Abstract |
We previously showed that genetic inactivation of malonyl-CoA decarboxylase (MCD), which regulates fatty acid oxidation, protects mice against high-fat diet-induced insulin resistance. Development of insulin resistance has been associated with activation of the inflammatory response. Therefore, we hypothesized that the protective effect of MCD inhibition might be caused by a favorable effect on the inflammatory response. We examined if pharmacological inhibition of MCD protects neonatal cardiomyocytes and peritoneal macrophages against inflammatory-induced metabolic perturbations. Cardiomyocytes and macrophages were treated with LPS to induce an inflammatory response, in the presence or absence of an MCD inhibitor (CBM-301106, 10 μM). Inhibition of MCD attenuated the LPS-induced inflammatory response in cardiomyocytes and macrophages. MCD inhibition also prevented LPS impairment of insulin-stimulated glucose uptake in cardiomyocytes and increased phosphorylation of Akt. Additionally, inhibition of MCD strongly diminished LPS-induced activation of palmitate oxidation. We also found that treatment with an MCD inhibitor prevented LPS-induced collapse of total cellular antioxidant capacity. Interestingly, treatment with LPS or an MCD inhibitor did not alter intracellular triacylglycerol content. Furthermore, inhibition of MCD prevented LPS-induced increases in the level of ceramide in cardiomyocytes and macrophages while also ameliorating LPS-initiated decreases in PPAR binding. This suggests that the anti-inflammatory effect of MCD inhibition is mediated via accumulation of long-chain acyl-CoA, which in turn stimulates PPAR binding. Our results also demonstrate that pharmacological inhibition of MCD is a novel and promising approach to treat insulin resistance and its associated metabolic complications.
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Authors | Victor Samokhvalov, John R Ussher, Natasha Fillmore, Ian K G Armstrong, Wendy Keung, Daniel Moroz, David G Lopaschuk, John Seubert, Gary D Lopaschuk |
Journal | American journal of physiology. Endocrinology and metabolism
(Am J Physiol Endocrinol Metab)
Vol. 303
Issue 12
Pg. E1459-68
(Dec 15 2012)
ISSN: 1522-1555 [Electronic] United States |
PMID | 23074239
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- Cardiotonic Agents
- Ceramides
- Enzyme Inhibitors
- Phenylurea Compounds
- methyl 5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)morpholine-4-carboxamido)pentanoate
- Proto-Oncogene Proteins c-akt
- Carboxy-Lyases
- malonyl-CoA decarboxylase
- Glucose
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Topics |
- Animals
- Animals, Newborn
- Anti-Inflammatory Agents, Non-Steroidal
(pharmacology)
- Biological Transport
(drug effects)
- Carboxy-Lyases
(antagonists & inhibitors, metabolism)
- Cardiotonic Agents
(pharmacology)
- Cells, Cultured
- Ceramides
(metabolism)
- Enzyme Inhibitors
(pharmacology)
- Glucose
(metabolism)
- Insulin Resistance
- Lipid Metabolism
(drug effects)
- Macrophage Activation
(drug effects)
- Macrophages, Peritoneal
(cytology, drug effects, immunology, metabolism)
- Mice
- Myocytes, Cardiac
(cytology, drug effects, immunology, metabolism)
- Phenylurea Compounds
(pharmacology)
- Phosphorylation
(drug effects)
- Protein Processing, Post-Translational
(drug effects)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Rats
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