Losartan, an angiotensin-II type 1 receptor blocker, attenuates the liver fibrosis development of non-alcoholic steatohepatitis in the rat
© Yoshiji et al; licensee BioMed Central Ltd. 2009
Received: 10 February 2009
Accepted: 05 May 2009
Published: 05 May 2009
Apart from simple steatosis, the non-alcoholic steatohepatitis (NASH) can progress into liver fibrosis and cirrhosis. To date, however, no widely accepted therapeutic modalities have been established against NASH in the clinical practice. To find out promising new therapeutic agents, it is important to employ an appropriate experimental model of NASH, such as association with insulin resistance.
In the current study, we found that losartan, a clinically used angiotensin-II type 1 receptor blocker, significantly attenuated a choline-deficient L-amino acid-defined (CDAA) diet-induced steatohepatitis in obese diabetic- and insulin resistance-associated Otsuka Long-Evans Tokushima Fatty (OLETF) rats. The transforming growth factor-beta, a well-known major fibrogenic cytokine, was also suppressed in a similar magnitude to that of the fibrosis area. Noteworthy was the finding that these inhibitory effects were achieved even at a clinically comparable low dose.
Since losartan is widely used without serious side effects in the clinical practice, this agent may be an effective new therapeutic strategy against NASH.
The spectrum of non-alcoholic fatty liver diseases (NAFLD) ranges from simple steatosis to cirrhosis. Whereas simple steatosis seems to be a benign and non-progressive condition, non-alcoholic steatohepatitis (NASH) is recognized as a potentially progressive disease that may cause cirrhosis, an end-stage liver disease, and hepatocellular carcinoma (HCC) [1, 2]. The patients with NAFLD frequently have many clinical complications, such as obesity, type 2 diabetes mellitus, and insulin resistance . While sustained weight loss should be very effective to improve NAFLD, it is somewhat difficult for many patients to change their life style. Accordingly, efforts are currently directed worldwide at overcoming NAFLD, especially NASH. Since insulin resistance is nearly universal in the patients with NASH, and it plays a pivotal role in the pathogenesis of NASH, many studies attempted to employ insulin sensitizer as a therapeutic modality against NASH. Although pioglitazone, a selective peroxisome proliferator-activated receptor gamma agonist, has shown some beneficial effects in the patients with NASH , there are still several unsolved questions. Since a long-term treatment is required to maintain the therapeutic benefits, the long-term safety of these drugs in the patients with chronic liver diseases should be proven. Another member of thiazolidinedione (TZD) class; namely, triglitazone caused fulminant hepatitis in several patients. Moreover, recent studies have questioned the long-term safety of TZD, especially rosiglitazone. Furthermore, it has been reported that TZD alone without lifestyle alternation may not achieve the anticipated clinical benefit . Collectively, some time may be still required until the common application of TZD, including pioglitazone, for the treatment of NASH in the clinical practice.
Effect of Losartan on several markers of the OLETF rats
Body weight (g)
671.3 ± 35.2
662 ± 41.1
Liver weight (g)
25.8 ± 4.3
22.4 ± 4.0
271.3 ± 41.0
262.0 ± 36.8
128.0 ± 10.4
117.2 ± 9.6
102.4 ± 17.8
96.7 ± 16.6
Total bilirubin (mg/dl)
0.11 ± 0.07
0.14 ± 0.08
Total cholesterol (nmol/l)
1.04 ± 0.12
0.93 ± 0.11
TGF-β (ng/mg liver)
56.6 ± 14.3
34.3 ± 10.1*
Noteworthy was the finding that this inhibitory effect was achieved even at a clinically comparable low dose. Since losartan is widely used in the clinical practice without serious side effects, this agent may be an alternative therapeutic agent against NASH. Actually, a pilot study has shown that ARB may exert beneficial effects in the patients with NASH . A large-scale prospective randomized clinical trial is required in the future.
Banyu Pharmaceutical Co., Ltd (Tokyo, Japan) generously supplied the losartan.
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