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

• 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.

• 作者：

  Xiaojuan Wang    Xiang Zhang    Eagle Chu    Chen Xiaoting    Wei Kang    Wu Feng    Kafai To    Wong Vincent W.S.    Henry lik yuen Chan    Matthew Chan    沈祖堯     William ka kei Wu    Jun Yu   

• 刊名：

  FASEB Journal

• 在线出版时间：

  2018