Inhibition of ACLY leads to suppression of osteoclast differentiation and function via regulation of histone acetylation

AbstractATP citrate lyase (ACLY), generating most of the nucleocytosolic acetyl coenzyme A (acetyl-CoA) for histone acetylation, links cell metabolism to epigenetic regulation. Recent investigations demonstrated that ACLY activated by metabolic reprogramming played an essential role in both M1 and M2 macrophage activation via histone acetylation, previous studies also revealed that histone methylation and acetylation were critical for transcriptional regulation of osteoclast-specific genes. Considering that osteoclast differentiation also undergoes metabolic reprogramming and the activity of ACLY is always Akt-dependent, we inferred that RANK activation might enhance the activity of ACLY through downstream pathways and ACLY might play a role in osteoclast formation. In the current study, we found that ACLY was gradually activated during RANKL-induced osteoclast differentiation from bone marrow-derived macrophages (BMMs), both ACLY knock-down and small molecular ACLY inhibitor BMS-303141 significantly decreased nucleocytosolic acetyl-CoA in BMMs and osteoclasts and suppressed osteoclast formation in vitro, BMS-303141 also suppressed osteoclast formation in vivo and prevents OVX-induced bone loss. Further investigations showed that RANKL triggered ACLY translocation into nucleus, consistent with the increasing histone H3 acetylation which was correlated to ACLY. The H3 lysine residues influenced by ACLY were in accordance with GCN5 targets, using GCN5 knock-down and overexpress...
Source: Journal of Bone and Mineral Research - Category: Orthopaedics Authors: Tags: Original Article Source Type: research