Glucose directly links to lipid metabolism through high affinity interaction with peroxisome proliferator-activated receptor alpha.
The pathophysiology of diabetes is characterized not only by elevated glucose but also elevated long chain fatty acid levels. We show for the first time that the peroxisome proliferator-activated receptor-alpha (PPARalpha) binds glucose and glucose metabolites with high affinity, resulting in significantly altered PPARalpha secondary structure. Glucose decreased PPARalpha interaction with fatty acid metabolites and steroid receptor coactivator-1 while increasing PPARalpha interaction with DNA. Concomitantly, glucose increased PPARalpha interaction with steroid receptor coactivator-1, DNA binding, and transactivation of beta-oxidation pathways in the presence of activating ligands. Heterodimerization of PPARalpha to the retinoid X receptor-alpha resulted in even larger increases in transactivation with the addition of glucose. These data suggest that PPARalpha is responsible for maintaining energy homeostasis through a concentration-dependent regulation of both lipids and sugars and that hyperglycemic injury mediated by PPARalpha occurs not only indirectly through elevated long chain fatty acid levels but also through direct action of glucose on PPARalpha.
Department of Physiology, Texas A&M University, College Station, Texas 77843-4467, USA.
Heather A
HA
Hostetler
Huan
H
Huang
Ann B
AB
Kier
Friedhelm
F
Schroeder
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D056920:Nuclear Receptor Coactivator 1; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017433:Protein Structure, Secondary / Q000187:drug effects / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
D005227:Fatty Acids; D047493:PPAR alpha; D047490:Retinoid X Receptor alpha; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D005947:Glucose