PMID- 38265294
OWN - NLM
STAT- MEDLINE
DCOM- 20240125
LR  - 20240322
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Print)
IS  - 0892-6638 (Linking)
VI  - 38
IP  - 2
DP  - 2024 Feb
TI  - Evidence for hypoxia-induced dysregulated cholesterol homeostasis in 
      preeclampsia: Insights into the mechanisms from human placental cells and 
      tissues.
PG  - e23431
LID - 10.1096/fj.202301708RR [doi]
LID - e23431
AB  - 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)-2alpha 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.
CI  - (c) 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on 
      behalf of Federation of American Societies for Experimental Biology.
FAU - Fuenzalida, Barbara
AU  - Fuenzalida B
AUID- ORCID: 0000-0002-5128-570X
AD  - Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University 
      of Bern, Bern, Switzerland.
FAU - Yanez, Maria Jose
AU  - Yanez MJ
AUID- ORCID: 0000-0002-7990-2079
AD  - School of Medical Technology, Faculty of Medicine and Science, Universidad San 
      Sebastian, Santiago, Chile.
FAU - Mueller, Martin
AU  - Mueller M
AUID- ORCID: 0000-0001-5594-0532
AD  - Division of Gynecology and Obstetrics, Lindenhofgruppe, Bern, Switzerland.
AD  - Department for BioMedical Research, University of Bern, Bern, Switzerland.
FAU - Mistry, Hiten D
AU  - Mistry HD
AUID- ORCID: 0000-0003-2564-7348
AD  - Department of Women and Children's Health, School of Life Course and Population 
      Health Sciences, King's College London, London, UK.
FAU - Leiva, Andrea
AU  - Leiva A
AUID- ORCID: 0000-0001-7349-5380
AD  - School of Medical Technology, Faculty of Medicine and Science, Universidad San 
      Sebastian, Santiago, Chile.
FAU - Albrecht, Christiane
AU  - Albrecht C
AUID- ORCID: 0000-0002-7846-6930
AD  - Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University 
      of Bern, Bern, Switzerland.
AD  - Swiss National Center of Competence in Research, NCCR TransCure, University of 
      Bern, Bern, Switzerland.
LA  - eng
GR  - OC-2019-019/Swiss 3R Competence Centre/
GR  - 310030_197408/Swiss National Science Foundation (SNSF)/
GR  - FS/15/32/31604/British Heart Foundation (BHF)/
GR  - 1190250/Fondo Nacional de Desarrollo Cientifico y Tecnologico FONDECYT/
GR  - 11200592/Fondo Nacional de Desarrollo Cientifico y Tecnologico FONDECYT/
GR  - 1221362/Fondo Nacional de Desarrollo Cientifico y Tecnologico FONDECYT/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
SB  - IM
MH  - Pregnancy
MH  - Humans
MH  - Female
MH  - *Placenta
MH  - *Pre-Eclampsia
MH  - Biological Transport
MH  - Hypoxia
MH  - Homeostasis
PMC - PMC10953329
OTO - NOTNLM
OT  - cholesterol
OT  - hypoxia
OT  - placenta
OT  - preeclampsia
OT  - reactive oxygen species
OT  - trophoblast
EDAT- 2024/01/24 12:42
MHDA- 2024/01/25 06:44
PMCR- 2024/03/20
CRDT- 2024/01/24 10:03
PHST- 2023/12/21 00:00 [revised]
PHST- 2023/08/24 00:00 [received]
PHST- 2024/01/04 00:00 [accepted]
PHST- 2024/01/25 06:44 [medline]
PHST- 2024/01/24 12:42 [pubmed]
PHST- 2024/01/24 10:03 [entrez]
PHST- 2024/03/20 00:00 [pmc-release]
AID - FSB223431 [pii]
AID - 10.1096/fj.202301708RR [doi]
PST - ppublish
SO  - FASEB J. 2024 Feb;38(2):e23431. doi: 10.1096/fj.202301708RR.