Enhanced synthesis and reduced metabolism of endothelin-1 (ET-1) by hepatocytes--an important mechanism of increased endogenous levels of ET-1 in liver cirrhosis

J Hepatol. 2000 Nov;33(5):725-32. doi: 10.1016/s0168-8278(00)80302-5.


Background/aims: Hepatic concentration of endothelin-1 (ET-1) is increased in human and experimental liver cirrhosis. Because of its potent actions in the liver, ET-1 has been suggested to play an important role in the pathophysiology of cirrhosis. Since hepatocytes are the major cell type to metabolize ET-1, we investigated whether their reduced capacity to degrade ET-1 is a mechanism of its elevated levels in cirrhosis.

Methods: The expression of ET-1 receptors, ET-1 and endothelin converting enzyme (ECE), and metabolism of ET-1 and ECE activity were compared in hepatocytes isolated from control and carbon tetrachloride-induced cirrhotic rats.

Results: ET-1 receptor density and receptor-mediated internalization of ET-1 were significantly increased in cirrhotic hepatocytes relative to the control cells. However, compared to control hepatocytes, metabolism of ET-1 by the cirrhotic cells was reduced significantly. Interestingly, hepatocytes were found to contain preproET-1 mRNA, ECE-1 mRNA and ET-1. PreproET-1 mRNA and ET-1 levels were increased in cirrhotic hepatocytes but their ECE mRNA and ECE activity were not altered.

Conclusions: These results provide the first evidence that hepatocytes have the ability to synthesize ET-1 and demonstrate that decreased metabolism and enhanced synthesis, of ET-1 in hepatocytes are an important mechanism of its elevated levels in cirrhosis.

Publication types

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

MeSH terms

  • Animals
  • Aspartic Acid Endopeptidases / metabolism
  • Cells, Cultured
  • Endothelin-1 / metabolism*
  • Endothelin-Converting Enzymes
  • Hepatocytes / metabolism*
  • Liver Cirrhosis / metabolism*
  • Male
  • Metalloendopeptidases
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A
  • Receptors, Endothelin / analysis


  • Endothelin-1
  • Receptor, Endothelin A
  • Receptors, Endothelin
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • ECE1 protein, human
  • Endothelin-Converting Enzymes