Diacylglycerol Kinase-{theta} Couples FXR-Dependent Bile Acid Signaling to Akt Activation and Glucose Homeostasis in Hepatocytes

Diacylglycerol kinases (DGKs) catalyze the conversion of diacylglycerol into phosphatidic acid (PA), a positive modulator of mammalian target of rapamycin (mTOR). We have found that chenodeoxycholic acid and the synthetic farnesoid X receptor (FXR) ligand GW4064 induce the mRNA and protein expression of DGKQ in the HepG2 cell line and in primary human hepatocytes. Reporter gene studies using 1.5 kB of the DGKQ promoter fused to the luciferase gene revealed that bile acids increase DGKQ transcriptional activity. Mutation of putative FXR binding sites attenuated the ability of GW4046 to increase DGKQ luciferase activity. Consistent with this finding, chromatin immunoprecipitation (ChIP) assays demonstrated that bile acid signaling increased the recruitment of FXR to the DGKQ promoter. Further, 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, and that silencing DGKQ expression significantly abrogated ability of GW4046 to promote the phosphorylation of these PA-regulated targets. DGKQ was also required for bile acid-dependent decreased glucose production. Taken together, our results establish DGKQ as a key mediator of bile acid-stimulated modulation of mTORC2, the Akt pathway, and glucose homeostasis.

Source: BJ Signal - June 17, 2013 Category: Biochemistry Authors: K Cai, M B Sewer Tags: BJ Signal Source Type: research