Changes in the expression of genes related to bile acid synthesis and transport by the rat liver during hepatocarcinogenesis.

The relationship between BA (bile acid) secretion (measured by GC-MS) and the expression of genes (measured by reverse transcription real-time PCR) involved in liver BA transport and metabolism was investigated at 20 and 32 weeks during rat hepatocarcinogenesis. A progressive loss of mRNA for transporters (more marked for Ntcp, Bsep and Mrp2 than for Oatp1/Oatp1a1, Oatp2/Oatp1a4 and Oatp4/Oatp1b2) was found. The mRNA levels of Cyp7a1 and the nuclear receptors FXR (farnesoid X receptor), SHP (small heterodimer partner) and FTF (alpha-fetoprotein transcription factor) were not modified, whereas those of Cyp8b1 were enhanced and those of Cyp27 were reduced. Biliary secretion of CA (cholic acid) remained unchanged, whereas that of CDCA (chenodeoxycholic acid) and other non-C(12)-hydroxylated BAs was diminished. The re-appearance of 'flat-BAs' (mainly allo-BAs at 20 weeks and Delta(4)-unsaturated-BAs at 32 weeks) probably reflects the progressive decrease observed in the expression of 3-oxo-Delta(4)-steroid 5beta-reductase, together with the maintenance of steroid 5alpha-reductase type I. A significant correlation between the 5alpha-reductase/5beta-reductase ratio and bile output of 'flat-BAs' was found. In conclusion, during rat hepatocarcinogenesis, the expression of transporters/enzymes responsible for BA homoeostasis is changed due to mechanisms other than those controlled by FXR/SHP/FTF. These modifications result in the re-appearance of 'flat-BAs', together with an increased CA/CDCA ratio in bile.