Physiology and pathophysiology of steroid biosynthesis, transport and metabolism in the human placenta

*Figure (Figure 4 of the article)

Waranya Chatuphonprasert1,2, Kanokwan Jarukamjorn3, and Isabella Ellinger1*   1Pathophysiology of the Placenta, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University Vienna, Vienna, Austria 2 Faculty of Medicine, Mahasarakham University, Maha Sarakham, Thailand 3 Research Group for Pharmaceutical Activities of Natural Products using Pharmaceutical Biotechnology (PANPB), Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand

The steroid hormones progestagens, estrogens, androgens and glucocorticoids as well as their precursor cholesterol are required for successful establishment and maintenance of pregnancy and proper development of the fetus. The human placenta forms at the interface of maternal and fetal circulation. It participates in biosynthesis and metabolism of steroids as well as their regulated exchange between maternal and fetal compartment. This review outlines the mechanisms of human placental handling of steroid compounds. Cholesterol is transported from mother to offspring involving lipoprotein receptors such as low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SRB1) as well as ATP-binding cassette (ABC)-transporters, ABCA1 and ABCG1. Additionally, cholesterol is also a precursor for placental progesterone and estrogen synthesis. Hormone synthesis is predominantly performed by members of the cytochrome P-450 (CYP) enzyme family including CYP11A1 or CYP19A1 and hydroxysteroid dehydrogenases (HSD) such as 3β-HSD and 17β-HSD. Placental estrogen synthesis requires delivery of sulfate-conjugated precursor molecules from fetal and maternal serum. Placental uptake of these precursors is mediated by members of the solute carrier (SLC) family including sodium-dependent organic anion transporter (SOAT), organic anion transporter 4 (OAT4), and organic anion transporting polypeptide 2B1 (OATP2B1). Maternal-fetal glucocorticoid transport has to be tightly regulated in order to ensure healthy fetal growth and development. For that purpose, the placenta expresses the enzymes 11β-HSD 1 and 2 as well as the transporter ABCB1. This article also summarizes the impact of diverse compounds and diseases on the expression level and activity of the involved transporters, receptors, and metabolizing enzymes and concludes that the regulatory mechanisms changing the physiological to a pathophysiological state are barely explored. The structure and the cellular composition of the human placental barrier are introduced. While steroid production, metabolism and transport in the placental syncytiotrophoblast have been explored for decades, few information is available for the role of placental-fetal endothelial cells in these processes. With regard to placental structure and function, significant differences exist between species. To further decipher physiologic pathways and their pathologic alterations in placental steroid handling, proper model systems are mandatory.

Keywords: Cholesterol, Progestogens, Estrogens, Glucocorticoids, Gestational diabetes mellitus (GDM), Preeclampsia, Intrauterine growth retardation (IUGR), Oxysterols (cholesterol oxidation products)

Received: 11 Apr 2018; Accepted: 24 Aug 2018.

Edited by: Tea Lanisnik Rizner, Faculty of Medicine, University of Ljubljana, Slovenia

Access: https://www.frontiersin.org/articles/10.3389/fphar.2018.01027/full

*Figure  (Figure 4 of the article)

Proposed model for placental uptake of cholesterol from maternal lipoproteins, cholesterol metabolism and materno-fetal transport of cholesterol.

Solid arrows indicate pathways that have been demonstrated in vitro. Dashed arrows indicate hypothetic routes.

Abbreviations: Apolipoprotein (Apo), ATP-binding cassette transporters (ABC transporter), Cytochromes P-450 enzymes (CYPs), Cytotrophoblast (CTB), Placental-fetal endothelial cells (pFEC), High-density lipoprotein  (HDL), Heat shock protein (HSP), Low-density lipoprotein (LDL), Low-density lipoprotein receptor (LDLR), Lipoprotein receptor-related proteins (LRP), Liver X receptor (LXR), Protein disulfide isomerase (PDI), Microsomal triglyceride transfer protein (MTP), Retinoid X receptor (RXR), Scavenger receptor class B type 1 (SRB1), StAR-related lipid transfer domain protein3 (STARD3), Syncytiotrophoblast (STB), Very low-density lipoprotein (VLDL), Very low-density lipoprotein receptor (VLDLR).