Dokument: Zellvolumen-abhängige Regulation des hepatischen Methyl- und Cholinstoffwechsels
| Titel: | Zellvolumen-abhängige Regulation des hepatischen Methyl- und Cholinstoffwechsels | |||||||
| Weiterer Titel: | Cell volume dependent regulation of hepatic methyl- and choline metabolism | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=9811 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20090122-095742-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Hoffmann, Lars [Autor] | |||||||
| Dateien: |
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| Beitragende: | Schwahn, Bernd Christian [Gutachter] Prof. Dr. Willbold, Dieter [Gutachter] | |||||||
| Stichwörter: | Osmoregulation, Organische Osmolyte, Cholinstoffwechsel | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibungen: | Durch die Identifizierung der BHMT als osmotisch reguliertes Enzym wurde klar, dass nicht nur Transportvorgänge, sondern auch metabolische Vorgänge durch tonizitätsvermittelte Volumenänderungen der Zelle beeinflusst werden. Die enge Verknüpfung der wichtigsten hepatischen organischen Osmolyte mit dem Cholin- und Methylstoffwechsel in der Leber ließ vermuten, dass die Umgebungsosmolarität weitreichenden Einfluss auf den Stoffwechsel und die übrigen Funktionen der Leber hat. Durch die Expressionsanalysen konnte die tonizitätsinduzierte Regulation der BHMT bestätigt und gleichzeitig eine solche Regulation der Enzyme DMGDH und SARDH neu identifiziert werden. Die Ergebnisse zeigten eine fein abgestufte Sensitivität gegenüber osmotischen Veränderungen der DMGDH und für alle drei Enzyme eine zeitabhängige Veränderung ihrer mRNA Expression, die sich auch in der Proteinexpression wiederfand. Durch den Einsatz alternativer Osmolyte wurde gezeigt, dass die Stoffwechselenzyme BHMT, DMGDH und SARDH durch die Zellvolumenänderung reguliert werden und nicht durch die Ionenstärke oder die Osmolaritätsänderung per se, was auf eine Signalübertragung durch Integrine hinweist. Die Enzyme CHK und PEMT zeigten nur kurzfristige Änderungen in ihrer mRNA Expression in Abhängigkeit von Osmolaritätsänderungen während die Enzyme MS, MTHFR, CBS und PCYT1A keine oder nur geringfügige Änderungen zeigten. Mit Hilfe von Inhibitoren ließen sich Hinweise auf die beteiligten Signaltransduktionswege für die Regulation der BHMT und DMGDH finden. Durch die Quantifizierung relevanter Stoffwechselmetabolite wurde versucht die komplexen Zusammenhänge zwischen Genregulation und physiologischem Effekt aufzuzeigen, was nur teilweise gelang. Es traten Diskrepanzen zwischen dem Zellkulturmodell und dem Tiermodell auf, was darauf schließen lässt, dass sowohl die physiologischen als auch die genregulatorischen Auswirkungen in vivo von weiteren Faktoren beeinflusst werden. Durch die koordinierte Regulation des Cholin und Methylstoffwechsels durch anisoosmolare Reize ist davon auszugehen, dass organische Osmolyte auch in den Parenchymzellen der Leber eine Rolle bei der Aufrechterhaltung des Zellvolumens spielen und dass Zellvolumenänderungen durchaus funktionelle Bedeutung für die gesamte Methylierung haben. Daraus folgt, dass eine gestörte Bereitstellung von Betain und anderer organischer Osmolyte zu chronischen Schädigungen der Leber beitragen kann, wie sie in angeborenen Störungen der Methylierung gefunden werden.By identifiing BHMT as an osmotic regulated enzyme, it becomes evident, that not only transport events, but also metabolic events can be regulated by changing the surrounding osmolarity. The close connection between the most crucial hepatic Osmolytes and the Choline and Methyl metabolism pointed to Osmolarity as a major Regulator to all functions of the liver.
Expression analysis confirmed BHMT as an osmoregulated gene and further more DMGDH and SARDH were newly established as regulated by osmolarity. The expression profile of DMGDH showed a sensitive response to osmotic changes and for all 3 enzymes a time dependent expression change could be established, which was validated on the protein level. The use of alternative osmolytes such as Manitol it was shown that the trigger of the regulatory changes are not the ions themselves, but the change in cell volume, pointing to a signal transduction starting at the integrines in the cell membrane. In this work, other genes like CHK and PEMT only showed short time expression changes due to osmotic alterations, while genes like MS, MTHFR,CBS and PCYT1a showed no clear reaction to a change in the osmotic enviroment. The use of inhibitors made it possible to draw first conclusions about the signal transduction pathways involved in osmotic regulation. By quantifying relevant metabolic substrates and products it was attempted to corellate the regulatory changes in gene expression to physiological effects, which was only partly successful. There were dicrepancies between the cell culture model and the animal model of MTHFR deficiency, that leads to the conclusion, that physiological and generegulatory changes in vivo depend on more factors besides osmolarity. It was clearly shown that choline metabolism can be regulated coordinately by osmotic changes, which points to the fact that organic osmolytes do play a significant role in maintaining celllular integrity and cell volume. Cell volume changes seem to have a functional importance for methylation as well. This leads to the point that disturbed availability of betaine and other organic osmolytes may have a negative effect on the liver and possibly leads to chronic liver diseases, like it is found in inherited methylation defects (MTHFR deficiency) | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie | |||||||
| Dokument erstellt am: | 22.01.2009 | |||||||
| Dateien geändert am: | 12.01.2009 | |||||||
| Promotionsantrag am: | 10.09.2008 | |||||||
| Datum der Promotion: | 10.11.2008 |
