Copyright © 2006, European Society of Cardiology
Role of malonyl-CoA in heart disease and the hypothalamic control of obesity
Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada
* Corresponding author. 423 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. Tel.: +1 780 492 2170; fax: +1 780 492 9753. Email address: gary.lopaschuk{at}ualberta.ca
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.
KEYWORDS Malonyl-CoA; Fatty acid oxidation; Carnitine palmitoyltransferase 1; Malonyl-CoA decarboxylase; AMP-activated protein kinase; Acetyl-CoA carboxylase
Time for primary review 20 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. R. Ussher and G. D. Lopaschuk The malonyl CoA axis as a potential target for treating ischaemic heart disease Cardiovasc Res, July 15, 2008; 79(2): 259 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Napoli, W. C. Stanley, and L. J. Ignarro Nutrition and cardiovascular disease: Putting a pathogenic framework into focus Cardiovasc Res, January 15, 2007; 73(2): 253 - 256. [Full Text] [PDF]
|
|