Impact of L-FABP and glucose on polyunsaturated fatty acid induction of PPAR-regulated -oxidative enzymes.
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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- (PPAR) transcription of proteins involved in long-chain fatty acid (LCFA) -oxidation. This issue was addressed in cultured primary hepatocytes from wild-type, L-FABP-null, and PPAR-null mice with these major findings: 1) PUFA-mediated increase in the expression of PPAR-regulated LCFA -oxidative enzymes, LCFA/LCFA-CoA binding proteins (L-FABP, ACBP), and PPAR itself was L-FABP dependent; 2) PPAR transcription, robustly potentiated by high glucose but not maltose, a sugar not taken up, correlated with higher protein levels of these LCFA -oxidative enzymes and with increased LCFA -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 PPAR 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 PPAR. Ablation of L-FABP or PPAR as well as treatment with MK886 (PPAR inhibitor) abolished/reduced PUFA-mediated PPAR 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/PPAR interaction reveals not only the importance of L-FABP for PUFA induction of PPAR target genes in fatty acid -oxidation but also the significance of a high glucose enhancement effect in diabetes.
