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      Diacylglycerol kinase θ couples farnesoid X receptor-dependent bile acid signalling to Akt activation and glucose homoeostasis in hepatocytes.

      1 ,
      The Biochemical journal
      Portland Press Ltd.

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          Abstract

          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.

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          Author and article information

          Journal
          Biochem. J.
          The Biochemical journal
          Portland Press Ltd.
          1470-8728
          0264-6021
          Sep 01 2013
          : 454
          : 2
          Affiliations
          [1 ] Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, 92093-0704, USA.
          Article
          BJ20130609 NIHMS567683
          10.1042/BJ20130609
          3976421
          23767959
          cb6c2b0f-eb3d-4cc6-9ddb-fec51ebd34fb
          History

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