| 20305288 |
Cao R, Cronk ZX, Zha W, Sun L, Wang X, Fang Y, Studer E, Zhou H, Pandak WM, Dent P, Gil G, Hylemon PB: Bile acids regulate hepatic gluconeogenic genes and FXR via G-alpha-i protein coupled receptor (s) and the AKT pathway. J Lipid Res. 2010 Mar 20.
Bile acids are important regulatory molecules that can activate specific nuclear receptors and cell signaling pathways in the liver and gastrointestinal tract. In the current study, the chronic bile fistula (CBF) rat model and primary rat hepatocytes (PRH) were used to study the regulation of gluconeogenic genes (PEPCK and G-6-Pase) and the gene encoding short heterodimeric partner (SHP) by taurocholate (TCA). The intestinal infusion of TCA into the CBF rat rapidly (1h) activated the AKT (~9-fold) and ERK 1/2 (3 to 5-fold) signaling pathways, down-regulated (~50%, 30 min) the mRNA levels of PEPCK and G-6-Pase, and induced (14-fold in 3 h) SHP mRNA. TCA rapidly (~50%, 1 to 2 h) down-regulated PEPCK and G-6-Pase mRNA levels in PRH. The down-regulation of these genes by TCA was blocked by pre-treatment of PRH with pertussis toxin. In PRH, TCA plus insulin showed a significantly stronger inhibition of glucose secretion/synthesis from lactate and pyruvate than either alone. The induction of SHP mRNA in PRH was strongly blocked by inhibition of PI3 kinase or PKC zeta by specific chemical inhibitors or knock-down of PKC zeta by siRNA encoded by a recombinant lentivirus. Activation of the insulin signaling pathway appears to be linked to the up regulation of FXR functional activity and SHP induction. |
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