{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T03:35:29Z","timestamp":1785814529818,"version":"3.56.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","license":[{"start":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T00:00:00Z","timestamp":1629763200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:p>Lysosomes are intracellular acidic organelles with catabolic functions that contribute to the activation of autophagy. Although autophagy abnormality is associated with defects in lysosomal acidification during the progression of nonalcoholic fatty liver disease (NAFLD), the mechanisms of control of lysosomal acidification are not well understood at the molecular level. Thus, we aimed to elucidate the role of the orphan nuclear receptor retinoic acid\u2013related orphan receptor \u03b1 (ROR\u03b1) in lysosomal acidification and autophagic flux, particularly in nutrition\u2010enriched hepatocytes. First, lysosomal acidity was much lower in the hepatocytes obtained from hepatocyte\u2010specific ROR\u03b1\u2010deleted (ROR\u03b1\u2010LKO) mice, whereas the infusion of an adenovirus encoding ROR\u03b1 in wild\u2010type hepatocytes increased lysosomal acidity, as determined by LysoSensor. Second, the lysosomal translocation of the mechanistic target of rapamycin was increased and immature cathepsin D was accumulated in the liver of ROR\u03b1\u2010LKO mice. Third, the accumulation of LC3\u2010II, p62\/sequestosome 1 (SQSTM1), and neighbor of BRCA1 gene 1 (NBR1) was increased in the livers of ROR\u03b1\u2010LKO mice, indicating an impaired autophagic flux in the livers. Consistently, the number of autolysosomes containing mitochondria and lipid droplets was dramatically reduced in the ROR\u03b1\u2010deleted hepatocytes. Finally, we found that ROR\u03b1 induced the transcription of genes involved in lysosomal function, such as <jats:italic toggle=\"yes\">Atp6v1g1<\/jats:italic>, a vacuolar H<jats:sup>+<\/jats:sup>\u2010ATPase (v\u2010ATPase) subunit, which were largely down\u2010regulated in the livers of mice with high\u2010fat diet\u2013induced NAFLD and patients with hepatitis. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Targeting ROR\u03b1 may be a potential therapeutic strategy to restore lysosomal acidification, which inhibits the progression of NAFLD.<\/jats:p>","DOI":"10.1002\/hep4.1785","type":"journal-article","created":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T09:07:43Z","timestamp":1629796063000},"page":"2121-2138","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":23,"title":["ROR\u03b1 Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes"],"prefix":"10.1097","volume":"5","author":[{"given":"Hyeon\u2010Ji","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy,Seoul National University,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong\u2010Hyun","family":"Han","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology and Physiology,College of Pharmacy,Kangwon National University,Chuncheon,South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju\u2010Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy,Seoul National University,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi\u2010Ock","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy,Seoul National University,Seoul,Korea"},{"name":"Bio\u2010MAX Institute,Seoul National University,Seoul,Korea"},{"name":"Research Institute of Pharmaceutical 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