Metabolism of cholesterol and progesterone is differentially regulated in primary trophoblastic subtypes and might be disturbed in recurrent miscarriages

Sigrid Vondra, Victoria Kunihs, Tanja Eberhart, Karin Eigner, Raimund Bauer, Peter Haslinger, Sandra Haier, Karin Windsperger, Günter Klambauer, Birgit Schütz, Mario Mikula, Xiaowei Zhu, Alexander Urban, Roberta Hannibal, Julie Baker, Martin Knöfler, Herbert Stangl, Jürgen Pollheimer, Clemens Röhrl

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1922-1934
Number of pages13
JournalJournal of Lipid Research
Volume60
Issue number11
DOIs
Publication statusPublished - Sep 2019

Keywords

  • Abortion, Habitual/metabolism
  • Cholesterol/metabolism
  • Computational Biology
  • Female
  • Homeostasis
  • Humans
  • Pregnancy
  • Progesterone/metabolism
  • Sequence Analysis, RNA
  • Trophoblasts/metabolism

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