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Mechanisms of regulation of liver fatty acid-binding protein

  • Cellular Fatty Acid-Binding Proteins II
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Abstract

Liver fatty acid-binding protein (L-FABP) expression is modulated by developmental, hormonal, dietary, and pharmacological factors. The most pronounced induction is seen after treatment with peroxisome proliferators, which induce L-FABP coordinately with microsomal cytochrome P-450 4A1 and the enzymes of peroxisomal fatty acid β-oxidation. These effects of peroxisome proliferators may be mediated by a receptor which has been shown to be activated by peroxisome proliferators in mammalian cell transfection studies. However, the peroxisome proliferators tested thus far do not bind to this receptor, known as the peroxisome proliferator-activated receptor (PPAR), and its endogenous ligand(s) also remain unknown. Peroxisome proliferators inhibit mitochondrial β-oxidation, and one hypothesis is that the dicarboxylic fatty acid metabolites of accumulated LCFA, formed via the P-450 4A1 ω-oxidation pathway, serve as primary inducers of L-FABP and peroxisomal β-oxidation. We have tested this hypothesis in primary hepatocyte cultures exposed to clofibrate (CF). Inhibition of P-450 4A1 markedly diminished, via a pre-translational mechanism, the CF induction of L-FABP and peroxisomal β-oxidation. In further experiments, long-chain dicarboxylic acids, the final products of the P-450 4A1 ω-oxidation pathway, but not LCFA, induced L-FABP and peroxisomal β-oxidation pre-translationally. These results suggest a role, in part, for long-chain dicarboxylic acids in mediating the peroxisome proliferator induction of L-FABP and peroxisomal β-oxidation. We also found that LCFA, which undergo rapid hepatocellular metabolism, could become inducers of L-FABP and peroxisomal β-oxidation under conditions where their metabolism was inhibited. The role of the PPAR in mediating these effects is unknown, but clearly warrants further study. The induction of L-FABP and peroxisomal β-oxidation by LCFA and/or their ω-oxidized metabolites may provide a means for limiting the deleterious effects of increased intracellular concentrations of free LCFA, and thus act as an important hepatocellular adaptation to impairment or overload of mitochondrial LCFA oxidation.

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Authors and Affiliations

  1. Department of Medicine, University of California, 94143-0538, San Francisco, California, USA

    Raja M. Kaikaus & Nathan M. Bass

  2. Department of Pharmaceutical Chemistry, University of California, 94143-0538, San Francisco, California, USA

    William K. Chan & Paul R. Ortiz de Montellano

  3. Liver Center, University of California, 3rd. & Parnassus Avenues, Box 0538, 94143-0538, San Francisco, California, USA

    Raja M. Kaikaus, Paul R. Ortiz de Montellano & Nathan M. Bass

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  1. Raja M. Kaikaus
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  3. Paul R. Ortiz de Montellano
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  4. Nathan M. Bass
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Kaikaus, R.M., Chan, W.K., de Montellano, P.R.O. et al. Mechanisms of regulation of liver fatty acid-binding protein. Mol Cell Biochem 123, 93–100 (1993). https://doi.org/10.1007/BF01076479

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