Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3α-sulfated progesterone metabolites have been shown to be elevated in ICP, leading us to study the impact of sulfated progesterone metabolites on farnesoid X receptor (FXR)-mediated bile acid homeostasis pathways. Here we report that the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients. Mice challenged with cholic acid developed hypercholanemia and a hepatic gene expression profile indicative of FXR activation. However, coadministration of epiallopregnanolone sulfate with cholic acid exacerbated the hypercholanemia and resulted in aberrant gene expression profiles for hepatic bile acid-responsive genes consistent with cholestasis. We demonstrate that levels of epiallopregnanolone sulfate found in ICP can function as a partial agonist for FXR, resulting in the aberrant expression of bile acid homeostasis genes in hepatoma cell lines and primary human hepatocytes. Furthermore, epiallopregnanolone sulfate inhibition of FXR results in reduced FXR-mediated bile acid efflux and secreted FGF19. Using cofactor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of cofactor motifs to the FXR-ligand binding domain. Conclusion: Our results reveal a novel molecular interaction between ICP-associated levels of the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis. (Hepatology 2013;)
Highlights
Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death
We investigated whether epiallopregnanolone sulfate (PM5S) exhibits any partial agonist activity by analyzing bile salt export pump (BSEP) and short heterodimer partner (SHP) expression in primary human hepatocytes treated with PM5S or chenodeoxycholic acid (CDCA)
Our results conclusively show that ICP is associated with supraphysiological levels of the 3b-sulfated progesterone metabolite epiallopregnanolone sulfate (PM5S) and demonstrate potential mechanisms to explain gestational hypercholanemia and cholestasis
Summary
Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. Intrahepatic cholestasis of pregnancy (ICP) is the commonest pregnancy-specific liver disease It typically affects 0.5%-1.5% of pregnant women in Europe and is 2-3 times more prevalent in women of Chilean and Asian origin.[1] ICP presents in the second or third trimester of pregnancy with maternal pruritus, raised liver transaminases, and serum bile acids.[1] It may be complicated by fetal hypoxia, spontaneous preterm labor, and intrauterine death.[2,3] Genetic variation has been reported in bile acid homeostasis-related genes, including the hepatic bile acid receptor, farnesoid X receptor (FXR; NR1H4)[4] and its target genes, the bile salt export pump (BSEP; ABCB11),[5,6] MDR3 (ABCB4),[7,8,9,10] and MRP2 (ABCC2).[11] women with ICP are usually asymptomatic when they are not pregnant and the disease phenotype is unmasked by pregnancy in the majority of cases. It has been demonstrated that sulfated progesterone metabolites directly impair biliary transport of bile acids, it has not been established whether they influence hepatic pathways of bile acid homeostasis
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