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

FASEB J. 2018 Jan;32(1):37-51. doi: 10.1096/fj.201601393R. Epub 2017 Aug 25.


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.-Wang, X., Zhang, X., Chu, E. S. H., Chen, X., Kang, W., Wu, F., To, K.-F., Wong, V. W. S., Chan, H. L. Y., Chan, M. T. V., Sung, J. J. Y., Wu, W. K. K., Yu, J. Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis.

Keywords: NAFLD; asparagine synthetase; autophagy; lysosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Aspartate-Ammonia Ligase / deficiency
  • Aspartate-Ammonia Ligase / genetics
  • Aspartate-Ammonia Ligase / metabolism
  • Autophagosomes / metabolism*
  • Autophagy
  • Biomarkers / metabolism
  • Calcium / metabolism
  • Case-Control Studies
  • Cell Line
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress
  • Female
  • Gene Knockdown Techniques
  • Hep G2 Cells
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Lysosomes / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Microtubule-Associated Proteins / metabolism
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Sequestosome-1 Protein / metabolism


  • Biomarkers
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Aspartate-Ammonia Ligase
  • Calcium