Dokument: Dynamic computational modeling of fatty acid de novo synthesis in the liver and qualitative analysis of fatty acid metabolism

Titel:	Dynamic computational modeling of fatty acid de novo synthesis in the liver and qualitative analysis of fatty acid metabolism
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=65028
URN (NBN):	urn:nbn:de:hbz:061-20240222-144453-2
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Foko Kuate, Chilperic Armel [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 4,18 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 21.02.2024 / geändert 21.02.2024
Beitragender:	Univ.-Prof. Dr. Ebenhöh, Oliver [Gutachter]
Stichwörter:	Mathematical modeling, Biochemestry, Fatty acid metabolism
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	Mathematical modeling has nowadays become a cornerstone in the study of metabolic pathways. Mathematical models provide a framework for predicting and explaining observations made in experiments. In this work, mathematical modeling is used at two scales of detail to represent, on the one hand, the metabolism of fatty acids (FAs) in the liver and, on the other hand, the de novo synthesis of FAs in animals. Fatty acids are essential in metabolism as they play a crucial role in energy conversion and storage. Furthermore, they are involved in many other cellular functions, such as signaling and immune response, and are material for the cell wall. They are associated with metabolic syndromes, including mitochondrial fatty acid oxidation disorders (mFAODs). The recent investigation of some mFAODs suggests that the disorder impacts oxidation, synthesis, and pathways. However, the studies of mFAODs using dynamical mathematical modeling have been mainly focused on beta-oxidation. To explore mFAODS in a more global framework, one needs models of fatty acid metabolism that combine FA oxidation, synthesis, and degradation pathways. Additionally, I suspect FA metabolism must be a bistable system to satisfy both the safety and rapid response to energy constraints (switching from fed to fasted state and reciprocally). I start by reviewing the biochemistry of enzymes involved in FA synthesis and summarize the kinetic information of the corresponding enzymes. This step allows me to gather sufficient knowledge to develop the two models. The first model is a coarse-grained open model of fatty acid metabolism based on lumped enzyme kinetics and inhibitory mechanisms. The model includes four variables: acetyl-CoA, malonyl-CoA, fatty acids, and triglycerides, and eight reactions and eighteen parameters. I show that the model could exhibit bi-stability through a fatty acids pool. I also derive the conditions to be fulfilled by the parameterization of the system for it to be bi-stable. The second model is a semi-mechanistic model of the elongation part of FA de novo synthesis. I reduced its complex mechanism into four types of reactions modeled as elementary reactions associated with mass action kinetics. The model uses acetyl-CoA, malonyl-CoA, and NADPH to produce three FAs (myristic acid, palmitic acid, and stearic acid) and free CoA. The model is fitted to the time course data of three FAs. Under the resulting parametrization, each FA's production rate as a function of acetyl-CoA can be approximated by Michaelis-Menten rate equations as long as the malonyl-CoA in the system is at a low concentration. Under the latter consideration, the palmitic acid production rates as a function of malonyl-CoA or NADPH can also be approximated with Michaelis-Menten rate laws.
Lizenz:	Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät
Dokument erstellt am:	22.02.2024
Dateien geändert am:	22.02.2024
Promotionsantrag am:	11.01.2023
Datum der Promotion:	07.03.2023