Dokument: Crosstalk between neutral lipid and sphingolipid metabolism regulates cellular lipid homeostasis

Titel:	Crosstalk between neutral lipid and sphingolipid metabolism regulates cellular lipid homeostasis
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=63582
URN (NBN):	urn:nbn:de:hbz:061-20230911-094242-9
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Hertel, Manuel [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 5,69 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 04.09.2023 / geändert 04.09.2023
Beitragende:	Jun.-Prof. Dr. Beller, Mathias [Gutachter] Prof. Dr. Roden, Michael [Gutachter]
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	Obesity represents a major risk factor for type 2 diabetes and is characterized by excessive accumulation of triacylglycerols in ectopic tissues, like muscle and liver. At cellular level, triacylglycerols are stored in lipid droplets, which participate in an embracing dynamic network of functionally coupled organelles. Lipid droplet-endoplasmic reticulum interaction plays an important role in balancing cellular lipid homeostasis, preventing aggregations of lipotoxic and diabetes-relevant lipids such as diacylglycerol and sphingolipids. However, the dynamic interplay between lipid droplet consumption and sphingolipid synthesis and how the pathways regulate each other remains unknown. This work investigates whether proteins required for sphingolipid synthesis regulate lipid droplet consumption, and thus efficient interception of lipotoxic, diabetes-relevant metabolites. It is shown that Tsc3p, a stimulator of the serine palmitoyltransferase and thus of sphingolipid biosynthesis in the endoplasmic reticulum, is an essential regulator of lipid droplet consumption and ultimately of lipid droplet dynamics in yeast. Lipid droplet consumption and growth is impaired in tsc3 deletion cells as well as in cells with deletion of proteins of the sphingolipid biosynthesis downstream of the serine palmitoyltransferase. The rescue effect of phytosphingosine on lipid droplet consumption and growth in these cells suggests that the downregulated lipolysis and attenuated growth are due to low level of sphingolipids. One conceivable mechanism regulating both triacylglycerol breakdown and growth is the sphingolipid-regulated PP2A-Swe1-Cdc28 signaling pathway, although the exact sphingolipid species involved in this regulation remains uncertain. Moreover, a continuous re-esterification of lipolysis-derived fatty acids into triacylglycerol could have a concomitant influence on deficient lipid droplet consumption. In addition, this thesis shows that the human analog of Tsc3p, at least ssSPTb, is able to reconstitute the growth and rescue lipid droplet consumption defect in tsc3Δ cells, suggesting an essential role for ssSPTb in the regulation of lipid droplet dynamics in human cells. However, silencing of ssSPTb in human hepatocytes does not alter the concentration of any diacylglycerol, ceramide and sphingolipid species as well as the activity of the PKCɛ and the phosphorylation of the insulin receptor kinase. This suggests that the second stimulator of the serine palmitoyltransferase, ssSPTa, compensates for the absent activity of ssSPTb. A more profound and advanced knowledge of the interplay between sphingolipid metabolism and lipid droplet dynamics in mammalian cells could be beneficial for clinical detection of diabetes subtypes and the care of people suffering from it.
Lizenz:	Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz
Fachbereich / Einrichtung:	Sonstige Einrichtungen/Externe » An-Institute » Deutsches Diabetes-Zentrum Mathematisch- Naturwissenschaftliche Fakultät
Dokument erstellt am:	11.09.2023
Dateien geändert am:	11.09.2023
Promotionsantrag am:	23.03.2023
Datum der Promotion:	28.08.2023