Histone deacetylase 6 inhibitor ACY1215 offers a protective effect through the autophagy pathway in acute liver failure.

Abstract

AIM:

The purpose of the present study was to elucidate the protective effect of histone deacetylase 6 inhibitor ACY1215 on autophagy pathway in acute liver failure (ALF).

MAIN METHODS:

Lipopolysaccharide (LPS) and d-galactosamine (D-Gal) were used to induce ALF model in C57BL/6 mice. D-Gal and tumor necrosis factor alpha (TNF-α) were applied in L02 cell. Autophagy inhibitor 3-MA and ACY1215 were conducted to induce 3-MA group, ACY1215 group and ACY1215+3-MA group.

RESULTS:

ACY1215 improved liver histological and functional changes in ALF mice model, whereas the autophagy inhibitor 3-MA aggravated liver tissue pathological and functional damage in ALF mice model group. The apoptotic levels (including apoptotic index/rate and apoptotic proteins) in ALF mice and L02 cell were ameliorated with treatment ACY1215. 3-MA accentuated the apoptotic levels in ACY1215 group. D-Gal/TNF-α could reduce L02 cell mitochondrial membrane potential (ΔΨm) in control group. ACY1215 increased the ΔΨm in ALF model. 3-MA also further reduced the ΔΨm in ACY1215 group. ACY1215 could induce autophagy in ALF mice and cell model group accompanied with an increase in expression of LC3-II and beclin-1 proteins and down-regulation of p62 protein. Moreover, the expression of LC3-II and beclin1 proteins were greatly reduced and the expression of p62 protein was ascended after intervention with 3-MA in ACY1215 group.

SIGNIFICANCE:

Histone deacetylase 6 inhibitor ACY1215 could protect acute liver failure mice and L02 cell by inhibiting apoptosis pathway through enhancing autophagy way.

• Authors: Qian Chen, Yao Wang, Fang-Zhou Jiao, Chun-Xia Shi, Zuo-Jiong Gong
• Journal: Life sciences (Life Sci) Vol. 238 Pg. 116976 (Dec 01 2019) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 31634464 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Lipopolysaccharides
• Protective Agents
• Pyrimidines
• Histone Deacetylase 6
• ricolinostat

Topics

• Animals
• Apoptosis
• Autophagy (drug effects)
• Cells, Cultured
• Cytokines (metabolism)
• Disease Models, Animal
• Histone Deacetylase 6 (antagonists & inhibitors)
• Histone Deacetylase Inhibitors (pharmacology)
• Hydroxamic Acids (pharmacology)
• Lipopolysaccharides (toxicity)
• Liver Failure, Acute (chemically induced, metabolism, pathology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Protective Agents (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction