Methylation Status of Farnesoid X Receptor and Pregnane X Receptor Gene Promoters Modulates Bile Acid Profile in Patients with Intrahepatic Cholestasis of Pregnancy

CABRERIZO R; CASTANO GO; BURGUEÑO A,; FERNADEZ GIANNOTTI T; PIROLA CJ; SOOKOIAN S

BOSTON

Congreso; 63rd Annual Meeting American Association for the Study of Liver Diseases; 2012

AASLD

The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) involves the interplay among abnormal bile acids (BA) levels, sex hormones profiles, environmental factors and genetic susceptibility. ICP has usually a benign prognosis in the mothers; nevertheless, a high proportion of fetal complications were consistently described. Nuclear receptors, including Farnesoid X receptor (FXR, NR1H4) and Pregnane X receptor (PXR, NR1I2), are master regulators of BA homeostasis. It is known that ICP is characterized by an abnormal BA profile, but the mechanisms behind this finding are unknown. The dynamic nature of ICP that usually resolves soon after delivery strongly suggests the possibility that its pathobiology is under epigenetic modulation. In this study, we explored whether BA homeostasis is dysregulated in ICP patients due to an impairment of FXR and PXR caused by methylation of CpG-enriched sites at the gene promoter. Methods: 88 ICP patients and 173 healthy pregnant women in the third trimester of their pregnancies were included; BA profile was evaluated by capillary electrophoresis. Methylation status of candidate genes was assessed by quantitative HpaII PCR assay from genomic DNA extracted from peripheral blood cells; two putative methylation target CpG sites in the promoter of the FXR, located at positions relative to transcription starting site: −358 and −1890, and one for PXR (-1224) were explored. Correlations with clinicopathologic features in patients and controls were determined by Spearman rank test. Results: The status of FXR methylation at -1890 CpG site was significantly and positively correlated with serum levels of chenodeoxycholic (CDCA) R: 0.57, p=0.004, taurolithocholic (TLCA) R: 0.48, p=0.014, taurochenodeoxycholic (TCDCA) R: 0.53, p=0.01 and glycocholic acid (GCA) R: 0.45, p=0.02. The status of PXR methylation at -1224 CpG site was significantly and positively correlated with serum levels of TLCA R: 0.40, p=0.04, glycodeoxycholic (GDCA) R: 0.61, p=0.001, and TDCA R: 0.48, p=0.005. Interestingly, FXR methylation at -1890 CpG site was significantly and negatively correlated with anthropometrical variables of neonatal growth (cephalic perimeter R:- 0.24, p=0.02 and height R:-0.30, p=0.01). Conclusions: Dysregulated BA profile in ICP is strongly modulated by DNA methylation of FXR and PXR promoters. Epigenetic modifications are dynamic and reversible processes of considerable therapeutic implications.