Shi Li, Chen Hao, Zhang Yuxin, An Donghao, Qin Mengyao, Yu Wanting, Wen Bin, He Dandan, Hao Haiping, Xiong Jing
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
EMBO J. 2025 Mar;44(5):1442-1463. doi: 10.1038/s44318-025-00362-y. Epub 2025 Jan 17.
Metabolic requirements of dividing hepatocytes are prerequisite for liver regeneration after injury. In contrast to transcriptional dynamics during liver repair, its metabolic dependencies remain poorly defined. Here, we screened metabolic genes differentially regulated during liver regeneration, and report that SLC13A2, a transporter for TCA cycle intermediates, is decreased in rapid response to partial hepatectomy in mice and recovered along restoration of liver mass and function. Liver-specific overexpression or depletion of SLC13A2 promoted or attenuated liver regeneration, respectively. SLC13A2 increased cleavage of SREBP2, and expression of cholesterol metabolism genes, including LDLR and HMGCR. Mechanistically, SLC13A2 promotes import of citrate into hepatocytes, serving as building block for ACLY-dependent acetyl-CoA formation and de novo synthesis of cholesterol. In line, the pre-administration of the HMGCR inhibitor lovastatin abolished SLC13A2-mediated liver regeneration. Similarly, ACLY inhibition suppressed SLC13A2-promoted cholesterol synthesis for hepatocellular proliferation and liver regeneration in vivo. In sum, this study demonstrates that citrate transported by SLC13A2 acts as an intermediate metabolite to restore the metabolic homeostasis during liver regeneration, suggesting SLC13A2 as a potential drug target after liver damage.
分裂中的肝细胞的代谢需求是肝脏损伤后再生的先决条件。与肝脏修复过程中的转录动态不同，其代谢依赖性仍不清楚。在这里，我们筛选了肝脏再生过程中差异调节的代谢基因，并报告说，作为三羧酸循环中间产物转运体的SLC13A2，在小鼠部分肝切除术后迅速下降，并随着肝脏质量和功能的恢复而恢复。肝脏特异性过表达或缺失SLC13A2分别促进或减弱肝脏再生。SLC13A2增加了SREBP2的裂解以及包括LDLR和HMGCR在内的胆固醇代谢基因的表达。从机制上讲，SLC13A2促进柠檬酸盐进入肝细胞，作为ACLY依赖性乙酰辅酶A形成和胆固醇从头合成的基石。同样，预先给予HMGCR抑制剂洛伐他汀消除了SLC13A2介导的肝脏再生。类似地，ACLY抑制在体内抑制了SLC13A2促进的胆固醇合成以促进肝细胞增殖和肝脏再生。总之，本研究表明，由SLC13A2转运的柠檬酸盐作为中间代谢产物在肝脏再生过程中恢复代谢稳态，表明SLC13A2是肝脏损伤后潜在的药物靶点。
