Losartan reduces liver expression of plasminogen activator inhibitor-1 (PAI-1) in a high fat-induced rat nonalcoholic fatty liver disease model.
OBJECTIVE
To evaluate the effect of losartan-an angiotensin II type 1 receptor (AT1R) antagonist- and telmisartan-an AT1R blocker with insulin-sensitizing properties-, on the hepatic expression of plasminogen activator inhibitor-1 (PAI-1) in a rat model of nonalcoholic fatty liver disease (NAFLD).


METHODS
Rats were given a high-fat diet (HFD) for 8 weeks and after this period were randomly divided into 3 groups. For 12 weeks along with the same access to HFD, one group (9 rats) received losartan and another group received telmisartan (10 rats), both at 10mg/kg intraperitoneally (ip) every 24h. The third group (8 rats) received saline ip along with the HFD. Finally, a control group (6 rats) was fed with standard chow diet for 20 weeks.


RESULTS
Fatty liver was reverted by both losartan and telmisartan. Both drugs had beneficial effects on insulin resistance, reaching statistical significance in telmisartan group. Expression of hepatic mRNA of PAI-1 showed a 42% decrease in losartan-treated rats in comparison with both HFD group and telmisartan-treated rats. To further evaluate this differential effect on PAI-1 expression, we explored the effect of the drugs on liver expression of TNFalpha, PEPCK-C and PPARalpha, and no significant differences were observed.


CONCLUSIONS
These results indicate that AT1R blockers could be eligible drugs for reducing hepatic lipid accumulation in patients with NAFLD. However, only 12 weeks of losartan treatment strongly reduced hepatic PAI-1 gene expression. These differences could provide even more effective options for preventing fatty liver disease and its cardiovascular complications.
Rosselli
Maria Soledad
MS
Laboratory of Clinical and Molecular Hepatology, Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research, University of Buenos Aires-CONICET, Ciudad Autónoma de Buenos Aires, Argentina.
Burgueño
Adriana L
AL
Carabelli
Julieta
J
Schuman
Mariano
M
Pirola
Carlos J
CJ
Sookoian
Silvia
S
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use; D001565:Benzoates / Q000627:therapeutic use; D004041:Dietary Fats / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D047493:PPAR alpha / Q000235:genetics; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077333:Telmisartan; D014280:Triglycerides / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D004041:Dietary Fats; D047493:PPAR alpha; D017395:Plasminogen Activator Inhibitor 1; D014280:Triglycerides; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D019808:Losartan; D000077333:Telmisartan