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.
OBJECTIVE
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.
Kuddus
R H
RH
Thomas E. Starzl Transplantation Institute, University of Pittsburgh and Veterans Administration Medical Center, PA 15213, USA.
Nalesnik
M A
MA
Subbotin
V M
VM
Rao
A S
AS
Gandhi
C R
CR
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D022781:Hepatocytes / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000032:analysis
D019332:Endothelin-1; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes