Inhibition of ACLY Leads to Suppression of Osteoclast Differentiation and Function Via Regulation of Histone Acetylation
Inhibition of ACLY Leads to Suppression of Osteoclast Differentiation and Function Via Regulation of Histone Acetylation
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抑制 ACLY 通过调节组蛋白乙酰化导致破骨细胞分化和功能受到抑制
DOI：
10.1002/jbmr.4399
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发表时间：
2021-07-26
影响因子：
6.2
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Guo, Qian;Kang, Honglei;Li, Feng
ATP-柠檬酸裂解酶（ACLY）产生用于组蛋白乙酰化的大部分核胞浆乙酰辅酶A（乙酰辅酶A），将细胞代谢与表观遗传调节联系起来。最近的研究表明，代谢重编程激活的ACLY通过组蛋白乙酰化在M1和M2巨噬细胞活化中起重要作用。以往的研究也表明，组蛋白甲基化和乙酰化对破骨细胞特异性基因的转录调控至关重要。考虑到破骨细胞的分化也经历代谢重编程，并且ACLY的活性总是依赖于Akt，我们推测NF-κ B受体激活剂（RANK）激活可能通过下游途径增强ACLY的活性，ACLY可能在破骨细胞形成中起作用。在目前的研究中，我们发现ACLY在RANK配体（RANKL）诱导的骨髓源性巨噬细胞（BMSCs）破骨细胞分化过程中逐渐活化。ACLY敲低和小分子ACLY抑制剂BMS-303141均显著降低了BclA和破骨细胞中的核胞质乙酰辅酶A，并抑制了体外破骨细胞形成。BMS-303141还抑制体内破骨细胞形成，并防止卵巢切除术（OVX）诱导的骨丢失。进一步研究表明，RANKL触发ACLY易位到细胞核中，与组蛋白H3乙酰化增加一致，这与ACLY相关。受ACLY影响的H3赖氨酸残基与GCN 5靶标一致。使用GCN 5敲低和过表达，我们发现ACLY和GCN 5在组蛋白H3乙酰化的相同途径中起作用。对RANK激活下游通路的分析表明，ACLY是Akt依赖性的，主要影响Akt通路。在RNA测序的帮助下，我们发现Rac 1是ACLY的下游调节因子，它参与了shACLY介导的破骨细胞分化、细胞骨架组织和信号转导的抑制，并通过组蛋白H3乙酰化被ACLY转录调节。总之，我们的研究结果证明，ATP-柠檬酸裂解酶的抑制导致抑制破骨细胞的分化和功能，通过调节组蛋白乙酰化。Rac 1可能是ACLY的下游调节因子。(c)2021年美国骨与矿物质研究学会（ASBMR）。
ATP-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 receptor activator of NF-kappa B (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 RANK ligand (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 ovariectomy (OVX)-induced bone loss. Further investigations showed that RANKL triggered ACLY translocation into nucleus, consistent with 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 overexpression, we showed that ACLY and GCN5 functioned in the same pathway for histone H3 acetylation. Analysis of pathways downstream of RANK activation revealed that ACLY was Akt-dependent and predominately affected Akt pathway. With the help of RNA-sequencing, we discovered Rac1 as a downstream regulator of ACLY, which was involved in shACLY-mediated suppression of osteoclast differentiation, cytoskeleton organization, and signal transduction and was transcriptionally regulated by ACLY via histone H3 acetylation. To summarize, our results proved that inhibition of ATP-citrate lyase led to suppression of osteoclast differentiation and function via regulation of histone acetylation. Rac1 could be a downstream regulator of ACLY. (c) 2021 American Society for Bone and Mineral Research (ASBMR).