eplerenone and Non-alcoholic-Fatty-Liver-Disease

Tissue expansion and chronic inflammation in adipose tissue (AT) are closely related to nonalcoholic steatohepatitis (NASH) pathology. Angiogenesis is initiated by the detachment of pericytes (PCs) from vessels in AT. This process is necessary for the development of AT in obesity. The detachment is caused by excessive platelet-derived growth factor B (PDGF-B) derived from M1-macrophages (Mφ) infiltrating obese AT. On the other hand, AT of tamoxifen-induced systemic PDGF receptor-β knockout mice showed decreased detachment of PCs from vessels in obesity, thereby attenuating hypertrophy of AT mediated by neoangiogenesis, resulting in protection from the development of chronic AT inflammation and systemic insulin resistance. The selective mineralocorticoid receptor (MR) inhibitor eplerenone (Ep) suppresses chronic inflammation in fat and the liver, improves glucose and lipid metabolism, and inhibits body weight and fat mass gain in mice fed a high-fat diet. As a novel mechanism, Ep increases energy expenditure and suppresses fat accumulation, thereby controlling the polarity of visceral AT Mφ from inflammatory M1 to anti-inflammatory M2 dominant. In addition, Ep directly inhibits the activation of signals 1 and 2 of NLRP3-inflammasomes in Mφ, which is an inflammatory mechanism closely involved in the development of NASH. Thus, we propose novel therapeutic approaches to NASH. Inhibition of PDGF receptor-β signaling prevents AT hypertrophy by regulating AT angiogenesis, and MR inhibitors directly suppress chronic inflammation in the AT and liver.

Topics: Adipose Tissue; Animals; Chronic Disease; Eplerenone; Humans; Hypertrophy; Inflammasomes; Inflammation; Macrophages; Mice; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Neovascularization, Pathologic; NLR Family, Pyrin Domain-Containing 3 Protein; Non-alcoholic Fatty Liver Disease; Proto-Oncogene Proteins c-sis; Receptors, Mineralocorticoid

Non-alcoholic fatty liver disease is common in human immunodeficiency virus, but there are no approved therapies. The aim of this open-label proof-of-concept study was to determine the effect of the mineralocorticoid receptor antagonist eplerenone on hepatic fat in human immunodeficiency virus-infected patients with hepatic fat ≥5% by magnetic resonance spectroscopy.. Five subjects received eplerenone (25 mg daily × 1 week followed by 50 mg daily × 23 weeks). Laboratory tests were done at each visit, and the primary endpoint, change in hepatic fat content, was determined by MRI spectroscopy at baseline and week 24.. The study was stopped early after observing unexpected significant increases in hepatic fat at week 24 (mean increase 13.0 ± 7.3%, P = .02). The increases in steatosis were accompanied by a tendency for transaminase values to decrease (alanine aminotransferase mean change -14 ± 16 IU/L, P = .14). There were no consistent changes in other metabolic parameters or blood pressure. Repeat assessment of hepatic steatosis 1-2 months after stopping study medication revealed improvements in steatosis towards baseline values.. The unexpected observation of increased hepatic steatosis with the administration of eplerenone led to early termination of the investigation. While limited because of the small number of participants and the open-label design, this study provides data to suggest that mineralocorticoid receptor antagonism with eplerenone may not be an effective approach to treat hepatic steatosis in human immunodeficiency virus or the general population. Additional research is needed to determine the pathophysiological mechanism behind these unanticipated observations.

Topics: Adult; Alanine Transaminase; Eplerenone; Fatty Liver; Female; HIV Infections; Humans; Liver; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Non-alcoholic Fatty Liver Disease; Proof of Concept Study

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.. To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH.. 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.. 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.. 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.

Topics: Animals; Biomarkers; Disease Models, Animal; Eplerenone; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Receptors, Mineralocorticoid; Spironolactone

Because the renin-angiotensin-aldosterone system has been implicated in the development of insulin resistance and promotion of fibrosis in some tissues, such as the vasculature, we examined the effect of eplerenone, a selective mineralocorticoid receptor (MR) antagonist, on nonalcoholic steatohepatitis (NASH) and metabolic phenotypes in a mouse model reflecting metabolic syndrome in humans. We adopted liver-specific transgenic (Tg) mice overexpressing the active form of sterol response element binding protein-1c (SREBP-1c) fed a high-fat and fructose diet (HFFD) as the animal model in the present study. When wild-type (WT) C57BL/6 and liver-specific SREBP-1c Tg mice grew while being fed HFFD for 12 wk, body weight and epididymal fat weight increased in both groups with an elevation in blood pressure and dyslipidemia. Glucose intolerance and insulin resistance were also observed. Adipose tissue hypertrophy and macrophage infiltration with crown-like structure formation were also noted in mice fed HFFD. Interestingly, the changes noted in both genotypes fed HFFD were significantly ameliorated with eplerenone. HFFD-fed Tg mice exhibited the histological features of NASH in the liver, including macrovesicular steatosis and fibrosis, whereas HFFD-fed WT mice had hepatic steatosis without apparent fibrotic changes. Eplerenone effectively ameliorated these histological abnormalities. Moreover, the direct suppressive effects of eplerenone on lipopolysaccharide-induced TNFα production in the presence and absence of aldosterone were observed in primary-cultured Kupffer cells and bone marrow-derived macrophages. These results indicated that eplerenone prevented the development of NASH and metabolic abnormalities in mice by inhibiting inflammatory responses in both Kupffer cells and macrophages.

Topics: Animals; Cells, Cultured; Diet, High-Fat; Dietary Carbohydrates; Eplerenone; Fatty Liver; Fructose; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Non-alcoholic Fatty Liver Disease; Phenotype; Rats; Rats, Wistar; Spironolactone; Sterol Regulatory Element Binding Protein 1