Gestational diabetes mellitus (GDM) may affect placental cholesterol metabolism via liver-X receptor (LXR) activation due to increased oxysterol levels in cells and in the fetal circulation (UP, CW, GD, unpublished; 1, 2). LXRs promote formation of high-density lipoproteins (HDL) which exert anti-inflammatory actions on endothelial cells and LXRs modulate immune regulatory functions and can reduce inflammation (3). 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. The student will investigate effects of placental inflammatory environment as well as of LXR activation by oxysterols or synthetic agonist TO901317 on (reduced) expression of inflammatory genes along with altered cellular cholesterol metabolism (4) in term fetoplacental endothelial cells. Techniques applied will include RTQ-PCR, immunoblotting, ELISA, IHC and functional assays for ABC transporters A1 and G1, well established in our laboratory. 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.
1. Stefulj J, Panzenboeck U1, Becker T, Hirschmugl B, Schweinzer C, Lang I, Marsche G, Sadjak A, Lang U, Desoye G, 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. doi: 10.1161/CIRCRESAHA.108.185066
2. 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. doi: 10.1210/jc.2011-1942
3. 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. doi: 10.1016/j.molmed.2016.05.006
4. 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. doi: 10.3233/JAD-2011-110854.