TY - JOUR
T1 - Increased cardiac fatty acid oxidation in a mousemodel with decreasedmalonyl-CoA sensitivity of CPT1B
AU - van Weeghel, Michel
AU - Abdurrachim, Desiree
AU - Nederlof, Rianne
AU - Argmann, Carmen A.
AU - Houtkooper, Riekelt H.
AU - Hagen, Jacob
AU - Nabben, Miranda
AU - Denis, Simone
AU - Ciapaite, Jolita
AU - Kolwicz, Stephen C.
AU - Lopaschuk, Gary D.
AU - Auwerx, Johan
AU - Nicolay, Klaas
AU - Des Rosiers, Christine
AU - Wanders, Ronald J.
AU - Zuurbier, Coert J.
AU - Prompers, Jeanine J.
AU - Houten, Sander M.
PY - 2018
Y1 - 2018
N2 - 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 CPT1BE3A mutant enzyme, which has reduced sensitivity to malonyl-CoA. In isolated perfused hearts, FAO was 1.9-fold higher in Cpt1bE3A/E3A hearts compared with Cpt1bWT/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 Cpt1bE3A/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.
AB - 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 CPT1BE3A mutant enzyme, which has reduced sensitivity to malonyl-CoA. In isolated perfused hearts, FAO was 1.9-fold higher in Cpt1bE3A/E3A hearts compared with Cpt1bWT/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 Cpt1bE3A/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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85054010573&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29635338
U2 - https://doi.org/10.1093/cvr/cvy089
DO - https://doi.org/10.1093/cvr/cvy089
M3 - Article
C2 - 29635338
SN - 0008-6363
VL - 114
SP - 1324
EP - 1334
JO - Cardiovascular research
JF - Cardiovascular research
IS - 10
ER -