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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\u2010esterified cholesterol levels were significantly increased. This coincided with an upregulation of HMG\u2010CoA\u2010reductase and HMG\u2010CoA\u2010synthase (key genes regulating cholesterol biosynthesis), and a decrease in acetyl\u2010CoA\u2010acetyltransferase\u20101 (ACAT1), which mediates cholesterol esterification. Hypoxia and H\/R also increased the intracellular levels of reactive oxygen species and elevated the expression of hypoxia\u2010inducible factor (HIF)\u20102\u03b1 and sterol\u2010regulatory\u2010element\u2010binding\u2010protein (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\u2010BI) and the ATP\u2010binding cassette transporter G1 (ABCG1). Despite these metabolic alterations, mitogen\u2010activated\u2010protein\u2010kinase (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\u2010esterified cholesterol may have critical implications for both the mother and the fetus during pregnancy, potentially contributing to an elevated cardiovascular risk later in life.<\/jats:p>","DOI":"10.1096\/fj.202301708rr","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T10:15:00Z","timestamp":1706091300000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Evidence for hypoxia\u2010induced dysregulated cholesterol homeostasis in preeclampsia: Insights into the mechanisms from human placental cells and tissues"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5128-570X","authenticated-orcid":false,"given":"Barbara","family":"Fuenzalida","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, Faculty of Medicine University of Bern  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