Endocrine Abstracts

Introduction: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder which is associated with higher incidence of gallstone disease. ICP symptoms are usually presented in the third trimester of gestation and their severity advances in parallel with the increase in serum sulphated progesterone metabolites (P4-S) in the mother. Liver X receptor α (LXRα) actively participates in the regulation of lipid metabolism functioning as a cholesterol sensor. We aimed to investigate if ICP levels of P4-S could modulate the LXRα transcriptome and thus contribute to gallstone formation by increasing biliary cholesterol sectretion.

Methods: The influence of ICP levels of P4-S on LXRα as well as its target genes was assessed in human hepatoma cells using RT-PCR and western blotting. LXRα reporter assays were employed to determine which domain of the nuclear receptor mediates the impact of the sulphated progesterone metabolites.

Results: Lucifease reporter assays demonstrated that the P4-S epiallopregnanolonesulphate (PM5S), epiallo-pregnanediol 3-sodium sulphate (EPAS) and epipregnanolonesulphate (EPS) were able to attenuate the basal as well as the agonist-induced transactivity of LXRα in a dose-dependent manner. Also, PM5S, EPAS and EPS were able to specifically modulate the activity of the LXRα ligand binding domain±the hinge region as shown using recombinant GAL4-LXRa vectors. Quantitative RT-PCT showed that PM5S, EPAS and EPS could decrease the mRNA levels of the LXRα target ABCG1in a dose-dependent manner while the gene expression of of LXRα itself is reduced by PM5S only. Protein analysis also showed that PM5S, EPAS and EPS diminish the levels of LXRα in the nucleus.

Conclusion: Murine studies have shown that the lack of ABCG1 causes increased biliary cholesterol secretion which is a key pathophysiological event in the development of gallstones. Supraphysiological levels of P4-S contribute to the formation of gallstones in ICP by dowregulating LXRα and its target ABCG1.

Declaration of funding: This work was supported by the Welcome Trust Grant (P30874, 2010).