TY - JOUR
T1 - Metabolism of cholesterol and progesterone is differentially regulated in primary trophoblastic subtypes and might be disturbed in recurrent miscarriages
AU - Vondra, Sigrid
AU - Kunihs, V.
AU - Eberhart, T.
AU - Eigner, Karin
AU - Bauer, R.
AU - Haslinger, Peter
AU - Haider, S.
AU - Windsperger, K.
AU - Klambauer, Günter
AU - Schütz, Birgit
AU - Mikula, M.
AU - Zhu, X.
AU - Urban, Alexander E.
AU - Hannibal, Roberta L.
AU - Baker, Julie
AU - Knöfler, Martin
AU - Stangl, Herbert
AU - Pollheimer, Jürgen
AU - Röhrl, Clemens
N1 - Copyright © 2019 Vondra et al.
PY - 2019/11
Y1 - 2019/11
N2 - During pregnancy, extravillous trophoblasts (EVTs) invade the maternal decidua and remodel the local vasculature to establish blood supply for the growing fetus. Compromised EVT function has been linked to aberrant pregnancy associated with maternal and fetal morbidity and mortality. However, metabolic features of this invasive trophoblast subtype are largely unknown. Using primary human trophoblasts isolated from first trimester placental tissues, we show that cellular cholesterol homeostasis is differentially regulated in EVTs compared with villous cytotrophoblasts. Utilizing RNA-sequencing, gene set-enrichment analysis, and functional validation, we provide evidence that EVTs display increased levels of free and esterified cholesterol. Accordingly, EVTs are characterized by increased expression of the HDL-receptor, scavenger receptor class B type I, and reduced expression of the LXR and its target genes. We further reveal that EVTs express elevated levels of hydroxy-delta-5-steroid dehydrogenase 3 beta- and steroid delta-isomerase 1 (HSD3B1) (a rate-limiting enzyme in progesterone synthesis) and are capable of secreting progesterone. Increasing cholesterol export by LXR activation reduced progesterone secretion in an ABCA1-dependent manner. Importantly, HSD3B1 expression was decreased in EVTs of idiopathic recurrent spontaneous abortions, pointing toward compromised progesterone metabolism in EVTs of early miscarriages. Here, we provide insights into the regulation of cholesterol and progesterone metabolism in trophoblastic subtypes and its putative relevance in human miscarriage.
AB - During pregnancy, extravillous trophoblasts (EVTs) invade the maternal decidua and remodel the local vasculature to establish blood supply for the growing fetus. Compromised EVT function has been linked to aberrant pregnancy associated with maternal and fetal morbidity and mortality. However, metabolic features of this invasive trophoblast subtype are largely unknown. Using primary human trophoblasts isolated from first trimester placental tissues, we show that cellular cholesterol homeostasis is differentially regulated in EVTs compared with villous cytotrophoblasts. Utilizing RNA-sequencing, gene set-enrichment analysis, and functional validation, we provide evidence that EVTs display increased levels of free and esterified cholesterol. Accordingly, EVTs are characterized by increased expression of the HDL-receptor, scavenger receptor class B type I, and reduced expression of the LXR and its target genes. We further reveal that EVTs express elevated levels of hydroxy-delta-5-steroid dehydrogenase 3 beta- and steroid delta-isomerase 1 (HSD3B1) (a rate-limiting enzyme in progesterone synthesis) and are capable of secreting progesterone. Increasing cholesterol export by LXR activation reduced progesterone secretion in an ABCA1-dependent manner. Importantly, HSD3B1 expression was decreased in EVTs of idiopathic recurrent spontaneous abortions, pointing toward compromised progesterone metabolism in EVTs of early miscarriages. Here, we provide insights into the regulation of cholesterol and progesterone metabolism in trophoblastic subtypes and its putative relevance in human miscarriage.
KW - Abortion, Habitual/metabolism
KW - Cholesterol/metabolism
KW - Computational Biology
KW - Female
KW - Homeostasis
KW - Humans
KW - Pregnancy
KW - Progesterone/metabolism
KW - Sequence Analysis, RNA
KW - Trophoblasts/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85074445605&partnerID=8YFLogxK
U2 - 10.1194/jlr.P093427
DO - 10.1194/jlr.P093427
M3 - Article
C2 - 31530576
SN - 0022-2275
VL - 60
SP - 1922
EP - 1934
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 11
ER -