Cultured
Chenodeoxycholic Acid / metabolism*
Diacylglycerol Kinase / antagonists & inhibitors,  chemistry,  genetics,  metabolism*
Gene Expression Regulation / drug effects
Gene Silencing
Genes, Reporter
Glucose / metabolism*
Hep G2 Cells
Hepatocytes / cytology,  drug effects,  metabolism*
Humans
Isoenzymes / antagonists & inhibitors,  chemistry,  genetics,  metabolism
Isoxazoles / pharmacology
Multiprotein Complexes / metabolism
Mutation
Phosphatidic Acids / metabolism
Phosphorylation / drug effects
Promoter Regions, Genetic / drug effects
Protein Processing, Post-Translational / drug effects
Proto-Oncogene Proteins c-akt / metabolism*
Receptors, Cytoplasmic and Nuclear / agonists,  genetics,  metabolism*
Recombinant Proteins / agonists,  antagonists & inhibitors,  metabolism
Signal Transduction* / drug effects
TOR Serine-Threonine Kinases / metabolism
Grant Support
ID/Acronym/Agency:
DK084178/DK/NIDDK NIH HHS; R01 DK084178/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/GW 4064; 0/Isoenzymes; 0/Isoxazoles; 0/Multiprotein Complexes; 0/Phosphatidic Acids; 0/Receptors, Cytoplasmic and Nuclear; 0/Recombinant Proteins; 0/TOR complex 2; 0/farnesoid X-activated receptor; 0GEI24LG0J/Chenodeoxycholic Acid; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.1.107/Diacylglycerol Kinase; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; IY9XDZ35W2/Glucose
Comments/Corrections

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