Modification of dietary substrates impacts glucose homeostasis in very long-chain Acyl-CoA dehydrogenase deficient (VLCAD-/-) mice

Abstract: The body has strict regulations, called glucose homeostasis, to maintain blood glucose levels. The defect in particular enzymes, including very long-chain acyl CoA dehydrogenase (VLCAD), can lead to disruptions in glucose homeostasis. VLCAD deficiency (VLCADD; OMIM: 201475) is a mitochondrial long-chain fatty acid oxidation disorder. VLCADD is included in newborn screening (NBS) programs worldwide, resulting in a significant increase in the number of patients identified since then. This allows immediate treatment for VLCADD, which is primarily a dietary-based treatment plan. Common dietary treatment strategies include restricting long-chain fat and supplementing medium-chain fatty acids. As a result of early diagnosis and treatment many identified patients do not have severe disease. Currently, a new type of medium-chain fatty acids, triheptanoin, has been included in dietary regimens in VLCADD.6 Triheptanoin is a triglyceride composed of three odd-chain fatty acids (C7; heptanoate) and glycerol. Some individuals identified by screening remain asymptomatic without preventive measures7 suggesting that also individual compensatory mechanisms do play a role and may explain the heterogeneous clinical presentations. An important treatment goal is to keep glucose homeostasis stable. To maintain glucose homeostasis, the liver regulates glucose production, glucose consumption, and stores glycogen. Therefore, the main questions in this thesis are: how glucose homeostasis is affected in VLCADD and how modification of dietary substrates acts on glucose metabolism and homeostasis?
Two independent animal studies were performed in this thesis using very long-chain acyl-CoA deficient (VLCAD-/-) mice as the disease model. Study I examined the effect of long-term (1 year) dietary treatment on glucose homeostasis. Both WT and VLCAD-/- mice were randomly assigned to three dietary groups: normal-chow diet (control), high protein diet (protein), and triheptanoin diet. In Study II, the effects of the two gluconeogenic substrates of triheptanoin (glycerol and heptanoate) on glucose homeostasis was investigated separately.
As important results, liver glycogen content was significantly reduced in VLCAD-/- mice as compared to WT after one year of the control diet, representing the clinical phenotype of the disease without intervention. Despite low glycogen, blood glucose remained normal suggesting effective compensatory mechanisms. In VLCAD-/- mice fed the triheptanoin diet, liver glycogen content was normal compared to WT, suggesting a significant treatment effect. However, blood glucose concentration was increased. These results were consistent with changes in glycogen metabolism gene and protein expression. While the control diet significantly downregulated protein expression of both, glycogen synthesis and glycogen degradation in VLCAD-/- mice, the triheptanoin diet significantly increased their expression. Whereas the triheptanoin diet significantly affected glycogen metabolism in the liver of VLCAD-/- mice, the effects of a high protein diet were minor. With respect to study II using the isotope tracer, the incorporation of 13C3-glycerol into blood glucose was higher in VLCAD-/- mice than in WT mice. The difference in label accumulation disappears with heptanoate (C7) treatment, suggesting that C7 acts as an alternative gluconeogenic precursor. The computational model showed that both, the rate constant of utilization (ku) and the clearance (k2) were not affected by genotype.
VLCAD-/- mice show a significantly increased glycogen breakdown already under normal living conditions. Liver glycogen, therefore, plays a central role in maintaining glucose homeostasis in VLCAD-/- mice. Among dietary modifications used in this thesis, the triheptanoin diet has a high gluconeogenic potential. A very important finding was that triheptanoin not only compensates for low glycogen levels by increased glycogen synthesis but by increased glycogen cycling, which means increased synthesis and increased breakdown at the same time. Although sufficient glycogen storage is essential in VLCAD-/- mice, overaccumulation of glycogen may lead to steatohepatitis. Therefore, triheptanoin supplementation has to be applied in adjusted and controlled doses long-term

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2023

Classification and Topics

• Keyword: Ernährung

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2023
• Creator: Nurjanah, Siti
• Contributor: Köhn, Maja ; Spiekerkötter, Ute ; Groß, Olaf ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie ; Klinik für Allgemeine Kinder- und Jugendmedizin

Further information

• DOI: 10.6094/UNIFR/236640
• URN: urn:nbn:de:bsz:25-freidok-2366402
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:26 AM CEST