Histone deacetylase 6 inhibitor ACY1215 ameliorates mitochondrial dynamic and function injury in hepatocytes by activating AMPK signaling pathway in acute liver failure mice.

Abstract

Acute liver failure (ALF) is often accompanied by dynamic and functional disorders of mitochondria in hepatocytes. The histone deacetylase 6 inhibitor Rocilinostat (ACY1215) has a hepatoprotective effect. However, its protective effect on mitochondria of hepatocytes and its related mechanisms in ALF remain unknown. The purpose of the present study was to elucidate the protective effect of ACY1215 on mitochondrial of hepatocytes in ALF by regulating AMPK signaling pathway. LPS and D-Gal were used to induce ALF model in C57BL/6 mice. D-Gal and TNF-α were applied in L02 cells as model group. ACY1215 was administered to the mice or culture cells before the model' s establishment as ACY1215 group. The normal group in mice and L02 cells was not given any drug intervention. ACY1215 improves liver histological and functional changes in ALF model mice. Compared with normal group, the expression of p-AMPK and p-ACC proteins was decreased in model group. ACY1215 activated the AMPK signaling pathway with an increase of p-AMPK and p-ACC proteins level in model group. ACY1215 treatment decreased levels of mitochondrial fission proteins DRP1 and FIS1, and enhanced levels of mitochondrial fusion proteins MFN1, MFN2 and OPA1 in models. MtDNA copies in model group was decreased compared with normal group, but ACY1215 elevated the mtDNA copies in models. Mitochondrial respiratory electron transfer chain Complex I-III and citrate synthase (CS) activities in model group were decreased compared with normal group, but ACY1215 treatment enhanced these activities in model group. ACY1215 protects against dynamic disorders and dysfunction of mitochondria in hepatocytes in ALF by activating AMPK signaling pathway.