PMID- 24129399
OWN - NLM
STAT- MEDLINE
DCOM- 20140212
LR  - 20181202
IS  - 1522-1555 (Electronic)
IS  - 0193-1849 (Linking)
VI  - 305
IP  - 11
DP  - 2013 Dec 1
TI  - Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in 
      liver-specific SREBP-1c Tg mice fed high-fat and high-fructose diet.
PG  - E1415-25
LID - 10.1152/ajpendo.00419.2013 [doi]
AB  - 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 TNFalpha 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.
FAU - Wada, Tsutomu
AU  - Wada T
AD  - Department of Clinical Pharmacology and.
FAU - Miyashita, Yusuke
AU  - Miyashita Y
FAU - Sasaki, Motohiro
AU  - Sasaki M
FAU - Aruga, Yusuke
AU  - Aruga Y
FAU - Nakamura, Yuto
AU  - Nakamura Y
FAU - Ishii, Yoko
AU  - Ishii Y
FAU - Sasahara, Masakiyo
AU  - Sasahara M
FAU - Kanasaki, Keizo
AU  - Kanasaki K
FAU - Kitada, Munehiro
AU  - Kitada M
FAU - Koya, Daisuke
AU  - Koya D
FAU - Shimano, Hitoshi
AU  - Shimano H
FAU - Tsuneki, Hiroshi
AU  - Tsuneki H
FAU - Sasaoka, Toshiyasu
AU  - Sasaoka T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131015
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Dietary Carbohydrates)
RN  - 0 (Mineralocorticoid Receptor Antagonists)
RN  - 0 (Srebf1 protein, mouse)
RN  - 0 (Sterol Regulatory Element Binding Protein 1)
RN  - 27O7W4T232 (Spironolactone)
RN  - 30237-26-4 (Fructose)
RN  - 6995V82D0B (Eplerenone)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Diet, High-Fat/adverse effects
MH  - Dietary Carbohydrates/administration & dosage
MH  - Eplerenone
MH  - Fatty Liver/etiology/*prevention & control
MH  - Fructose/administration & dosage
MH  - Liver/metabolism/pathology
MH  - Male
MH  - Metabolic Syndrome/complications/*drug therapy
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Mineralocorticoid Receptor Antagonists/*administration & dosage
MH  - Non-alcoholic Fatty Liver Disease
MH  - Phenotype
MH  - Rats
MH  - Rats, Wistar
MH  - Spironolactone/administration & dosage/*analogs & derivatives
MH  - Sterol Regulatory Element Binding Protein 1/*genetics
OTO - NOTNLM
OT  - Kupffer cells
OT  - eplerenone
OT  - inflammation
OT  - nonalcoholic steatohepatitis
OT  - sterol response element-binding protein-1c
OT  - transgenic
EDAT- 2013/10/17 06:00
MHDA- 2014/02/13 06:00
CRDT- 2013/10/17 06:00
PHST- 2013/10/17 06:00 [entrez]
PHST- 2013/10/17 06:00 [pubmed]
PHST- 2014/02/13 06:00 [medline]
AID - ajpendo.00419.2013 [pii]
AID - 10.1152/ajpendo.00419.2013 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2013 Dec 1;305(11):E1415-25. doi: 
      10.1152/ajpendo.00419.2013. Epub 2013 Oct 15.