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Inhibition of malonyl-CoA decarboxylase reduces the inflammatory response associated with insulin resistance.

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.
AuthorsVictor Samokhvalov, John R Ussher, Natasha Fillmore, Ian K G Armstrong, Wendy Keung, Daniel Moroz, David G Lopaschuk, John Seubert, Gary D Lopaschuk
JournalAmerican 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
PMID23074239 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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