Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis
Publication in refereed journal

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摘要Autophagic impairment is implicated in nonalcoholic fatty liver disease (NAFLD), but the molecular mechanism is unclear. We found that autophagic flux was significantly inhibited in 3 murine models of NAFLD. Interestingly, the number of acidic organelles and the level of mature cathepsin D were reduced, suggesting defective lysosome acidification. Asparagine synthetase (ASNS) was induced by endoplasmic reticulum stress, leading to the generation of asparagine, which inhibited lysosome acidification. Both steatotic- and asparagine-treated hepatocytes showed reduced lysosomal acidity and retention of lysosomal calcium. Knockdown of ASNS in steatotic hepatocytes restored autophagic flux. As a potential biomarker, increased serum p62/sequestosome 1 (SQSTM1) level was an independent risk factor for patients with steatosis and lobular inflammation. Impaired autophagy in NAFLD is elicited by defective lysosome acidification, which is caused by ASNS-induced asparagine synthesis under endoplasmic reticulum stress and subsequent retention of lysosomal calcium. p62/SQSTM1 could be used as a noninvasive biomarker in the diagnosis of NAFLD patients.
出版社接受日期14.08.2017
著者Xiaojuan Wang, Xiang Zhang, Eagle S. H. Chu, Xiaoting Chen, Wei Kang, Feng Wu, Ka-Fai To, Vincent W. S. Wong, Henry L. Y. Chan, Matthew T. V. Chan, Joseph J. Y. Sung, William K. K. Wu, Jun Yu
期刊名稱The FASEB Journal
出版年份2018
月份1
卷號32
期次1
頁次37 - 51
國際標準期刊號0892-6638
語言英式英語

上次更新時間 2020-05-08 於 03:20