| Autor: |
Yang N; Endocrine Research, Lilly Research Laboratories, Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Kays JS, Skillman TR, Burris L, Seng TW, Hammond C |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2005 Jan; Vol. 312 (1), pp. 127-33. Date of Electronic Publication: 2004 Sep 08. |
| DOI: |
10.1124/jpet.104.074104 |
| Abstrakt: |
Carnitine palmitoyltransferase 1beta (CPT-1beta) is a key regulator of the beta 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 alpha-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-1beta 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-1beta and other CPT-1 isoforms but that it does not activate CPT-1 through antagonism of malonyl CoA binding. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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