Lipopolysaccharide results in a marked decrease in hepatocyte nuclear factor 4 alpha in rat liver

Hepatology. 2001 Nov;34(5):979-89. doi: 10.1053/jhep.2001.28885.


The acute-phase response can result in decreased liver-specific functions and death as a result of liver failure. We show here that lipopolysaccharide (LPS), an endotoxin that induces the acute-phase response, results in a marked decrease in the major isoforms of the transcription factor, hepatocyte nuclear factor 4 alpha (HNF-4 alpha), in livers of rats. HNF-4 alpha is a nuclear receptor that is critical for the expression of several liver-specific genes. This decrease in HNF-4 alpha is primarily the result of a posttranscriptional mechanism, because mRNA levels are normal, and there are no major changes in the splicing patterns. This decrease was of functional significance, because expression of a gene that is highly dependent on HNF-4 alpha, HNF-1 alpha, was reduced. Interleukin-1 beta (IL-1 beta) is a cytokine whose levels are increased in vivo in response to LPS. IL-1 beta resulted in a decrease in HNF-4 alpha levels in HepG2 cells. This IL-1 beta-induced decrease was likely caused by degradation via the proteasome, because it was prevented by the addition of the proteasome inhibitor, MG132. We conclude that the decrease in HNF-4 alpha that occurs in vivo after the administration of LPS may be the result of IL-1 beta-induced degradation, and likely contributes to the liver insufficiency that occurs. IL-1 beta antagonists or proteasome inhibitors might increase HNF-4 alpha protein levels in the acute-phase response, which could result in increased liver function and survival.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • DNA / metabolism
  • DNA-Binding Proteins*
  • Hepatocyte Nuclear Factor 4
  • Immunohistochemistry
  • Interleukin-1 / pharmacology
  • Intracellular Membranes / metabolism
  • Lipopolysaccharides / pharmacology*
  • Liver / metabolism*
  • Male
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Isoforms / antagonists & inhibitors
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Repetitive Sequences, Nucleic Acid
  • Tissue Distribution
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured


  • DNA-Binding Proteins
  • Hepatocyte Nuclear Factor 4
  • Interleukin-1
  • Lipopolysaccharides
  • Phosphoproteins
  • Protein Isoforms
  • RNA, Messenger
  • Transcription Factors
  • DNA