title: 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.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: S R
authors.initials: SR
authors.lastname: Cai
authors.forename: C
authors.initials: C
authors.lastname: Gao
authors.forename: F M
authors.initials: FM
authors.lastname: Sladek
authors.forename: K P
authors.initials: KP
authors.lastname: Ponder
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012091:Repetitive Sequences, Nucleic Acid; D014018:Tissue Distribution; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D007375:Interleukin-1; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D014157:Transcription Factors; D004247:DNA