Liver type fatty acid binding protein (L-FABP) gene ablation reduces nuclear ligand distribution and peroxisome proliferator-activated receptor-α activity in cultured primary hepatocytes

The effect of liver type fatty acid binding protein (L-FABP) gene ablation on the uptake and distribution of long chain fatty acids (LCFA) to the nucleus by real-time laser scanning confocal imaging and peroxisome proliferator-activated receptor-alpha (PPAR alpha) activity was examined in cultured primary hepatocytes from livers wild-type L-FABP+/+ and gene ablated L-FABP-/- mice. Cultured primary hepatocytes from livers of L-FABP-/- mice exhibited: (i) reduced oxidation of palmitic acid, a common dietary long chain fatty acid (LCFA); (ii) reduced expression of fatty acid oxidative enzymes-proteins transcriptionally regulated by PPAR alpha (iii) reduced palmitic acid-induced PPAR alpha co-immunoprecipitation with coactivator SRC-1 concomitant with increased PPAR alpha. co-immunoprecipitation with coinhibitor N-CoR; (iv) reduced palmitic acid-induced PPAR alpha. Diminished PPAR alpha. activation in L-FABP null hepatocytes was associated with lower uptake of common dietary LCFA (palmitic acid as well as its fluorescent derivative BODIPY FL C-16), reduced level of total unesterified LCFA, and real-time redistribution of BODIPY FL C-16 from the central nucleoplasm to the nuclear envelope. Taken together, these studies support the hypothesis that L-FABP may facilitate ligand (LCFA)-activated PPAR alpha transcriptional activity at least in part by increasing total LCFA ligand available to PPAR alpha for inducing PPAR alpha-mediated transcription of proteins involved in LCFA metabolism. (C) 2009 EIsevier Inc. All rights reserved.