title: Beneficial effects of mineralocorticoid receptor blockade in experimental non-alcoholic steatohepatitis.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Margarita
authors: M
authors: Pizarro
authors: Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Nancy
authors: N
authors: Solís
authors: Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Pablo
authors: P
authors: Quintero
authors: Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Francisco
authors: F
authors: Barrera
authors: Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.|Departamento de Ciencias Químico-Biológicas, Universidad Bernardo O Higgins, Santiago, Chile.
authors: Daniel
authors: D
authors: Cabrera
authors: Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Pamela
authors: P
authors: Rojas-de Santiago
authors: Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Juan P
authors: JP
authors: Arab
authors: Departamento de Salud Pública, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Oslando
authors: O
authors: Padilla
authors: Departamento de Patología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Juan C
authors: JC
authors: Roa
authors: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Han
authors: H
authors: Moshage
authors: Department of Pediatrics, University of California, San Diego, CA, USA.
authors: Alexander
authors: A
authors: Wree
authors: Department of Pediatrics, University of California, San Diego, CA, USA.
authors: Eugenia
authors: E
authors: Inzaugarat
authors: Department of Pediatrics, University of California, San Diego, CA, USA.
authors: Ariel E
authors: AE
authors: Feldstein
authors: Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Carlos E
authors: CE
authors: Fardella
authors: Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Rene
authors: R
authors: Baudrand
authors: Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Arnoldo
authors: A
authors: Riquelme
authors: Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Marco
authors: M
authors: Arrese
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D004195:Disease Models, Animal; D000077545:Eplerenone; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy*; D018384:Oxidative Stress / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D015415:Biomarkers; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000077545:Eplerenone
keywords: NASH; fatty liver; fibrosis; inflammation; steatohepatitis
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