Keywords:Fetoplacental endothelial barrier, cholesterol metabolism, oxysterols, liver-X receptors, cytokines, oxidative stress, high-density lipoproteins, gestational diabetes mellitus, metabolic syndrome
Research interest: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 reported earlier that LXR target genes (ABCA1, ABCG1 and PLTP) are centrally involved in HDL mediated cholesterol efflux from fetoplacental endothelial cells (HPEC) (2, 3, 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 Unpublished results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
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 κB (NF-κB), 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 TNFα along with modulating cellular cholesterol metabolism
(5). We hypothesize that endogenous
Collaborations within the DP-iDP:
Collaborating research groups where PhD students could perform their research stay abroad:
Know-how and infrastructure of the research group:Ute Panzenboeck has profound research experience in the field of lipid and lipoprotein metabolism with a focus on anti-atherogenic and anti-neurodegenerative activities of HDL. She has established her own ‘Lipid Research’ group at the Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Chair of Pathophysiology and Immunology at the Medical University of Graz in 2006 and has been employing 2 post-docs and 11 PhD students from funded research projects since then. The principal recent findings of the research group include characterization of mechanisms of HDL- and apolipoprotein-mediated cholesterol transport at specific endothelial barriers, (i) the fetoplacental and (ii) the blood–brain barrier and highlight the role of nuclear receptors (in particular LXRs) as lipid sensors and regulators of (chole)sterol transport and generation of HDL-like particles. Expertise in Ute Panzenboeck’s group includes isolation and culture of primary EC (and other cells), in vitro models of the BBB consisting of polarized brain capillary EC cultured on Transwell filters, co-culture models, methods for isolation and qualitative and quantitative (lipid and protein) analysis of lipoproteins, standard molecular biological methods, real-time PCR, cloning and transfection, standard and special immunological methods, radiobio-chemical methods, in situ hybridization histochemistry, and experience with animal studies. The local infrastructure comprises cell culture facilities, a fluorescence microscopy facility, a fluorescence-activated cell sorting facility, HPLC laboratory, molecular biology and immunology laboratory, histology and laboratory, radionuclide laboratory, and an animal facility.
Scientific concepts and techniques that students will learn in this laboratory:DP-iDP students students will gain specific knowledge on the important role of fetoplacental endothelial cells providing both a barrier as well as an exchange surface between the fetus and the maternal circulation. Specifically, they will learn about molecular and regulatory mechanisms of interaction of peripheral and placental lipid and lipoprotein metabolism under healthy conditions as well as during lipid-related metabolic (metabolic syndrome, gestational diabetes mellitus) and pregnancy disorders. By combining studies performed on in vitro models of the placental endothelial barrier with complementary clinical studies (in close collaboration with G. Desoye and C. Wadsack), DP-iDP students will contribute to establish the protective effects of HDL against lipid-related neurodegenerative diseases. The students will further acquire practical know-how in a broad array of laboratory techniques including biochemical, radiochemical, molecular biological and immunological techniques.