Journal article
A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH)
Hepatology (Baltimore, Md.), Vol.66(2), pp.466-480
08/2017
DOI: 10.1002/hep.29230
PMCID: PMC5519412
PMID: 28437865
Abstract
Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established, mandating more in-depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of astrocyte elevated gene-1(AEG-1)/metadherin in NASH using a transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) and a conditional hepatocyte-specific AEG-1 knockout mouse (AEG-1
). Alb/AEG-1 mice developed spontaneous NASH whereas AEG-1
mice were protected from high-fat diet (HFD)-induced NASH. Intriguingly, AEG-1 overexpression was observed in livers of NASH patients and wild-type (WT) mice that developed steatosis upon feeding HFD. In-depth molecular analysis unraveled that inhibition of peroxisome proliferator-activated receptor alpha activity resulting in decreased fatty acid β-oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased nuclear factor kappa B-mediated inflammation act in concert to mediate AEG-1-induced NASH. Therapeutically, hepatocyte-specific nanoparticle-delivered AEG-1 small interfering RNA provided marked protection from HFD-induced NASH in WT mice.
AEG-1 might be a key molecule regulating initiation and progression of NASH. AEG-1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. (Hepatology 2017;66:466-480).
Details
- Title: Subtitle
- A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH)
- Creators
- Jyoti Srivastava - Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VAChadia L Robertson - Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VAKareem Ebeid - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IAMikhail Dozmorov - Department of Biostatistics, Virginia Commonwealth University, Richmond, VADevaraja Rajasekaran - Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VARachel Mendoza - Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VAAyesha Siddiq - Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VAMaaged A Akiel - Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VANidhi Jariwala - Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VAXue-Ning Shen - Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VAJolene J Windle - Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VAMark A Subler - Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VANitai D Mukhopadhyay - Department of Biostatistics, Virginia Commonwealth University, Richmond, VAShah Giashuddin - Department of Pathology and Laboratory Medicine, New York Methodist Hospital, Brooklyn, NYShobha Ghosh - Department of Internal Medicine, Virginia Commonwealth University, Richmond, VAZhao Lai - Greehey Children's Cancer Research Institute, San Antonio, TXYidong Chen - Computational Biology and Bioinformatics, University of Texas Health Science Center San Antonio, San Antonio, TXPaul B Fisher - Department of VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VAAliasger K Salem - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IAArun J Sanyal - Department of Internal Medicine, Virginia Commonwealth University, Richmond, VADevanand Sarkar - Department of VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA
- Resource Type
- Journal article
- Publication Details
- Hepatology (Baltimore, Md.), Vol.66(2), pp.466-480
- DOI
- 10.1002/hep.29230
- PMID
- 28437865
- PMCID
- PMC5519412
- NLM abbreviation
- Hepatology
- ISSN
- 0270-9139
- eISSN
- 1527-3350
- Grant note
- T32 DK007150 / NIDDK NIH HHS P30 ES005605 / NIEHS NIH HHS R21 CA183954 / NCI NIH HHS R01 DK107451 / NIDDK NIH HHS R01 CA138540 / NCI NIH HHS P30 CA016059 / NCI NIH HHS
- Language
- English
- Date published
- 08/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering
- Record Identifier
- 9984216673802771
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