title: Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in liver-specific SREBP-1c Tg mice fed high-fat and high-fructose diet.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology and.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Wada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Miyashita
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sasaki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Aruga
authors.forename: Yuto
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishii
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sasahara
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kitada
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuneki
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sasaoka
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D000077545:Eplerenone; D005234:Fatty Liver / Q000209:etiology / Q000517:prevention & control*; D005632:Fructose / Q000008:administration & dosage; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D065626:Non-alcoholic Fatty Liver Disease; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*
chemical_list: D004040:Dietary Carbohydrates; D000451:Mineralocorticoid Receptor Antagonists; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D013148:Spironolactone; D005632:Fructose; D000077545:Eplerenone
keywords: Kupffer cells; eplerenone; inflammation; nonalcoholic steatohepatitis; sterol response element-binding protein-1c; transgenic