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- Title
Beneficial effects of mineralocorticoid receptor blockade in experimental non-alcoholic steatohepatitis.
- Authors
Pizarro, Margarita; Solís, Nancy; Quintero, Pablo; Barrera, Francisco; Cabrera, Daniel; Rojas‐de Santiago, Pamela; Arab, Juan P.; Padilla, Oslando; Roa, Juan C.; Moshage, Han; Wree, Alexander; Inzaugarat, Eugenia; Feldstein, Ariel E.; Fardella, Carlos E.; Baudrand, Rene; Riquelme, Arnoldo; Arrese, Marco
- Abstract
Background Therapeutic options to treat Non-alcoholic steatohepatitis ( NASH) are limited. Mineralocorticoid receptor ( MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH. Aim To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH. Methods C57bl6 mice were fed a choline-deficient and amino acid-defined ( CDAA) diet for 22 weeks with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content ( HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic, oxidative stress-associated genes and of MR were also assessed. Results CDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic and oxidative stress-associated genes. Hepatic MR mRNA levels significantly correlated with the expression of pro-inflammatory and pro-fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA-fed animals. Eplerenone administration was associated to a reduction in histological steatosis and attenuation of liver fibrosis development, which was associated to a significant decrease in the expression of collagen-α1, collagen type III, alpha 1 and Matrix metalloproteinase-2. Conclusion The expression of MR correlates with inflammation and fibrosis development in experimental NASH. Specific MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. These data identify eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted.
- Subjects
THERAPEUTICS; FATTY liver; MINERALOCORTICOID receptors; AMINOTRANSFERASES; ANALYSIS of triglycerides; ALDOSTERONE; OXIDATIVE stress; MATRIX metalloproteinases
- Publication
Liver International, 2015, Vol 35, Issue 9, p2129
- ISSN
1478-3223
- Publication type
Article
- DOI
10.1111/liv.12794