RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes

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...

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Autores principales:	Hyeon‐Ji Kim, Yong‐Hyun Han, Ju‐Yeon Kim, Mi‐Ock Lee
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/50f230311ab34304a7a6483c380a92df
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spelling	oai:doaj.org-article:50f230311ab34304a7a6483c380a92df2021-11-30T13:39:17ZRORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes2471-254X10.1002/hep4.1785https://doaj.org/article/50f230311ab34304a7a6483c380a92df2021-12-01T00:00:00Zhttps://doi.org/10.1002/hep4.1785https://doaj.org/toc/2471-254XLysosomes 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–related orphan receptor α (RORα) in lysosomal acidification and autophagic flux, particularly in nutrition‐enriched hepatocytes. First, lysosomal acidity was much lower in the hepatocytes obtained from hepatocyte‐specific RORα‐deleted (RORα‐LKO) mice, whereas the infusion of an adenovirus encoding RORα in wild‐type 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 RORα‐LKO mice. Third, the accumulation of LC3‐II, p62/sequestosome 1 (SQSTM1), and neighbor of BRCA1 gene 1 (NBR1) was increased in the livers of RORα‐LKO mice, indicating an impaired autophagic flux in the livers. Consistently, the number of autolysosomes containing mitochondria and lipid droplets was dramatically reduced in the RORα‐deleted hepatocytes. Finally, we found that RORα induced the transcription of genes involved in lysosomal function, such as Atp6v1g1, a vacuolar H+‐ATPase (v‐ATPase) subunit, which were largely down‐regulated in the livers of mice with high‐fat diet–induced NAFLD and patients with hepatitis. Conclusion: Targeting RORα may be a potential therapeutic strategy to restore lysosomal acidification, which inhibits the progression of NAFLD.Hyeon‐Ji KimYong‐Hyun HanJu‐Yeon KimMi‐Ock LeeWileyarticleDiseases of the digestive system. GastroenterologyRC799-869ENHepatology Communications, Vol 5, Iss 12, Pp 2121-2138 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Diseases of the digestive system. Gastroenterology RC799-869 Hyeon‐Ji Kim Yong‐Hyun Han Ju‐Yeon Kim Mi‐Ock Lee RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes
description	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–related orphan receptor α (RORα) in lysosomal acidification and autophagic flux, particularly in nutrition‐enriched hepatocytes. First, lysosomal acidity was much lower in the hepatocytes obtained from hepatocyte‐specific RORα‐deleted (RORα‐LKO) mice, whereas the infusion of an adenovirus encoding RORα in wild‐type 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 RORα‐LKO mice. Third, the accumulation of LC3‐II, p62/sequestosome 1 (SQSTM1), and neighbor of BRCA1 gene 1 (NBR1) was increased in the livers of RORα‐LKO mice, indicating an impaired autophagic flux in the livers. Consistently, the number of autolysosomes containing mitochondria and lipid droplets was dramatically reduced in the RORα‐deleted hepatocytes. Finally, we found that RORα induced the transcription of genes involved in lysosomal function, such as Atp6v1g1, a vacuolar H+‐ATPase (v‐ATPase) subunit, which were largely down‐regulated in the livers of mice with high‐fat diet–induced NAFLD and patients with hepatitis. Conclusion: Targeting RORα may be a potential therapeutic strategy to restore lysosomal acidification, which inhibits the progression of NAFLD.
format	article
author	Hyeon‐Ji Kim Yong‐Hyun Han Ju‐Yeon Kim Mi‐Ock Lee
author_facet	Hyeon‐Ji Kim Yong‐Hyun Han Ju‐Yeon Kim Mi‐Ock Lee
author_sort	Hyeon‐Ji Kim
title	RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes
title_short	RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes
title_full	RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes
title_fullStr	RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes
title_full_unstemmed	RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes
title_sort	rorα enhances lysosomal acidification and autophagic flux in the hepatocytes
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/50f230311ab34304a7a6483c380a92df
work_keys_str_mv	AT hyeonjikim roraenhanceslysosomalacidificationandautophagicfluxinthehepatocytes AT yonghyunhan roraenhanceslysosomalacidificationandautophagicfluxinthehepatocytes AT juyeonkim roraenhanceslysosomalacidificationandautophagicfluxinthehepatocytes AT miocklee roraenhanceslysosomalacidificationandautophagicfluxinthehepatocytes
_version_	1718406561121959936

RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes

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