Effect of losartan on early liver fibrosis development in a rat model of nonalcoholic steatohepatitis.
OBJECTIVE
Nonalcoholic steatohepatitis (NASH) is a metabolic disorder of the liver that may evolve into fibrosis or cirrhosis. Recent studies have shown reduction of experimental liver fibrosis with the use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor antagonists. The aim of this study was to determine whether losartan can influence the early phase of fibrogenesis in an animal model of NASH.


METHODS
To induce NASH, a choline-deficient diet (CDD) was given to Sprague-Dawley rats for 12 weeks. These animals were then compared with a control group receiving choline-supplemented diet (CSD) and a group fed a CDD plus losartan (10 mg/kg/day). Biochemical (serum levels of alanine aminotransferase and aspartate aminotransferase) and histological evaluation of fatty liver was performed by conventional techniques. Hydroxyproline content in liver tissue was assayed by spectrophotometry. In addition, mRNA levels of procollagen I and transforming growth factor (TGF)-beta were assessed by semiquantitative RT-PCR and stellate cell activation by alpha-actin immunofluorescence stain.


RESULTS
After 12 weeks CDD induced a marked elevation of serum aminotranferases, a severe fatty liver infiltration with mild histological inflammation and fibrosis. These findings correlated with a significant increase in mRNA levels of both procollagen I and TGF-beta and significant increased liver hydroxyproline content. No differences were seen between rats receiving CDD alone and rats receiving CDD plus losartan with regard to the biochemical, morphological or molecular alterations induced by the CDD.


CONCLUSIONS
Losartan does not seem to influence liver injury and fibrogenic events in the CDD model of NASH.
Ibañez
Patricio
P
Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Solis
Nancy
N
Pizarro
Margarita
M
Aguayo
Gloria
G
Duarte
Ignacio
I
Miquel
Juan Francisco
JF
Accatino
Luigi
L
Arrese
Marco
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D002796:Choline Deficiency; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications / Q000188:drug therapy*; D006909:Hydroxyproline / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000517:prevention & control*; D008111:Liver Function Tests; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan; D006909:Hydroxyproline