RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes

초록

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 alpha (ROR alpha) in lysosomal acidification and autophagic flux, particularly in nutrition-enriched hepatocytes. First, lysosomal acidity was much lower in the hepatocytes obtained from hepatocyte-specific ROR alpha-deleted (ROR alpha-LKO) mice, whereas the infusion of an adenovirus encoding ROR alpha 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 ROR alpha-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 ROR alpha-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 ROR alpha-deleted hepatocytes. Finally, we found that ROR alpha 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 ROR alpha may be a potential therapeutic strategy to restore lysosomal acidification, which inhibits the progression of NAFLD.

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