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Role of malonyl-CoA in heart disease and the hypothalamic control of obesity.

Abstract
Obesity is an important contributor to the risk of developing insulin resistance, diabetes, and heart disease. Alterations in tissue levels of malonyl-CoA have the potential to impact on the severity of a number of these disorders. This review will focus on the emerging role of malonyl-CoA as a key "metabolic effector" of both obesity and cardiac fatty acid oxidation. In addition to being a substrate for fatty acid biosynthesis, malonyl-CoA is a potent inhibitor of mitochondrial carnitine palmitoyltransferase (CPT) 1, a key enzyme involved in mitochondrial fatty acid uptake. A decrease in myocardial malonyl-CoA levels and an increase in CPT1 activity contribute to an increase in cardiac fatty acid oxidation. An increase in malonyl-CoA degradation due to increased malonyl-CoA decarboxylase (MCD) activity may be one mechanism responsible for this decrease in malonyl-CoA. Another mechanism involves the inhibition of acetyl-CoA carboxylase (ACC) synthesis of malonyl-CoA, due to AMP-activated protein kinase (AMPK) phosphorylation of ACC. Recent studies have demonstrated a role of malonyl-CoA in the hypothalamus as a regulator of food intake. Increases in hypothalamic malonyl-CoA and inhibition of CPT1 are associated with a decrease in food intake in mice and rats, while a decrease in hypothalamic malonyl-CoA increases food intake and weight gain. The exact mechanism(s) responsible for these effects of malonyl-CoA are not clear, but have been proposed to be due to an increase in the levels of long chain acyl CoA, which occurs as a result of malonyl-CoA inhibition of CPT1. Both hypothalamic and cardiac studies have demonstrated that control of malonyl-CoA levels has an important impact on obesity and heart disease. Targeting enzymes that control malonyl-CoA levels may be an important therapeutic approach to treating heart disease and obesity.
AuthorsClifford D L Folmes, Gary D Lopaschuk
JournalCardiovascular research (Cardiovasc Res) Vol. 73 Issue 2 Pg. 278-87 (Jan 15 2007) ISSN: 0008-6363 [Print] England
PMID17126822 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
Chemical References
  • Acyl Coenzyme A
  • Multienzyme Complexes
  • Malonyl Coenzyme A
  • Carnitine O-Palmitoyltransferase
  • Protein Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase
Topics
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase (metabolism)
  • Acyl Coenzyme A (metabolism)
  • Animals
  • Appetite Regulation (physiology)
  • Carnitine O-Palmitoyltransferase (metabolism)
  • Energy Metabolism
  • Heart Diseases (metabolism)
  • Humans
  • Hypothalamus (physiology)
  • Malonyl Coenzyme A (physiology)
  • Multienzyme Complexes (metabolism)
  • Obesity (metabolism)
  • Protein Serine-Threonine Kinases (metabolism)

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