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  2. Evidence for hypoxia-induced dysregulated cholesterol homeostasis in preeclampsia: Insights into the mechanisms from human placental cells and tissues

Evidence for hypoxia-induced dysregulated cholesterol homeostasis in preeclampsia: Insights into the mechanisms from human placental cells and tissues

  • FASEB J. 2024 Feb;38(2):e23431. doi: 10.1096/fj.202301708RR.
Barbara Fuenzalida 1 Maria Jose Yañez 2 Martin Mueller 3 4 Hiten D Mistry 5 Andrea Leiva 2 Christiane Albrecht 1 6
Affiliations

Affiliations

  • 1 Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, Bern, Switzerland.
  • 2 School of Medical Technology, Faculty of Medicine and Science, Universidad San Sebastián, Santiago, Chile.
  • 3 Division of Gynecology and Obstetrics, Lindenhofgruppe, Bern, Switzerland.
  • 4 Department for BioMedical Research, University of Bern, Bern, Switzerland.
  • 5 Department of Women and Children's Health, School of Life Course and Population Health Sciences, King's College London, London, UK.
  • 6 Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Abstract

Preeclampsia (PE) poses a considerable risk to the long-term cardiovascular health of both mothers and their offspring due to a hypoxic environment in the placenta leading to reduced fetal oxygen supply. Cholesterol is vital for fetal development by influencing placental function. Recent findings suggest an association between hypoxia, disturbed Cholesterol homeostasis, and PE. This study investigates the influence of hypoxia on placental Cholesterol homeostasis. Using primary human trophoblast cells and placentae from women with PE, various aspects of Cholesterol homeostasis were examined under hypoxic and hypoxia/reoxygenation (H/R) conditions. Under hypoxia and H/R, intracellular total and non-esterified Cholesterol levels were significantly increased. This coincided with an upregulation of HMG-CoA-reductase and HMG-CoA-synthase (key genes regulating Cholesterol biosynthesis), and a decrease in acetyl-CoA-acetyltransferase-1 (ACAT1), which mediates Cholesterol esterification. Hypoxia and H/R also increased the intracellular levels of Reactive Oxygen Species and elevated the expression of hypoxia-inducible factor (HIF)-2α and sterol-regulatory-element-binding-protein (SREBP) transcription factors. Additionally, exposure of trophoblasts to hypoxia and H/R resulted in enhanced Cholesterol efflux to maternal and fetal serum. This was accompanied by an increased expression of proteins involved in Cholesterol transport such as the scavenger receptor class B type I (SR-BI) and the ATP-binding cassette transporter G1 (ABCG1). Despite these metabolic alterations, mitogen-activated-protein-kinase (MAPK) signaling, a key regulator of Cholesterol homeostasis, was largely unaffected. Our findings indicate dysregulation of Cholesterol homeostasis at multiple metabolic points in both the trophoblast hypoxia model and placentae from women with PE. The increased Cholesterol efflux and intracellular accumulation of non-esterified Cholesterol may have critical implications for both the mother and the fetus during pregnancy, potentially contributing to an elevated cardiovascular risk later in life.

Keywords

cholesterol; hypoxia; placenta; preeclampsia; reactive oxygen species; trophoblast.

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