Octanoate is differentially metabolized in liver and muscle and fails to rescue cardiomyopathy in CPT2 deficiency
Autor: | Arvin H. Soepriatna, Andrea S. Pereyra, Eric S. Goetzman, Yuxun Zhang, Kate L. Harris, Craig J. Goergen, Jessica M. Ellis, Quin A. Waterbury, Sivakama S. Bharathi, Kelsey H. Fisher-Wellman |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
medicine.medical_specialty CPT1 carnitine palmitoyltransferase 1 medium-chain fatty acids Carnitine-acylcarnitine translocase QD415-436 Carnitine shuttle Oxidative phosphorylation 030204 cardiovascular system & hematology Biochemistry 03 medical and health sciences PC phosphatidylcholine 0302 clinical medicine Endocrinology Carnitine palmitoyltransferase 1 ACSM3 medium-chain acyl-CoA synthetase 3 OctD octanoate diet Internal medicine medicine Carnitine carnitine shuttle CPT2 carnitine palmitoyltransferase 2 Beta oxidation fatty acid oxidation LCKD long-chain fatty acid ketogenic diet chemistry.chemical_classification biology Carnitine O-Palmitoyltransferase mTOR mechanistic target of rapamycin Fatty acid Skeletal muscle MCAD medium-chain acyl-CoA dehydrogenase Cell Biology mFAO mitochondrial fatty acid oxidation CrOT carnitine O-octanoyltransferase LCAC long-chain acylcarnitine PDH pyruvate dehydrogenase carnitine palmitoyltransferase mitochondria 030104 developmental biology medicine.anatomical_structure chemistry biology.protein CD control diet Metabolism Inborn Errors medicine.drug Research Article CACT carnitine-acylcarnitine translocase |
Zdroj: | Journal of Lipid Research Journal of Lipid Research, Vol 62, Iss, Pp 100069-(2021) |
ISSN: | 1539-7262 0022-2275 |
Popis: | Long-chain fatty acid oxidation is frequently impaired in primary and systemic metabolic diseases affecting the heart; thus, therapeutically increasing reliance on normally minor energetic substrates, such as ketones and medium-chain fatty acids, could benefit cardiac health. However, the molecular fundamentals of this therapy are not fully known. Here, we explored the ability of octanoate, an eight-carbon medium-chain fatty acid known as an unregulated mitochondrial energetic substrate, to ameliorate cardiac hypertrophy in long-chain fatty acid oxidation-deficient hearts because of carnitine palmitoyltransferase 2 deletion (Cpt2M−/−). CPT2 converts acylcarnitines to acyl-CoAs in the mitochondrial matrix for oxidative bioenergetic metabolism. In Cpt2M−/− mice, high octanoate-ketogenic diet failed to alleviate myocardial hypertrophy, dysfunction, and acylcarnitine accumulation suggesting that this alternative substrate is not sufficiently compensatory for energy provision. Aligning this outcome, we identified a major metabolic distinction between muscles and liver, wherein heart and skeletal muscle mitochondria were unable to oxidize free octanoate, but liver was able to oxidize free octanoate. Liver mitochondria, but not heart or muscle, highly expressed medium-chain acyl-CoA synthetases, potentially enabling octanoate activation for oxidation and circumventing acylcarnitine shuttling. Conversely, octanoylcarnitine was oxidized by liver, skeletal muscle, and heart, with rates in heart 4-fold greater than liver and, in muscles, was not dependent upon CPT2. Together, these data suggest that dietary octanoate cannot rescue CPT2-deficient cardiac disease. These data also suggest the existence of tissue-specific mechanisms for octanoate oxidative metabolism, with liver being independent of free carnitine availability, whereas cardiac and skeletal muscles depend on carnitine but not on CPT2. |
Databáze: | OpenAIRE |
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