Impact of L-FABP and glucose on polyunsaturated fatty acid induction of PPARα-regulated β-oxidative enzymes

Petrescu AD, Huang H, Martin GG, McIntosh AL, Storey SM, Landrock D, Kier AB, Schroeder F. Impact of L-FABP and glucose on polyunsaturated fatty acid induction of PPAR alpha-regulated beta-oxidative enzymes. Am J Physiol Gastrointest Liver Physiol 304: G241-G256, 2013. First published December 13, 2012; doi:10.1152/ajpgi.00334.2012.-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-alpha (PPAR alpha) transcription of proteins involved in long-chain fatty acid (LCFA) beta-oxidation. This issue was addressed in cultured primary hepatocytes from wild-type, L-FABP-null, and PPAR alpha-null mice with these major findings: 1) PUFA-mediated increase in the expression of PPAR alpha-regulated LCFA beta-oxidative enzymes, LCFA/LCFA-CoA binding proteins (L-FABP, ACBP), and PPAR alpha itself was L-FABP dependent; 2) PPAR alpha transcription, robustly potentiated by high glucose but not maltose, a sugar not taken up, correlated with higher protein levels of these LCFA beta-oxidative enzymes and with increased LCFA beta-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 alpha 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 alpha. Ablation of L-FABP or PPAR alpha as well as treatment with MK886 (PPAR alpha inhibitor) abolished/reduced PUFA-mediated PPAR alpha 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 alpha interaction reveals not only the importance of L-FABP for PUFA induction of PPAR alpha target genes in fatty acid beta-oxidation but also the significance of a high glucose enhancement effect in diabetes.