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other·preclinical research, endocrinology, pediatrics, biomedical research, research methods·PMC10649308

Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect

Nutrients · 8 authors, 6 centres

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Using a VLCAD-deficient mouse model, this preclinical study found that heptanoate acts as an alternative gluconeogenic substrate, reducing the contribution of glycerol to endogenous glucose production and potentially improving TCA cycle efficiency.

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Furthermore, the study demonstrated that heptanoate, a component of the drug triheptanoin, acts as an alternative gluconeogenic substrate, reducing the liver's reliance on glycerol for glucose production. Limitations include the use of a 6-hour fast which may not capture metabolic derangement during more severe stress, and the inability to distinguish between acetyl-CoA and propionyl-CoA contributions from heptanoate metabolism.

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other

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preclinical research

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ORIGINAL PAPER

PMC10649308

Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect

Nutrients

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ABSTRACT

Abstract Defects in mitochondrial fatty acid β-oxidation (FAO) impair metabolic flexibility, which is an essential process for energy homeostasis. Very-long-chain acyl-CoA dehydrogenase (VLCADD; OMIM 609575) deficiency is the most common long-chain mitochondrial FAO disorder presenting with hypoglycemia as a common clinical manifestation. To prevent hypoglycemia, triheptanoin—a triglyceride composed of three heptanoates (C7) esterified with a glycerol backbone—can be used as a dietary treatment, since it is metabolized into precursors for gluconeogenesis. However, studies investigating the effect of triheptanoin on glucose homeostasis are limited. To understand the role of gluconeogenesis in the pathophysiology of long-chain mitochondrial FAO defects, we injected VLCAD-deficient (VLCAD −/− ) mice with 13 C 3 -glycerol in the presence and absence of heptanoate (C7). The incorporation of 13 C 3 -glycerol into blood glucose was higher in VLCAD −/− mice than in WT mice, whereas the difference disappeared in the presence of C7. The result correlates with 13 C enrichment of liver metabolites in VLCAD −/− mice. In contrast, the C7 bolus significantly decreased the 13 C enrichment. These data suggest that the increased contribution of gluconeogenesis to the overall glucose production in VLCAD −/− mice increases the need for gluconeogenesis substrate, thereby avoiding hypoglycemia. Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect. Keywords: fatty acid oxidation disorder, glycerol, glucose homeostasis, heptanoate, stable isotope, very long-chain acyl-CoA dehydrogenase, VLCAD deficiency

CITATION EXPORT

Siti Nurjanah, Albert Gerding, Marcel A Vieira-Lara et al.. Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect. Nutrients. (2023). https://doi.org/10.3390/nu15214689

AUTHORS

8 · 6 CENTRES

Siti Nurjanah, Albert Gerding, Marcel A Vieira-Lara, Bernard Evers, Miriam Langelaar-Makkinje, Ute Spiekerkoetter, Barbara M Bakker, Sara Tucci

1Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Centre, Faculty of Medicine, University of Freiburg, 79106 Freiburg, [email protected] (U.S.)
2Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
3Laboratory of Pediatrics, Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The [email protected] (M.L.-M.)
4Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
5Pharmacy, Medical Center, University of Freiburg, 79106 Freiburg, Germany
6G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Prosthetic Dentistry, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany