Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Berger, N.
The impact of metabolic serine hydrolases on lipid homeostasis and signaling in the human term placenta
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 91
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Schicho Rudolf
- Wadsack Christian
- Altmetrics:
- Abstract:
- The human placenta represents a metabolic and endocrine active organ, which serves as interface between the maternal and foetal compartments. The growing foetus directly depends on proper placental function and detrimental development can affect the interaction between the mother and the foetus. The metabolic state of women before and during pregnancy determines the intrauterine environment and metabolic derangements promote adverse effects which eventually lead to pregnancy pathologies. Placental lipid metabolism implies highly dynamic and tightly regulated processes, which need to adapt to the specific demands throughout the entire period of gestation. This is accomplished by the action of lipid metabolizing enzymes, which regulate different pools of lipids and ensure an on- demand supply of certain bioactive lipid molecules. Bioactive lipids, which encompass different lipid species like endocannabinoids, sphingolipids or membrane phospholipids, are involved in cell signaling processes and hence represent potent modulators of a vast variety of (patho) physiological mechanisms. Herein, we focused on enzymes which are characterised by the presence of an active site serine and their role in the regulation of placental lipid homeostasis. In the first part of this thesis, we characterized the endocannabinoid-synthesizing enzymes diacylglycerol lipase α/β (DAGLα/β). This is the first report on the function of these enzymes in the human placenta at term. We elaborated that DAGLβ transcripts were substantially elevated compared to DAGLα in placental tissues and clearly located DAGLβ to trophoblasts. The predominance of DAGLβ was further corroborated by activity-based protein profiling (ABPP). By the utilization of the ex vivo placental perfusion system and pharmacological approaches, we demonstrated that DAGLβ is significantly involved in the formation of the bioactive lipid 2-arachidonoylgylcerol. We further observed changes in diacylglycerol levels upon inhibition of the enzyme, indicating a function in triacylglycerol metabolism. These results suggest that DAGLβ plays a key role in regulating lipid homeostasis and bioactive lipid signaling in the human placenta. In the second part of this thesis, ABPP was applied to generate a profile of enzyme activities comparing healthy control tissues to preeclamptic placentas (PE). PE represents a multifactorial pregnancy disorder which has been linked to dyslipidemia and concomitant alterations in enzyme expression. We could show that the activity of enzymes involved in phospholipid (PNPLA6) and sphingolipid (SPTLC3) metabolism are significantly elevated in PE placentas which was linked to substantial changes in phospholipid and sphingolipid levels. These data emphasize that metabolic disturbances are an important feature of PE, which may affect the regulation of placental tissue homeostasis and function. Overall, this thesis highlights the pivotal role of bioactive lipid metabolism of the human placenta in pregnancy physiology and pathophysiology. Our data strongly suggest that associated enzyme activities are significant determinants in the regulation of placental lipid homeostasis