Glucose Directly Links to Lipid Metabolism through High Affinity Interaction with Peroxisome Proliferator-activated Receptor α*
- Departments of ‡Physiology and Pharmacology and §Pathobiology, Texas A&M University, College Station, Texas 77843-4467
- 1 To whom correspondence should be addressed: Dept. of Physiology and Pharmacology, Texas A & M University, TVMC, College Station, TX 77843-4466. Tel.: 979-862-1433; Fax: 979-862-4929; E-mail: fschroeder{at}cvm.tamu.edu.
Abstract
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-α (PPARα) binds glucose and glucose metabolites with high affinity, resulting in significantly altered PPARα secondary structure. Glucose decreased PPARα interaction with fatty acid metabolites and steroid receptor coactivator-1 while increasing PPARα interaction with DNA. Concomitantly, glucose increased PPARα interaction with steroid receptor coactivator-1, DNA binding, and transactivation of β-oxidation pathways in the presence of activating ligands. Heterodimerization of PPARα to the retinoid X receptor-α resulted in even larger increases in transactivation with the addition of glucose. These data suggest that PPARα is responsible for maintaining energy homeostasis through a concentration-dependent regulation of both lipids and sugars and that hyperglycemic injury mediated by PPARα occurs not only indirectly through elevated long chain fatty acid levels but also through direct action of glucose on PPARα.
Footnotes
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↵ 2 The abbreviations used are: PPARα, peroxisome proliferator-activated receptor α; LCFA, long chain fatty acid; SRC-1, steroid receptor coactivator-1; RXRα, retinoid X receptor α; G-1-P, glucose-1-phosphate; G-6-P, glucose-6-phosphate; PPRE, peroxisome proliferator response element; L-FABP, liver fatty acid-binding protein; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; LSCM, laser scanning confocal microscopy.
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↵ 3 A. L. McIntosh, B. P. Atshaves, H. Huang, H. R. Payne, H. A. Hostetler, J. Davis, A. B. Kier, and F. Schroeder, unpublished observation.
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↵* This work was supported in part by the United States Public Health Service National Institutes of Health Grant DK41402 (to F. S. and A. B. K.), Administrative Supplement “Drug Screening Program for Diabetic Complications” to Grant DK41402 (to F. S. and A. B. K.), National Institutes of Health National Research Service Award DK066732 (to H. A. H.), and National Institutes of Health K99 Award DK77573 (to H. A. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received June 21, 2007.
- Revision received November 28, 2007.
- The American Society for Biochemistry and Molecular Biology, Inc.
