Why you should be stocking up on SLinSane for the DCP release...
l Chem. 2010 Nov 8. [Epub ahead of print]
Role of peroxisome proliferator-activated receptor delta/beta in hepatic metabolic regulation.
Liu S, Hatano B, Zhao M, Yen CC, Kang K, Reilly SM, Gangl M, Gorgun C, Balschi JA, Ntambi JM, Lee CH.
Harvard School of Public Health, United States;
Pharmacological activation of peroxisome proliferator-activated receptor δ/β (PPARδ/β) improves glucose handling and insulin sensitivity. The target tissues of drug actions remain unclear. We demonstrate here that adenovirus mediated liver-restricted PPARδ activation reduces fasting glucose levels in chow and high fat fed mice. This effect is accompanied by hepatic glycogen and lipid deposition as well as up-regulation of glucose utilization and de novo lipogenesis pathways. Promoter analyses indicate that PPARδ regulates hepatic metabolic programs through both direct and indirect transcriptional mechanisms partly mediated by its co-activator, PGC-1β. Assessment of the lipid composition reveals that PPARδ increases the production of monounsaturated fatty acids (MUFAs), which are PPAR activators, and reduces that of saturated FAs. Despite the increased lipid accumulation, adeno-PPARδ infected livers exhibit less damage and show a reduction in c-Jun N-terminal kinase (JNK) stress signaling, suggesting that PPARδ-regulated lipogenic program may protect against lipotoxicity. The altered substrate utilization by PPARδ also results in a secondary effect on AMP kinase (AMPK) activation, which likely contributes to the glucose-lowering activity. Collectively, our data suggest that PPARδ controls hepatic energy substrate homeostasis by coordinated regulation of glucose and fatty acid metabolism, which provide a molecular basis for developing PPARδ agonists to manage hyperglycemia and insulin resistance.