Beneficial effects of mineralocorticoid receptor blockade in experimental non-alcoholic steatohepatitis.
Beneficial effects of mineralocorticoid receptor blockade in experimental non-alcoholic steatohepatitis.
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DOI：
10.1111/liv.12794
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Arrese M
中科院分区：
文献类型：
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作者：
Pizarro M;Solís N;Quintero P;Barrera F;Cabrera D;Rojas-de Santiago P;Arab JP;Padilla O;Roa JC;Moshage H;Wree A;Inzaugarat E;Feldstein AE;Fardella CE;Baudrand R;Riquelme A;Arrese M
治疗非酒精性脂肪性肝炎(NASH)的治疗选择有限。盐皮质激素受体(MR)的激活可能在肝纤维化形成中起作用，其调节可能有利于NASH的发生。目的：研究特异性MR拮抗剂依普利酮是否能改善实验性NASH的肝损伤。C57BL6小鼠饲喂胆碱缺乏氨基酸限定(CDAA)饲料22周，同时补充或不补充依普利酮。测定血清转氨酶和醛固酮水平，并对肝脏脂肪变性、炎症和纤维化进行组织学评分。同时检测肝脏甘油三酯含量(HTC)和肝脏促炎症、氧化应激相关基因及MR的mRNA水平。CDAA饮食可有效诱导肝纤维化NASH，增加肝脏促炎、促肝纤维化和氧化应激相关基因的表达。肝脏MR mRNA水平与促炎和促纤维化基因的表达显著相关，在CDAA喂养的动物的肝星状细胞中显著增加。依普利酮治疗可减轻组织学脂肪变性，延缓肝纤维化的发展，这与胶原-α1、III型胶原、α1和基质金属蛋白酶-2的表达显著减少有关。MR的表达与实验性NASH的炎症和纤维化发展密切相关。依普利酮特异性MR阻断具有抗肝脏脂肪变性和抗肝纤维化的作用。这些数据证实依普利酮是治疗NASH的一种潜在的新疗法。考虑到它的安全性和FDA批准的地位，人体试验是有保证的
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-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 identifies eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted