A Novel Role of Astrocyte Elevated Gene-1 (AEG-1) in Regulating Nonalcoholic Steatohepatitis (NASH)

作者：Srivastava Jyoti; Robertson Chadia L; Ebeid Kareem; Dozmorov Mikhail; Rajasekaran Devaraja; Mendoza Rachel; Siddiq Ayesha; Akiel Maaged A; Jariwala Nidhi; Shen Xue Ning; Windle Jolene J; Subler Mark A; Mukhopadhyay Nitai D; Giashuddin Shah; Ghosh Shobha; Lai Zhao; Chen Yidong; Fisher Paul B; Salem Aliasger K; Sanyal Arun J; Sarkar Devanand^*

来源：Hepatology, 2017, 66(2): 466-480.

DOI：10.1002/hep.29230

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(Delta HEP)). Alb/AEG-1 mice developed spontaneous NASH whereas AEG-1(Delta HEP) 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 beta-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. Conclusion: 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.

• 出版日期2017-8