Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids

The farnesoid X-activated receptor (FXR; NR1H4), a member of the nuclear ho rmone receptor superfamily, induces gene expression in response to several bile acids, including chenodeoxycholic acid. Here we used suppression subtr active hybridization to identify apolipoprotein C-II (apoC-II) as an FXR ta rget gene. Retroviral expression of FXR in HepG2 cells results in induction of the mRNA encoding apoC-II in response to several FXR ligands. EMSAs dem onstrate that recombinant FXR and RXR bind to two FXR response elements tha t are contained within two important distal enhancer elements (hepatic cont rol regions) that lie 11 kb and 22 kb upstream of the transcription start s ite of the apoC-II gene. A luciferase reporter gene containing the hepatic control region or two copies of the wild-type FXR response element was acti vated when FXR-containing cells were treated with FXR ligands. In addition, we report that hepatic expression of both apoC-II and phospholipid transfe r protein mRNAs increases when mice are fed diets supplemented with cholic acid, an FXR ligand, and this induction is attenuated in FXR null mice. Fin ally, we observed decreased plasma triglyceride levels in mice fed cholic a cid-containing diets. These results identify a mechanism whereby FXR and it s ligands lower plasma triglyceride levels. These findings may have importa nt implications in the clinical management of hyperlipidemias.