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Biochim Biophys Acta. 2018 Sep;1863(9):968-979. doi: 10.1016/j.bbalip.2018.05.005. Epub 2018 May 18.

Gestational diabetes mellitus modulates cholesterol homeostasis in human fetoplacental endothelium.

Author information

  • 1Immunology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Austria.
  • 2Department of Obstetrics and Gynecology, Medical University of Graz, Austria.
  • 3Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
  • 4Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia; University of Melbourne, Department of Pediatrics, Melbourne, Australia.
  • 5Division of Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Sweden.
  • 6Department of Obstetrics and Gynecology, Medical University of Graz, Austria; BioTechMed-Graz, Graz, Austria. Electronic address: christian.wadsack@medunigraz.at.
  • 7Immunology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Austria. Electronic address: ute.panzenboeck@medunigraz.at.

Abstract

Gestational diabetes mellitus (GDM) is associated with excessive oxidative stress which may affect placental vascular function. Cholesterol homeostasis is crucial for maintaining fetoplacental endothelial function. We aimed to investigate whether and how GDM affects cholesterol metabolism in human fetoplacental endothelial cells (HPEC). HPEC were isolated from fetal term placental arterial vessels of GDM or control subjects. Cellular reactive oxygen species (ROS) were detected by H2DCFDA fluorescent dye. Oxysterols were quantified by gas chromatography-mass spectrometry analysis. Genes and proteins involved in cholesterol homeostasis were detected by real-time PCR and immunoblotting, respectively. Cholesterol efflux was determined from [3H]-cholesterol labeled HPEC and [14C]-acetate was used as cholesterol precursor to measure cholesterol biosynthesis and esterification. We detected enhanced formation of ROS and of specific, ROS-derived oxysterols in HPEC isolated from GDM versus control pregnancies. ROS-generated oxysterols were simultaneously elevated in cord blood of GDM neonates. Liver-X receptor activation in control HPEC by synthetic agonist TO901319, 7-ketocholesterol, or 7β-hydroxycholesterol upregulated ATP-binding cassette transporters (ABC)A1 and ABCG1 expression, accompanied by increased cellular cholesterol efflux. Upregulation of ABCA1 and ABCG1 and increased cholesterol release to apoA-I and HDL3 (78 ± 17%, 40 ± 9%, respectively) were also observed in GDM versus control HPEC. The LXR antagonist GGPP reversed ABCA1 and ABCG1 upregulation and reduced the increased cholesterol efflux in GDM HPEC. Similar total cellular cholesterol levels were detected in control and GDM HPEC, while GDM enhanced cholesterol biosynthesis along with upregulated 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and sterol O-acyltransferase 1 (SOAT1) mRNA and protein levels. Our results suggest that in GDM cellular cholesterol homeostasis in the fetoplacental endothelium is modulated via LXR activation and helps to maintain its proper functionality.

KEYWORDS:

Cholesterol metabolism; GDM; Human fetoplacental endothelial cells; Oxidative stress; Oxysterols

PMID:
29778664
DOI:
10.1016/j.bbalip.2018.05.005
[PubMed - in process]
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