Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome.
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 beta-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 [(14)C]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.
Cramer
Clay T
CT
Esperion Therapeutics, Inc., Ann Arbor, MI 48108, USA.
Goetz
Brian
B
Hopson
Krista L M
KL
Fici
Gregory J
GJ
Ackermann
Rose M
RM
Brown
Stephen C
SC
Bisgaier
Charles L
CL
Rajeswaran
W G
WG
Oniciu
Daniela C
DC
Pape
Michael E
ME
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002478:Cells, Cultured; D003065:Coenzyme A; D003998:Dicarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006949:Hyperlipidemias / Q000188:drug therapy*; D007328:Insulin / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008055:Lipids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D024821:Metabolic Syndrome / Q000188:drug therapy*; D009097:Multienzyme Complexes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D013261:Sterols / Q000096:biosynthesis; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; D003998:Dicarboxylic Acids; D005227:Fatty Acids; D007328:Insulin; D008055:Lipids; D009097:Multienzyme Complexes; D013261:Sterols; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D003065:Coenzyme A