Very long-chain specific acyl-CoA dehydrogenase, mitochondrial (VLCAD) (VLCAD)

Very long-chain specific acyl-CoA dehydrogenase, mitochondrial (VLCAD) is a critical enzyme located on the inner mitochondrial membrane that catalyzes the first step of the beta-oxidation spiral for fatty acids with 14 to 20 carbons (UniProt Consortium, 2024, P49748). This enzymatic process is essential for maintaining energy homeostasis, particularly during fasting or physiological stress when the body shifts from glucose to lipid metabolism (StatPearls, 2023). Deficiencies in this enzyme, caused by mutations in the ACADVL gene, lead to Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD), a condition characterized by life-threatening hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis (NIH, 2023). While VLCAD is often functionally absent in patients, it remains a focal point for therapeutic intervention. Triheptanoin is an FDA-approved synthetic triglyceride that serves as an alternative fuel source to bypass the metabolic block associated with VLCAD (FDA, 2020). Additionally, research has explored the use of PPAR agonists like bezafibrate to increase the expression of residual VLCAD protein in patients with certain genotypes (Bonnefont et al., 2009).

Other names

ACADVLVery-long-chain acyl-CoA dehydrogenaseVLCADHLCAD (historical/misnomer)

Triheptanoin acts as a substrate replacement therapy, providing odd-chain fatty acids that bypass the VLCAD-dependent step of beta-oxidation to provide anaplerotic substrates for the citric acid cycle (FDA, 2020). Bezafibrate functions as a PPAR agonist that induces the expression of the ACADVL gene, potentially increasing residual enzyme activity in patients with certain missense mutations (Bonnefont et al., 2009).