Transactivation of the Peroxisome Proliferator-Activated Receptor Is Differentially Modulated by Hepatocyte Nuclear factor-4

Gene Expr. 1994;4(1-2):53-62.

Abstract

Peroxisome proliferator-activated receptors (PPARs) stimulate the expression of several genes involved in lipid metabolism by binding to specific cis-acting peroxisome proliferator-responsive elements (PPREs) via cooper-ativity with retinoid X receptors. We demonstrate here that hepatocyte nuclear factor-4 (HNF-4), another member of the nuclear hormone receptor superfamily, bound with differing affinities to the PPREs from the genes encoding rat acyl-CoA oxidase and hydratase-dehydrogenase, the first two enzymes of the peroxisomal beta-oxidation pathway. In cotransfection assays, HNF-4 repressed rat PPAR-dependent activation of a reporter gene linked to the acyl-CoA oxidase PPRE, either in the absence or presence of the peroxisome proliferator, Wy-14,643. Rat PPAR-dependent activation of a reporter gene linked to the hydratase-dehydrogenase PPRE was less efficiently repressed by HNF-4 in the absence of Wy-14,643 than was activation from the acyl-CoA oxidase PPRE. However, in the presence of Wy-14,643, HNF-4 functioned cooperatively with PPAR to significantly enhanced induction from the hydratase-dehydrogenase PPRE. These results suggest that the genes encoding the first two enzymes of the peroxisomal beta-oxidation pathway are subject to differential regulation by the interplay of multiple members of the steroid/nuclear hormone receptor superfamily, mitigated in part by the structures of the PPREs and by the presence of activators of PPARs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Oxidase
  • Animals
  • Base Sequence
  • DNA Probes
  • DNA-Binding Proteins*
  • Hepatocyte Nuclear Factor 4
  • Microbodies / drug effects
  • Molecular Sequence Data
  • Oxidoreductases / metabolism
  • Phosphoproteins*
  • Pyrimidines / pharmacology
  • Rats
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transcriptional Activation*

Substances

  • DNA Probes
  • DNA-Binding Proteins
  • Hepatocyte Nuclear Factor 4
  • Phosphoproteins
  • Pyrimidines
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • pirinixic acid
  • Oxidoreductases
  • Acyl-CoA Oxidase