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SHR Neuro Cancer Cardio Metab Microb Lipid

Inflammatory Disorders in Pregnancy. Nuclear receptors regulating metabolism and inflammatory mediators in fetoplacental endothelial cells

Subproject of: Coordination of the Doctoral Program: Inflammatory Disorders in Pregnancy

Abstract: Rising evidence suggests that Gestational diabetes mellitus (GDM) modulates the placental endothelium to an altered metabolic state causing vascular dysfunction and altered fetal programming. GDM is associated with oxidative stress which may contribute to endothelial dysfunction. Oxysterols, generated from cholesterol oxidation either by CYP-450 reductase or by reactive oxygen species (ROS), are endogenous activators of liver-X receptors (LXRs), nuclear transcription factors centrally involved in important biological processes, including lipid/cholesterol and glucose metabolism (1).
LXRs promote high-density lipoprotein (HDL) formation by activating several target genes of reverse cholesterol transport. We earlier reported that LXR target genes (ABCA1, ABCG1 and PLTP) are centrally involved in HDL mediated cholesterol efflux from fetoplacental endothelial cells (HPEC) (2-4).
A current focus of our laboratory is to define the impact of oxysterols and pharmacological activators of LXRs on cholesterol-metabolic and inflammatory functions in the GDM feto-placental vasculature. Unpublished results of our group strongly suggest that the GDM environment modulates cholesterol homeostasis by enhancing cholesterol biosynthesis and cholesterol efflux in fetoplacental endothelial cells while cellular cholesterol homeostasis is largely maintained. Thus, GDM may affect placental cholesterol metabolism via LXR activation due to increased oxysterol levels in cells and/or in the fetal circulation.
While HDL itself exerts anti-inflammatory actions on endothelial cells, LXRs are also involved in immune regulatory functions and can reduce inflammation by sumoylation-dependent and -independent mechanisms (1). Upon activation, LXRs can be sumoylated and as a monomer can stabilize repressor complexes present on the promoter sequence of proinflammatory pathways such as activator protein 1 (AP-1) and nuclear factor kB (NF-kB), thereby preventing the expression of proinflammatory factors. In brain endothelial cells, LXR activation by oxysterols or synthetic agonist TO901317 significantly reduced expression of inflammatory genes COX-II and TNF along with modulating cellular cholesterol metabolism (5). We hypothesize that endogenous and/or pharmacologic activation of LXRs may improve fetoplacental endothelial function in conditions of GDM and other pregnancy complications related to metabolic diseases.

References:
1. Guillemot-Legris O, Mutemberezi V, Muccioli GG. Oxysterols in Metabolic Syndrome: From Bystander Molecules to Bioactive Lipids. Trends Mol Med. 2016; 22(7):594-614.
2. Stefulj J, Panzenboeck U1, Becker T, Hirschmugl B, Schweinzer C, Lang I, Marsche G, Sadjak A, Lang U, Desoye G, and Wadsack C. Human Endothelial Cells of the Placental Barrier Efficiently Deliver Cholesterol to the Fetal Circulation via ABCA1 and ABCG1. Circ Res. 2009; 104:600-608.
4. Scholler M, Wadsack C, Metso J, Chirackal Manavalan AP, Sreckovic I, Schweinzer C, Hiden U, Jauhiainen M, Desoye G, Panzenboeck U. Phospholipid transfer protein is differentially expressed in human arterial and venous placental endothelial cells and enhances cholesterol efflux to fetal HDL. J Clin Endocrinol Metab. 2012; 97:2466-74.
5. Scholler M, Wadsack C, Lang I, Etschmaier K, Schweinzer C, Marsche G, Dieber-Rotheneder M, Desoye G, Panzenboeck U. Phospholipid Transfer Protein in the Placental Endothelium Is Affected by Gestational Diabetes Mellitus. J Clin Endocrinol Metab. 2012; 97:437-45.
7. Schweinzer C, Kober A, Lang I, Etschmaier K, Scholler M, Kresse A, Sattler W, Panzenboeck U. Processing of Endogenous AβPP in Blood-Brain Barrier Endothelial Cells is Modulated by Liver-X Receptor Agonists and Altered Cellular Cholesterol Homeostasis. J Alzheimers Dis. 2011; 27(2):341-360.

Local Subprojectlead:: Wadsack Christian

Duration:: 01.10.2018-30.09.2022

Programme:: Doc.funds

Type of Research: basic research

Further information:

Staff: Wadsack, Christian, Project Leader; Stracke, Anika, Co-worker; George, Meekha, Co-worker

MUG Research Units: Department of Obstetrics and Gynaecology

Funded by: FWF, Fonds zur Förderung der Wissenschaftlichen Forschung, Wien, Austria