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<a href="http://doi.org/10.1074/jbc.M116.737015" target="_blank" rel="noreferrer noopener">http://doi.org/10.1074/jbc.M116.737015</a>
Pages
22482–22495
Issue
43
Volume
291
Dublin Core
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Title
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MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis.
Publisher
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The Journal of biological chemistry
Date
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2016
2016-10
Subject
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*adiponectin; *alcohol; *intestine; *iron; *liver injury; *Signal Transduction; Adiponectin/genetics/*metabolism; Alcoholic/genetics/*metabolism/pathology; Animals; Fatty Liver; Fibroblast Growth Factors/genetics/*metabolism; Humans; Iron-Binding Proteins/metabolism; Knockout; Male; Membrane Proteins/*deficiency/metabolism; Mice; NF-kappa B/genetics/metabolism; Sirtuin 1/genetics/metabolism
Creator
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Hu Xudong; Jogasuria Alvin; Wang Jiayou; Kim Chunki; Han Yoonhee; Shen Hong; Wu Jiashin; You Min
Description
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MitoNEET (mNT) (CDGSH iron-sulfur domain-containing protein 1 or CISD1) is an outer mitochondrial membrane protein that donates 2Fe-2S clusters to apo-acceptor proteins. In the present study, using a global mNT knock-out (mNTKO) mouse model, we investigated the in vivo functional role of mNT in the development of alcoholic steatohepatitis. Experimental alcoholic steatohepatitis was achieved by pair feeding wild-type (WT) and mNTKO mice with Lieber-DeCarli ethanol-containing diets for 4 weeks. Strikingly, chronically ethanol-fed mNTKO mice were completely resistant to ethanol-induced steatohepatitis as revealed by dramatically reduced hepatic triglycerides, decreased hepatic cholesterol level, diminished liver inflammatory response, and normalized serum ALT levels. Mechanistic studies demonstrated that ethanol administration to mNTKO mice induced two pivotal endocrine hormones, namely, adipose-derived adiponectin and gut-derived fibroblast growth factor 15 (Fgf15). The elevation in circulating levels of adiponectin and Fgf15 led to normalized hepatic and serum levels of bile acids, limited hepatic accumulation of toxic bile, attenuated inflammation, and amelioration of liver injury in the ethanol-fed mNTKO mice. Other potential mechanisms such as reduced oxidative stress, activated Sirt1 signaling, and diminished NF-kappaB activity also contribute to hepatic improvement in the ethanol-fed mNTKO mice. In conclusion, the present study identified adiponectin and Fgf15 as pivotal adipose-gut-liver metabolic coordinators in mediating the protective action of mNT deficiency against development of alcoholic steatohepatitis in mice. Our findings may help to establish mNT as a novel therapeutic target and pharmacological inhibition of mNT may be beneficial for the prevention and treatment of human alcoholic steatohepatitis.
Identifier
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<a href="http://doi.org/10.1074/jbc.M116.737015" target="_blank" rel="noreferrer noopener">10.1074/jbc.M116.737015</a>
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
*adiponectin
*alcohol
*intestine
*iron
*liver injury
*Signal Transduction
2016
Adiponectin/genetics/*metabolism
Alcoholic/genetics/*metabolism/pathology
Animals
Department of Pharmaceutical Sciences
Fatty Liver
Fibroblast Growth Factors/genetics/*metabolism
Han Yoonhee
Hu Xudong
Humans
Iron-Binding Proteins/metabolism
Jogasuria Alvin
Kim Chunki
Knockout
Male
Membrane Proteins/*deficiency/metabolism
Mice
NEOMED College of Pharmacy
NF-kappa B/genetics/metabolism
Shen Hong
Sirtuin 1/genetics/metabolism
The Journal of biological chemistry
Wang Jiayou
Wu Jiashin
You Min