Role of peroxisome proliferator-activated receptor {delta}/{beta} in hepatic metabolic regulation.
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, PPARγ co-activator-1β. Assessment of the lipid composition reveals that PPARδ increases the production of monounsaturated fatty acids, 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 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-activated protein kinase 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.
Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Sihao
S
Liu
Ben
B
Hatano
Minghui
M
Zhao
Chen-Chung
CC
Yen
Kihwa
K
Kang
Shannon M
SM
Reilly
Matthew R
MR
Gangl
Cem
C
Gorgun
James A
JA
Balschi
James M
JM
Ntambi
Chih-Hao
CH
Lee
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
D001786:Blood Glucose; D005229:Fatty Acids, Monounsaturated; C091778:Ppard protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D000263:Adenylate Kinase