Figure 1.

FXR-mediated increased expression of hepatic cholesterol transport genes is blocked by mutation of FXR at Tyr-67. A, heat maps of changes in hepatic gene expression in mice expressing Y67F-FXR compared with mice expressing WT-FXR from published RNA-Seq data (26) (n = 3 mice). B and C, FXR-floxed mice were co-infected with AAV-TBG-Cre and either AAV-TBG-GFP or AAV-TBG expressing WT-FXR or Y67F-FXR for 4 weeks (10 mice/group), and mice were fed a 0.5% CA chow for 6 h. B, levels of the indicated proteins were determined by IB. C, the mRNA levels of the indicated genes were measured by RT-qPCR (n = 10). D, diagram of hepatic genes involved in cholesterol transport and efflux for biliary excretion. E–G, FXR-LKO mouse studies. E, FXR-LKO mice were infected with AAV-TBG-GFP or AAV-TBG expressing WT-FXR or Y67F-FXR for 4 weeks (6–7 mice/group). Protein levels of hepatic FXR and p-Y67-FXR determined by IB are shown. F, the mRNA levels of the indicated genes were measured by RT-qPCR in the liver (left) or the duodenum (Duod), jejunum (Jejun), or ileum (right). G, the hepatic mRNA levels of Scarb1 and Abcg5/8 compared with their mRNA levels in control C57BL6 mice (set to 1) and FXR-floxed mice. All values are presented as mean ± S.D. (error bars) Statistical significance was measured using the Mann–Whitney test (C) or one-way ANOVA with the Tukey post-test (F and G). *, p < 0.05; **, p < 0.01; NS, statistically not significant.