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MK-0767, a novel dual PPARα/γ agonist, displays robust antihyperglycemic and hypolipidemic activities

Authors
Publisher
Elsevier Inc.
Publication Date
Volume
318
Issue
2
Identifiers
DOI: 10.1016/j.bbrc.2004.04.032
Keywords
  • Peroxisome Proliferator-Activated Receptor
  • Insulin Sensitizer
  • Hyperglycemia
  • Dyslipidemia
  • Type 2 Diabetes

Abstract

Abstract Here, we characterize the actions of MK-0767, a dual ligand of the nuclear receptors peroxisome proliferator-activated receptor (PPAR)α and PPARγ. In cell-based assays, MK-0767 produced potent activation of human PPARγ and PPARα with a γ:α potency ratio of ≈2. The dual agonist induced high affinity interactions of PPARα and PPARγ with the transcriptional coactivator CBP in vitro. In ob/ob mice, MK-0767 normalized hyperglycemia and hyperinsulinemia with equal or greater potency and efficacy than pioglitazone. Treatment of hamsters with MK-0767 produced substantial reductions in blood cholesterol and triglycerides. In dogs, MK-0767 reduced serum cholesterol levels with a potency more than 10-fold greater than simvastatin. The efficacies of MK-0767 and simvastatin were additive when given together. We conclude that MK-0767 is a potent dual PPARα/γ agonist with robust insulin sensitizing and hypolipidemic activities.

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