Regulatory enzymes of mitochondrial β-oxidation as targets for treatment of the metabolic syndrome
Summary Insulin sensitizers like metformin generally act through pathways triggered by adenosine monophosphate‐activated protein kinase. Carnitine palmitoyltransferase 1 (CPT1) controls mitochondrial β‐oxidation and is inhibited by malonyl‐CoA, the product of acetyl‐CoA carboxylase (ACC). The adenos...
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Veröffentlicht in: | Obesity reviews 2010-05, Vol.11 (5), p.380-388 |
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Sprache: | eng |
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Insulin sensitizers like metformin generally act through pathways triggered by adenosine monophosphate‐activated protein kinase. Carnitine palmitoyltransferase 1 (CPT1) controls mitochondrial β‐oxidation and is inhibited by malonyl‐CoA, the product of acetyl‐CoA carboxylase (ACC). The adenosine monophosphate‐activated protein kinase‐ACC‐CPT1 axis tightly regulates mitochondrial long‐chain fatty acid oxidation. Evidence indicates that ACC2, the isoform located in close proximity to CPT1, is the major regulator of CPT1 activity. ACC2 as well as CPT1 are therefore potential targets to treat components of the metabolic syndrome such as obesity and insulin resistance. Reversible inhibitors of the liver isoform of CPT1, developed to prevent ketoacidosis and hyperglycemia, have been found to be associated with side effects like hepatic steatosis. However, stimulation of systemic CPT1 activity may be an attractive means to accelerate peripheral fatty acid oxidation and hence improve insulin sensitivity. Stimulation of CPT1 can be achieved by elimination or inhibition of ACC2 activity and through activating transcription factors like peroxisome proliferator‐activated receptors and their protein partners. The latter leads to enhanced CPT1 gene expression. Recent developments are discussed, including a recently identified CPT1 isoform, i.e. CPT1C. This protein is highly expressed in the brain and may provide a target for new tools to prevent obesity. |
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ISSN: | 1467-7881 1467-789X |
DOI: | 10.1111/j.1467-789X.2009.00642.x |