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

FASEB J. 2018 Jan;32(1):37-51. Epub 2017 Aug 25
Xiaojuan Wang 1 , Xiang Zhang 1 , Eagle S H Chu 1 , Xiaoting Chen 2 , Wei Kang 3 , Feng Wu 3 , Ka-Fai To 3 , Vincent W S Wong 1 , Henry L Y Chan 1 , Matthew T V Chan 2 , Joseph J Y Sung 1 , William K K Wu 2 , Jun Yu 4
Xiaojuan Wang 1 , Xiang Zhang 1 , Eagle S H Chu 1 , Xiaoting Chen 2 , Wei Kang 3 , Feng Wu 3 , Ka-Fai To 3 , Vincent W S Wong 1 , Henry L Y Chan 1 , Matthew T V Chan 2 , Joseph J Y Sung 1 , William K K Wu 2 , Jun Yu 4
+ et al

[No authors listed]

Author information
  • 1 Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
  • 2 Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China; and.
  • 3 Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
  • 4 Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China; junyu@cuhk.edu.hk.

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.-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

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