2026-09-15T16:56:40Zhttps://gredos.usal.es/oai/request

oai:gredos.usal.es:10366/1691392026-01-22T01:01:44Zcom_10366_3992com_10366_3947com_10366_3946com_10366_3823col_10366_3993

Sanchón Sánchez, Paula Herráez Aguilar, Elisa Macias, Rocio I R Estiu, Maria C Fortes, Puri Monte Río, María Jesús García Marín, José Juan Rodríguez Romero, Marta 2026-01-21T12:54:32Z 2026-01-21T12:54:32Z 2024-02 Sanchon-Sanchez, P., Herraez, E., Macias, R. I. R., Estiu, M. C., Fortes, P., Monte, M. J., Marin, J. J. G., & Romero, M. R. (2024). Relationship between cholestasis and altered progesterone metabolism in the placenta-maternal liver tandem. Biochimica et biophysica acta. Molecular basis of disease, 1870(2), 166926. https://doi.org/10.1016/j.bbadis.2023.166926 1879-260X | 0925-4439 http://hdl.handle.net/10366/169139 10.1016/j.bbadis.2023.166926 37956602 1879-260X [EN]In intrahepatic cholestasis of pregnancy (ICP), there are elevated maternal serum levels of total bile acids, progesterone, and some sulfated metabolites, such as allopregnanolone sulfate, which inhibits canalicular function. To investigate the relationship between cholestasis and the expression of crucial enzymes involved in progesterone metabolism in the liver and placenta. Obstructive cholestasis was induced by bile duct ligation (BDL). RT-qPCR (mRNA) and western blot (protein) were used to determine expression levels. Srd5a1 and Akr1c2 enzymatic activities were assayed by substrate disappearance (progesterone and 5α-dihydroprogesterone, respectively), measured by HPLC-MS/MS. BDL induced decreased Srd5a1 and Akr1c2 expression and activity in rat liver, whereas both enzymes were up-regulated in rat placenta. Regarding sulfotransferases, Sult2b1 was also moderately up-regulated in the liver. In placenta from ICP patients, SRD5A1 and AKR1C2 expression was elevated, whereas both genes were down-regulated in liver biopsies collected from patients with several liver diseases accompanied by cholestasis. SRD5A1 and AKR1C2 expression was not affected by incubating human hepatoma HepG2 cells with FXR agonists (chenodeoxycholic acid and GW4064). Knocking-out Fxr in mice did not reduce Srd5a1 and Akr1c14 expression, which was similarly down-regulated by BDL. SRD5A1 and AKR1C2 expression was markedly altered by cholestasis. This was enhanced in the placenta but decreased in the liver, which is not mediated by FXR. These results suggest that the excess of progesterone metabolites in the serum of ICP patients can involve both enhanced placental production and decreased hepatic clearance. The latter may also occur in other cholestatic conditions. CIBERehd; Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain; “Junta de Castilla y Leon”; Fundació Marato TV3; University of Salamanca; AECC Scientific Foundation and FEEH, Juan Cordoba Fellowship, Grant 2021. application/pdf eng ELSEVIER Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Bile acids Gestation Hydroxysteroid dehydrogenases Liver Placenta Pregnancy Liver Pregnancy Complications Placenta Tandem Mass Spectrometry Rats Cholestasis Animals Humans Progesterone Mice 3209 Farmacología espectrometría de masas en tándem embarazo humanos animales placenta progesterona ratones ratas colestasis hígado complicaciones del embarazo Relationship between cholestasis and altered progesterone metabolism in the placenta-maternal liver tandem info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion https://doi.org/10.1016/j.bbadis.2023.166926 EHD15PI05/201 PI19/00819 PI20/00189 PI22/00526 Biochimica et biophysica acta. Molecular basis of disease 1870 2 166926