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

The FASEB JournalVolume 32, Issue 1 p. 37-51 ResearchFree to Read Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis Xiaojuan Wang, Xiaojuan Wang 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, Hong Kong, China These authors contributed equally to this work.Search for more papers by this authorXiang Zhang, Xiang Zhang 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, Hong Kong, China These authors contributed equally to this work.Search for more papers by this authorEagle S. H. Chu, Eagle S. H. Chu 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, Hong Kong, ChinaSearch for more papers by this authorXiaoting Chen, Xiaoting Chen Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, ChinaSearch for more papers by this authorWei Kang, Wei Kang Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, ChinaSearch for more papers by this authorFeng Wu, Feng Wu 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, Hong Kong, China Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, ChinaSearch for more papers by this authorKa-Fai To, Ka-Fai To Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, ChinaSearch for more papers by this authorVincent W. S. Wong, Vincent W. S. Wong 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, Hong Kong, ChinaSearch for more papers by this authorHenry L. Y. Chan, Henry L. Y. Chan 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, Hong Kong, ChinaSearch for more papers by this authorMatthew T. V. Chan, Matthew T. V. Chan Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, ChinaSearch for more papers by this authorJoseph J. Y. Sung, Joseph J. Y. Sung 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, Hong Kong, ChinaSearch for more papers by this authorWilliam K. K. Wu, Corresponding Author William K. K. Wu [email protected] 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, Hong Kong, China Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, ChinaCorrespondence: Department of Anesthesia and Intensive Care, Prince of Wales Hospital, The Chinese University of Hong Kong, 04C14, Main Clinical Block and Trauma Centre, Shatin, N.T., Hong Kong. E-mail: [email protected], Correspondence: Department of Medicine and Therapeutics, Institute of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong. E-mail: [email protected]Search for more papers by this authorJun Yu, Corresponding Author Jun Yu [email protected] 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, Hong Kong, ChinaCorrespondence: Department of Anesthesia and Intensive Care, Prince of Wales Hospital, The Chinese University of Hong Kong, 04C14, Main Clinical Block and Trauma Centre, Shatin, N.T., Hong Kong. E-mail: [email protected], Correspondence: Department of Medicine and Therapeutics, Institute of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong. E-mail: [email protected]Search for more papers by this author Xiaojuan Wang, Xiaojuan Wang 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, Hong Kong, China These authors contributed equally to this work.Search for more papers by this authorXiang Zhang, Xiang Zhang 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, Hong Kong, China These authors contributed equally to this work.Search for more papers by this authorEagle S. H. Chu, Eagle S. H. Chu 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, Hong Kong, ChinaSearch for more papers by this authorXiaoting Chen, Xiaoting Chen Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, ChinaSearch for more papers by this authorWei Kang, Wei Kang Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, ChinaSearch for more papers by this authorFeng Wu, Feng Wu 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, Hong Kong, China Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, ChinaSearch for more papers by this authorKa-Fai To, Ka-Fai To Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, ChinaSearch for more papers by this authorVincent W. S. Wong, Vincent W. S. Wong 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, Hong Kong, ChinaSearch for more papers by this authorHenry L. Y. Chan, Henry L. Y. Chan 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, Hong Kong, ChinaSearch for more papers by this authorMatthew T. V. Chan, Matthew T. V. Chan Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, ChinaSearch for more papers by this authorJoseph J. Y. Sung, Joseph J. Y. Sung 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, Hong Kong, ChinaSearch for more papers by this authorWilliam K. K. Wu, Corresponding Author William K. K. Wu [email protected] 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, Hong Kong, China Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, ChinaCorrespondence: Department of Anesthesia and Intensive Care, Prince of Wales Hospital, The Chinese University of Hong Kong, 04C14, Main Clinical Block and Trauma Centre, Shatin, N.T., Hong Kong. E-mail: [email protected], Correspondence: Department of Medicine and Therapeutics, Institute of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong. E-mail: [email protected]Search for more papers by this authorJun Yu, Corresponding Author Jun Yu [email protected] 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, Hong Kong, ChinaCorrespondence: Department of Anesthesia and Intensive Care, Prince of Wales Hospital, The Chinese University of Hong Kong, 04C14, Main Clinical Block and Trauma Centre, Shatin, N.T., Hong Kong. E-mail: [email protected], Correspondence: Department of Medicine and Therapeutics, Institute of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong. E-mail: [email protected]Search for more papers by this author First published: 25 August 2017 https://doi.org/10.1096/fj.201601393RCitations: 8 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract 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. FASEB J. 32, 37-51 (2018). www.fasebj.org Citing Literature Supporting Information Filename Description fsb2fj201601393r-sup-0001.docapplication/doc, 205 KB Supplementary Material 1 fsb2fj201601393r-sup-0002.jpgapplication/jpg, 692.1 KB Supplementary Material 1 fsb2fj201601393r-sup-0003.jpgapplication/jpg, 590.3 KB Supplementary Material 1 fsb2fj201601393r-sup-0004.jpgapplication/jpg, 175.6 KB Supplementary Material 1 fsb2fj201601393r-sup-0005.jpgapplication/jpg, 353.9 KB Supplementary Material 1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume32, Issue1January 2018Pages 37-51 RelatedInformation