C75 [4-Methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic Acid] Activates Carnitine Palmitoyltransferase-1 in Isolated Mitochondria and Intact Cells without Displacement of Bound Malonyl CoA
- 8 September 2004
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 312 (1), 127-133
- https://doi.org/10.1124/jpet.104.074104
Abstract
Carnitine palmitoyltransferase 1β (CPT-1β) is a key regulator of the β oxidation of long-chain fatty acids in skeletal muscle and therefore a potential therapeutic target for diseases associated with defects in lipid metabolism such as obesity and type 2 diabetes. C75 [4-methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic acid] is an α-methylene-butyrolactone that has been characterized as both an inhibitor of fatty acid synthase and more recently, an activator of CPT-1 (Thupari et al., 2002). Using human CPT-1β expressed in the yeast Pichia pastoris, we demonstrate that C75 can activate the skeletal muscle isoform of CPT-1 and overcome inactivation of the enzyme by malonyl CoA, an important physiological repressor of CPT-1, and the malonyl CoA mimetic Ro25-0187 [{5-[2-(naphthalen-2-yloxy)-ethoxy]-thiophen-2-yl}-oxo-acetic acid]. We also show that C75 can activate CPT-1 in intact hepatocytes to levels similar to those achieved with inhibition of acetyl-CoA carboxylase, the enzyme that produces malonyl CoA. Finally, we demonstrate that concentrations of C75 sufficient for activation of CPT-1 do not displace bound malonyl CoA. We conclude that CPT-1 is an activator of human CPT-1β and other CPT-1 isoforms but that it does not activate CPT-1 through antagonism of malonyl CoA binding.Keywords
This publication has 31 references indexed in Scilit:
- Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate dietsProceedings of the National Academy of Sciences of the United States of America, 2003
- Carnitine palmitoyl transferase I and the control of myocardial β-oxidation fluxBiochemical Society Transactions, 2001
- Continuous Fatty Acid Oxidation and Reduced Fat Storage in Mice Lacking Acetyl-CoA Carboxylase 2Science, 2001
- Prolonged Inhibition of Muscle Carnitine Palmitoyltransferase-1 Promotes Intramyocellular Lipid Accumulation and Insulin Resistance in RatsDiabetes, 2001
- Fatty acid oxidation and the regulation of malonyl-CoA in human muscle.Diabetes, 2000
- The N-terminal Domain of Rat Liver Carnitine Palmitoyltransferase 1 Mediates Import into the Outer Mitochondrial Membrane and Is Essential for Activity and Malonyl-CoA SensitivityJournal of Biological Chemistry, 1998
- Topology of carnitine palmitoyltransferase I in the mitochondrial outer membraneBiochemical Journal, 1997
- [14] Isolation of highly purified mitochondria from Saccharomyces cerevisiaeMethods in Enzymology, 1995
- The soraphens: A family of novel antifungal compounds from Sorangium cellulosum (myxobacteria). I. Soraphen A1.ALPHA.: Fermentation, isolation, biological properties.The Journal of Antibiotics, 1994
- Carnitine palmitoyltransferase. Activation by palmitoyl-CoA and inactivation by malonyl-CoABiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1985