Targeting specific FXR isoforms in the bile acid biosynthetic pathway
M. Boesjes1, J. Hageman1, V.W. Bloks1, H. Havinga1, F. Kuipers 1,2, A.K. Groen1,2
Laboratory of 1Pediatrics and 2Laboratory Medicine, Center for Liver, Digestive and
Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands
Bile acids (BA) are synthesized from cholesterol in the liver and are in control of lipid and
carbohydrate metabolism. The nuclear receptor Farnesoid X Receptor (FXR) acts as an
intracellular BA sensor and regulates the synthesis, secretion and uptake of BA. Four FXR
splice variants are known, FXR-4. Although these isoforms show differences in spatial
and tissue specific expression as well as transcriptional activity, their physiological
contribution is unknown yet. In this study we aimed to define the specific role of FXR2 and
FXR4 in control of BA metabolism.
Male FXR -/- mice were stably transduced with hepatic-specific scAAV expressing FXR2,
FXR or GFP. Mice either received chow or chow supplemented with 0.5% cholic acid
(CA).
Plasma cholesterol and triglyceride levels were decreased by 2 fold in FXR2 and FXR4
treated mice, in correcting the phenotype of FXR -/- mice to a similar extent. Comparing
hepatic microarray analysis data from FXR2 and FXR4 treated mice revealed primary
involvement of FXR2 in chenodeoxycholic acid (CDCA) and of FXR4 in CA production.
Fecal and biliary bile acid analysis indeed revealed an increased CDCA-derived BA pool in
FXR2 treated mice, while FXR4 mice showed increased CA-derived BA.
In conclusion, both FXR2 and FXR4 could rescue the plasma lipid profile in FXR -/- mice
by normalizing the plasma triglyceride and cholesterol levels. A differential effect of FXR2
and FXR4 on BA biosynthetic genes was observed, indicating a role of the FXR isoforms in
control of BA composition in mice.