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. Aim To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH. Methods C57bl6 mice were fed a choline-deficient-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 identifies eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted

The selective mineralocorticoid receptor antagonist eplerenone prevents decompensation of the liver in cirrhosis

“…Our data are in accordance with previous findings in a model of fatty liver disease and in hepatocellular carcinomas. In both studies, the expression of the MR was also decreased in hepatocytes and in HCC tumour tissue (Nie et al ., ; Pizarro et al ., ). We conclude that hypoxia induces activation of the MR, translocation into the nucleus, increased transcriptional activity and subsequent degradation.…”

“…Until now, not much attention has been given to the possible role of MR in cirrhosis, although the MR is expressed in the liver (Pizarro et al ., ; Paillard et al ., ), and the RAAS in cirrhosis is dysregulated (Kuiper et al ., ). In cirrhosis, portal hypertension leads to splanchnic and systemic vasodilatation and subsequent arterial hypotension inducing a compensatory activation of the RAAS with increased levels of renin, angiotensin II and aldosterone in blood plasma and ascites (Kuiper et al ., ; Tandon et al ., ).…”

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…In addition, spironolactone may be beneficial for the cardiovascular function of these patients (Ito et al, 2014). MR activation may be involved in liver fibrosis, as inferred from the beneficial effect of MRA in mice with nonalcoholic steatohepatitis (Pizarro et al, 2015). Spironolactone was also shown to limit skin (dermal) fibrosis (Mitts et al, 2010).…”

Unanticipated increases in hepatic steatosis among human immunodeficiency virus patients receiving mineralocorticoid receptor antagonist eplerenone for non‐alcoholic fatty liver disease

“…This model also demonstrated decreased levels of triglycerides and glucose, whereas our study showed no improvements in either parameter. Pizarro et al showed significantly lower steatosis and fibrosis scores in mice treated with eplerenone compared to controls. In contrast, the 2 participants in our study who had liver biopsies demonstrated worsening steatosis scores and no change in fibrosis after 24 weeks on eplerenone.…”

“…Additional murine studies have shown decreased hepatic fat, reduced inflammation or improved insulin resistance after treatment using an MR antagonist to block aldosterone binding. [12][13][14] While rodent models suggest a physiological role for MR blockade with eplerenone to improve metabolic parameters and hepatic steatosis, the benefits of this approach in humans remain to be determined. We therefore examined the effects of the MR antagonist eplerenone on hepatic and cardiac steatosis in HIV-infected adults with hepatic steatosis and abdominal fat accumulation.…”