Thioesterase activity and acyl-CoA/fatty acid cross-talk of hepatocyte nuclear factor-4{alpha}

J Biol Chem. 2005 Jul 1;280(26):24451-61. doi: 10.1074/jbc.M500732200. Epub 2005 May 3.

Abstract

Hepatocyte nuclear factor-4alpha (HNF-4alpha) activity is modulated by natural and xenobiotic fatty acid and fatty acyl-CoA ligands as a function of their chain length, unsaturation, and substitutions. The acyl-CoA site of HNF-4alpha is reported here to consist of the E-F domain, to bind long-chain acyl-CoAs but not the respective free acids, and to catalyze the hydrolysis of bound fatty acyl-CoAs. The free acid pocket, previously reported in the x-ray structure of HNF-4alpha E-domain, entraps fatty acids but excludes acyl-CoAs. The acyl-CoA and free acid sites are distinctive and noncongruent. Free fatty acid products of HNF-4alpha thioesterase may exchange with free acids entrapped in the fatty acid pocket of HNF-4alpha. Cross-talk between the acyl-CoA and free fatty acid binding sites is abrogated by high affinity, nonhydrolyzable acyl-CoA ligands of HNF-4alpha that inhibit its thioesterase activity. Hence, HNF-4alpha transcriptional activity is controlled by its two interrelated acyl ligands and two binding sites interphased in tandem by the thioesterase activity. The acyl-CoA/free-acid and receptor/enzyme duality of HNF-4alpha extends the paradigm of nuclear receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / metabolism*
  • Animals
  • Binding Sites
  • Boron Compounds / pharmacology
  • COS Cells
  • Cell Nucleus / metabolism
  • Crystallography, X-Ray
  • DNA, Complementary / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Fatty Acids / chemistry
  • Fatty Acids / metabolism*
  • Fluorescent Dyes / pharmacology
  • Hepatocyte Nuclear Factor 4
  • Kinetics
  • Ligands
  • Models, Biological
  • Phosphoproteins / metabolism*
  • Plasmids / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Rats
  • Recombinant Proteins / chemistry
  • Substrate Specificity
  • Thiolester Hydrolases / chemistry
  • Thiolester Hydrolases / metabolism*
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transfection
  • Triazenes / pharmacology

Substances

  • 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene
  • Acyl Coenzyme A
  • Boron Compounds
  • DNA, Complementary
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Fatty Acids
  • Fluorescent Dyes
  • Hepatocyte Nuclear Factor 4
  • Ligands
  • Phosphoproteins
  • Recombinant Proteins
  • Transcription Factors
  • Triazenes
  • triacsin C
  • Thiolester Hydrolases