Increased cardiac fatty acid oxidation in a mousemodel with decreasedmalonyl-CoA sensitivity of CPT1B

Michel van Weeghel, Desiree Abdurrachim, Rianne Nederlof, Carmen A. Argmann, Riekelt H. Houtkooper, Jacob Hagen, Miranda Nabben, Simone Denis, Jolita Ciapaite, Stephen C. Kolwicz, Gary D. Lopaschuk, Johan Auwerx, Klaas Nicolay, Christine Des Rosiers, Ronald J. Wanders, Coert J. Zuurbier, Jeanine J. Prompers, Sander M. Houten*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review


    Aims Mitochondrial fatty acid oxidation (FAO) is an important energy provider for cardiac work and changes in cardiac substrate preference are associated with different heart diseases. Carnitine palmitoyltransferase 1B (CPT1B) is thought to perform the rate limiting enzyme step in FAO and is inhibited by malonyl-CoA. The role of CPT1B in cardiac metabolism has been addressed by inhibiting or decreasing CPT1B protein or after modulation of tissue malonyl-CoA metabolism. We assessed the role of CPT1B malonyl-CoA sensitivity in cardiac metabolism. Methods and results We generated and characterized a knock in mouse model expressing the CPT1B(E3A) mutant enzyme, which has reduced sensitivity to malonyl-CoA. In isolated perfused hearts, FAO was 1.9-fold higher in Cpt1b(E3A/E3A) hearts compared with Cpt1b(WT/WT) hearts. Metabolomic, proteomic and transcriptomic analysis showed increased levels of malonylcarnitine, decreased concentration of CPT1B protein and a small but coordinated downregulation of the mRNA expression of genes involved in FAO in Cpt1b(E3A/E3A) hearts, all of which aim to limit FAO. In vivo assessment of cardiac function revealed only minor changes, cardiac hypertrophy was absent and histological analysis did not reveal fibrosis. Conclusions Malonyl-CoA-dependent inhibition of CPT1B plays a crucial role in regulating FAO rate in the heart. Chronic elevation of FAO has a relatively subtle impact on cardiac function at least under baseline conditions.
    Original languageEnglish
    Pages (from-to)1324-1334
    Number of pages11
    JournalCardiovascular Research
    Issue number10
    Publication statusPublished - 1 Aug 2018


    • Malonyl-CoA
    • Allosteric regulation of enzyme activity
    • Glucose-fatty acid cycle
    • Heart metabolism
    • Carnitine palmitoyltransferase
    • HEART

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