Regulatory enzymes of mitochondrial beta-oxidation as targets for treatment of the metabolic syndrome.
Insulin sensitizers like metformin generally act through pathways triggered by adenosine monophosphate-activated protein kinase. Carnitine palmitoyltransferase 1 (CPT1) controls mitochondrial beta-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.
Schreurs
M
M
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Kuipers
F
F
van der Leij
F R
FR
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007333:Insulin Resistance; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D024821:Metabolic Syndrome / Q000188:drug therapy*; D008928:Mitochondria / Q000201:enzymology*; D009765:Obesity / Q000188:drug therapy; D010084:Oxidation-Reduction; D047492:Peroxisome Proliferator-Activated Receptors; D014157:Transcription Factors
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007527:Isoenzymes; D047492:Peroxisome Proliferator-Activated Receptors; D014157:Transcription Factors; D002334:Carnitine O-Palmitoyltransferase; D000103:Acetyl-CoA Carboxylase