Lipopolysaccharide Results in a Marked Decrease in Hepatocyte Nuclear Factor 4 in Rat Liver

The acute-phase response can result in decreased liverspecific 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 (HNF-4 ), in livers of rats. HNF-4 is a nuclear receptor that is critical for the expression of several liver-specific genes. This decrease in HNF-4 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 , HNF-1 , was reduced. Interleukin-1 (IL-1 ) is a cytokine whose levels are increased in vivo in response to LPS. IL-1 resulted in a decrease in HNF-4 levels in HepG2 cells. This IL-1 –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 that occurs in vivo after the administration of LPS may be the result of IL-1 –induced degradation, and likely contributes to the liver insufficiency that occurs. IL-1 antagonists or proteasome inhibitors might increase HNF-4 protein levels in the acute-phase response, which could result in increased liver function and survival. (HEPATOLOGY 2001;34:979-989.)