Submitted on January 21, 2004
Revised on March 19, 2004
Accepted on April 14, 2004
Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome
Clay T. Cramer, Brian Goetz, 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. Pape
Cellular and Molecular Biology, Esperion Therapeutics, Ann Arbor, MI 48108
Corresponding Author: mikep{at}esperion.com
We have identified a novel omega-hydroxy-alkanedicarboxylic acid, ESP 55016, that favorably alters serum lipid variables in an animal model of diabetic dyslipidemia. In obese female Zucker (fa/fa) rats, ESP 55016 reduced serum nonHDL-C, triglyceride, and non-esterified fatty acid levels, while elevating 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-1)-dependent fashion. Furthermore, in primary rat hepatocytes ESP 55016 not only inhibited fatty acid synthesis from 14C-glucose, 14C-pyruvate, 14C-acetate, and 3H20, but inhibited sterol synthesis as well, with IC50s in the micromolar range for both pathways; inhibition occurred within five minutes. Sterol synthesis inhibition occurred at a step prior to mevalonate formation in the sterol biosynthetic pathway. The physiological relevance of the in vitro findings with ESP 55016 was confirmed in vivo, demonstrable by inhibition of both hepatic fatty acid and sterol synthesis within two hours of administration. The “dual inhibitor” activity of ESP 55016 in primary hepatocytes, was unlikely due to activation of the AMP-activated protein kinase (AMPK) pathway since 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 animal models of dyslipidemia in part, by initially inhibiting fatty acid and sterol synthesis plus enhancing oxidation of fatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis.
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