High glucose potentiates L-FABP mediated fibrate induction of PPAR in mouse hepatocytes.
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Although liver fatty acid binding protein (L-FABP) binds fibrates and PPAR in vitro and enhances fibrate induction of PPAR in transformed cells, the functional significance of these findings is unclear, especially in normal hepatocytes. Studies with cultured primary mouse hepatocytes show that: 1) At physiological (6mM) glucose, fibrates (bezafibrate, fenofibrate) only weakly activated PPAR transcription of genes in LCFA -oxidation; 2) High (11-20mM) glucose, but not maltose (osmotic control), significantly potentiated fibrate-induction of mRNA of these and other PPAR target genes to increase LCFA -oxidation. These effects were associated with fibrate-mediated redistribution of L-FABP into nuclei-an effect prolonged by high glucose-but not with increased de novo fatty acid synthesis from glucose; 3) Potentiation of bezafibrate action by high glucose required an intact L-FABP/PPAR signaling pathway as shown with L-FABP null, PPAR null, PPAR inhibitor-treated WT, or PPAR-specific fenofibrate-treated WT hepatocytes. High glucose alone in the absence of fibrate was ineffective. Thus, high glucose potentiation of PPAR occurred through FABP/PPAR rather than indirectly through other PPARs or glucose induced signaling pathways. These data indicated L-FABP's importance in fibrate-induction of hepatic PPAR LCFA -oxidative genes, especially in the context of high glucose levels.