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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 8, 2004; DOI: 10.1124/jpet.104.074104

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*BUTYROLACTONE


Received for publication July 13, 2004.
Revised August 26, 2004.
Accepted for publication September 8, 2004.

C75 activates carnitine palmitoyltransferase-1 in isolated mitochondria and intact cells without displacement of bound malonyl CoA

Nengyu Yang 1, Joanne S. Kays 1, Tiffanie R. Skillman 1, Lorri Burris 1, Thomas W. Seng 1, Craig Hammond 1*

1 Eli Lilly and Company

* Address correspondence to: E-mail: hammond_craig{at}lilly.com

Abstract

3 Carnitine palmitoyltransferase 1{beta} (CPT-1 {beta}) 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 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-1{beta} 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. 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-1 {beta}and other CPT-1 isoforms, but that it does not activate CPT-1 through antagonism of malonyl CoA binding.


Key words: C75, carnitine palmitoyltransferase, drug discovery, lipid metabolism, mitochondria, obesity


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