title: Impact of L-FABP and glucose on polyunsaturated fatty acid induction of PPARα-regulated β-oxidative enzymes.
abstract: Liver fatty acid binding protein (L-FABP) is the major soluble protein that binds very-long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) in hepatocytes. However, nothing is known about L-FABP's role in n-3 PUFA-mediated peroxisome proliferator activated receptor-α (PPARα) transcription of proteins involved in long-chain fatty acid (LCFA) β-oxidation. This issue was addressed in cultured primary hepatocytes from wild-type, L-FABP-null, and PPARα-null mice with these major findings: 1) PUFA-mediated increase in the expression of PPARα-regulated LCFA β-oxidative enzymes, LCFA/LCFA-CoA binding proteins (L-FABP, ACBP), and PPARα itself was L-FABP dependent; 2) PPARα transcription, robustly potentiated by high glucose but not maltose, a sugar not taken up, correlated with higher protein levels of these LCFA β-oxidative enzymes and with increased LCFA β-oxidation; and 3) high glucose altered the potency of n-3 relative to n-6 PUFA. This was not due to a direct effect of glucose on PPARα transcriptional activity nor indirectly through de novo fatty acid synthesis from glucose. Synergism was also not due to glucose impacting other signaling pathways, since it was observed only in hepatocytes expressing both L-FABP and PPARα. Ablation of L-FABP or PPARα as well as treatment with MK886 (PPARα inhibitor) abolished/reduced PUFA-mediated PPARα transcription of these genes, especially at high glucose. Finally, the PUFA-enhanced L-FABP distribution into nuclei with high glucose augmentation of the L-FABP/PPARα interaction reveals not only the importance of L-FABP for PUFA induction of PPARα target genes in fatty acid β-oxidation but also the significance of a high glucose enhancement effect in diabetes.
authors.affiliation: Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 77843, USA.
authors.forename: Anca D
authors.initials: AD
authors.lastname: Petrescu
authors.forename: Huan
authors.initials: H
authors.lastname: Huang
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Martin
authors.forename: Avery L
authors.initials: AL
authors.lastname: McIntosh
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Storey
authors.forename: Danilo
authors.initials: D
authors.lastname: Landrock
authors.forename: Ann B
authors.initials: AB
authors.lastname: Kier
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Schroeder
mesh_terms: D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D050556:Fatty Acid-Binding Proteins / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008320:Maltose / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009994:Osmolar Concentration; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013229:Stearic Acids / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D047493:PPAR alpha; D013229:Stearic Acids; D008320:Maltose; D042962:Acyl-CoA Oxidase; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose