Doctor of Philosophy
Dr. Murray Huff
The peroxisome proliferator-activated receptor (PPAR) δ is a ligand-dependent transcription factor that has been implicated in metabolic and inflammatory regulation. The molecular and physiological mechanisms by which PPARδ activation regulates lipid metabolism, inflammatory signaling and protection from atherosclerosis in states of metabolic disturbance such as insulin resistance and dyslipidemia, were investigated in a series of in vitro and in vivo studies. In vitro experiments demonstrated that PPARδ activation inhibits atherogenic lipoprotein-induced lipid accumulation and the associated proinflammatory responses. The primary mechanisms for these effects were increased fatty acid β-oxidation, decreased lipoprotein lipase (LPL) activity, reduced MAPK signaling and improved insulin signaling. With regard to cholesteryl ester (CE)-rich low-density lipoprotein (LDL), the PPARδ activators stimulated cholesterol efflux via ABCA1 to apoAI, resulting in the inhibition of native and modified LDL-induced CE accumulation. In vivo studies were conducted in high fat, high cholesterol (HFHC)-fed low-density lipoprotein receptor null (Ldlr-/-) mice. Following a 4-week induction phase of HFHC-feeding to stimulate early atherosclerotic lesion development, dietary supplementation with GW1516 for a subsequent 8-weeks prevented further plaque progression. This prevention was linked to inhibition of dyslipidemia, hyperinsulinemia, and glucose and insulin intolerance. Furthermore, GW1516 strongly attenuated aortic inflammation, insulin resistance and endoplasmic reticulum (ER)-stress, which likely contributed to inhibition of lesion progression. Additional studies in the liver showed that PPARδ activation inhibits hepatic TG accumulation induced by HFHC-feeding. To further probe the mechanism for this effect, experiments were conducted in primary mouse hepatocytes isolated from wild-type (WT) or adenosine monophosphate-activated protein kinase (AMPK) β1-/- mice. These studies revealed that PPARδ activation in the liver stimulates fat oxidation due to upregulation of the PPARδ-target gene carnitine palmitoyl transferase (Cpt) 1a, which was independent of AMPK activation. Furthermore, GW1516 inhibited de novo lipogenesis, which was partially dependent on AMPK activation. The residual inhibitory effect on fatty acid synthesis was associated with correction of selective hepatic insulin resistance. In summary, these studies provide significant insight and support for PPARδ activation as a therapeutic strategy to treat the dysregulation of lipid homeostasis, inflammatory signaling, metabolic disease, and their cardiovascular complications.
Bojic, Lazar A., "Regulation of Lipid Homeostasis, Inflammatory Signalling and Atherosclerosis by the Peroxisome Proliferator-Activated Receptor Delta" (2013). Electronic Thesis and Dissertation Repository. 1307.