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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M400018-JLR200 on April 21, 2004

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Journal of Lipid Research, Vol. 45, 1289-1301, July 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome

Clay T. Cramer1, Brian Goetz1, Krista L. M. Hopson, Gregory J. Fici, Rose M. Ackermann, Stephen C. Brown, Charles L. Bisgaier, W. G. Rajeswaran, Daniela C. Oniciu and Michael E. Pape2

Esperion Therapeutics, Inc., Ann Arbor, MI 48108

2 To whom correspondence should be addressed. e-mail: mikep{at}esperion.com

We have identified a novel {omega}-hydroxy-alkanedicarboxylic acid, ESP 55016, that favorably alters serum lipid variables in obese female Zucker (fa/fa) rats. ESP 55016 reduced serum non-HDL-cholesterol (non-HDL-C), triglyceride, and nonesterified fatty acid levels while increasing serum HDL-C and ß-hydroxybutyrate levels in a dose-dependent manner. ESP 55016 reduced fasting serum insulin and glucose levels while also suppressing weight gain. In primary rat hepatocytes, ESP 55016 increased the oxidation of [14C]palmitate in a dose- and carnitine palmitoyl transferase-I (CPT-I)-dependent manner. Furthermore, in primary rat hepatocytes and in vivo, ESP 55016 inhibited fatty acid and sterol synthesis. The "dual inhibitor" activity of ESP 55016 was unlikely attributable to the activation of the AMP-activated protein kinase (AMPK) pathway because AMPK and acetyl-CoA carboxylase (ACC) phosphorylation states as well as ACC activity were not altered by ESP 55016. Further studies indicated the conversion of ESP 55016 to a CoA derivative in vivo. ESP 55016-CoA markedly inhibited the activity of partially purified ACC. The activity of partially purified HMG-CoA reductase was not altered by the xenobiotic-CoA.

These data suggest that ESP 55016-CoA favorably alters lipid metabolism in a model of diabetic dyslipidemia in part by initially inhibiting fatty acid and sterol synthesis plus enhancing the oxidation of fatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis.

Supplementary key words hepatocytes • acetyl-CoA carboxylase • Zucker • AMP-activated protein kinase • xenobiotic-CoA


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