title: MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis.
abstract: 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-κB 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.
authors: From the College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio 44272.|the Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China, and.
authors: Xudong
authors: X
authors: Hu
authors: From the College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio 44272.
authors: Alvin
authors: A
authors: Jogasuria
authors: From the College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio 44272.
authors: Jiayou
authors: J
authors: Wang
authors: From the College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio 44272.
authors: Chunki
authors: C
authors: Kim
authors: From the College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio 44272.
authors: Yoonhee
authors: Y
authors: Han
authors: From the College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio 44272.|the Department of Liver Diseases, Guangdong Hospital of Traditional Chinese Medicine in Zhuhai, Zhuhai 519015, China.
authors: Hong
authors: H
authors: Shen
authors: From the College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio 44272.
authors: Jiashin
authors: J
authors: Wu
authors: From the College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio 44272, myou@neomed.edu.
authors: Min
authors: M
authors: You
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005235:Fatty Liver, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D033862:Iron-Binding Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D033862:Iron-Binding Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; C108526:fibroblast growth factor 15, mouse; C519501:mitoNEET protein, mouse; D005346:Fibroblast Growth Factors; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: adiponectin; alcohol; intestine; iron; liver injury