The FASEB journal, 2018-01, Vol.32 (1), p.37-51
2018
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- Autor(en) / Beteiligte
- Titel
- Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis
- Ist Teil von
- The FASEB journal, 2018-01, Vol.32 (1), p.37-51
- Ort / Verlag
- United States: Federation of American Societies for Experimental Biology
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0892-6638eISSN: 1530-6860DOI: 10.1096/fj.201601393RTitel-ID: cdi_proquest_miscellaneous_1932839133
- Format
- –
- Schlagworte
- Acidification, Acidity, Adult, Animal models, Animals, Asparagine, asparagine synthetase, Aspartate-ammonia ligase, Aspartate-Ammonia Ligase - deficiency, Aspartate-Ammonia Ligase - genetics, Aspartate-Ammonia Ligase - metabolism, Autophagosomes - metabolism, Autophagy, Biomarkers, Biomarkers - metabolism, Calcium, Calcium - metabolism, Case-Control Studies, Cathepsin D, Cell Line, Disease Models, Animal, Endoplasmic reticulum, Endoplasmic Reticulum Stress, Fatty liver, Female, Gene Knockdown Techniques, Hep G2 Cells, Hepatocytes, Hepatocytes - metabolism, Hepatocytes - pathology, Humans, Liver, Liver diseases, lysosome, Lysosomes - metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Microtubule-Associated Proteins - metabolism, Middle Aged, NAFLD, Non-alcoholic Fatty Liver Disease - etiology, Non-alcoholic Fatty Liver Disease - metabolism, Non-alcoholic Fatty Liver Disease - pathology, Organelles, Patients, Phagocytosis, Phagosomes, Retention, Risk factors, Sequestosome-1 Protein - metabolism, Steatosis