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

Abstract

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.

• Authors: B Wang, S R Cai, C Gao, F M Sladek, K P Ponder
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 34 Issue 5 Pg. 979-89 (Nov 2001) ISSN: 0270-9139 [Print] United States
• PMID: 11679969 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

• 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, genetics, metabolism)
• Protein Isoforms (antagonists & inhibitors)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Repetitive Sequences, Nucleic Acid
• Tissue Distribution
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Tumor Cells, Cultured