Hydroxycitrate delays early mortality in mice and promotes muscle regeneration while inducing a rich hepatic energetic status.

ATP citrate lyase (ACLY) inhibitors have the potential of modulating central processes in protein, carbohydrate, and lipid metabolism, which can have relevant physiological consequences in aging and age-related diseases. Here, we show that hepatic phospho-active ACLY correlates with overweight and Model for End-stage Liver Disease score in humans. Wild-type mice treated chronically with the ACLY inhibitor potassium hydroxycitrate exhibited delayed early mortality. In AML12 hepatocyte cultures, the ACLY inhibitors potassium hydroxycitrate, SB-204990, and bempedoic acid fostered lipid accumulation, which was also observed in the liver of healthy-fed mice treated with potassium hydroxycitrate. Analysis of soleus tissue indicated that potassium hydroxycitrate produced the modulation of wound healing processes. In vivo, potassium hydroxycitrate modulated locomotor function toward increased wire hang performance and reduced rotarod performance in healthy-fed mice, and improved locomotion in mice exposed to cardiotoxin-induced muscle atrophy. Our findings implicate ACLY and ACLY inhibitors in different aspects of aging and muscle regeneration. Overall design: C57BL/6 male mice were divided in different groups with a standard diet or standard diet supplemented with hydroxycitrate. AML12 cells were siRNA interfered for Acly expression and were treated with hydroxycitrate, SB-204990 or Bempedoic acid. RNAseq was performed from AML12 cells, liver, soleo and gastrocnemius.

ATP柠檬酸裂解酶（ATP citrate lyase, ACLY）抑制剂具备调控蛋白质、碳水化合物与脂质代谢核心过程的潜力，可对衰老及年龄相关疾病产生相关生理影响。本研究证实，人类肝脏中具有磷酸化活性的ACLY与超重及终末期肝病模型（Model for End-stage Liver Disease, MELD）评分存在相关性。长期给予ACLY抑制剂羟基柠檬酸钾处理的野生型小鼠，其早期死亡率出现延迟。在AML12肝细胞培养体系中，ACLY抑制剂羟基柠檬酸钾、SB-204990以及苯贝多酸（bempedoic acid）可促进脂质蓄积，该现象在经羟基柠檬酸钾处理的正常喂养小鼠肝脏中同样可见。对比目鱼肌（soleus tissue）组织的分析表明，羟基柠檬酸钾可调控伤口愈合相关过程。在体实验中，羟基柠檬酸钾可调节正常喂养小鼠的运动功能：使其悬线实验表现提升，而转棒实验表现下降；同时可改善心脏毒素诱导肌肉萎缩小鼠的运动能力。本研究结果提示ACLY及其抑制剂参与衰老与肌肉再生的不同环节。整体实验设计：将C57BL/6雄性小鼠分为不同组别，分别饲喂标准饲料或添加羟基柠檬酸的标准饲料。对AML12细胞进行Acly基因的小干扰RNA（siRNA）干扰，并分别用羟基柠檬酸、SB-204990及苯贝多酸处理。从AML12细胞、肝脏、比目鱼肌及腓肠肌中提取样本进行RNA测序（RNAseq）。