Xiong Jie, Chen Suzhen, Liu Junli
Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Metabol Open. 2023 Sep 22;23:100258. doi: 10.1016/j.metop.2023.100258. eCollection 2024 Sep.
During liver regeneration, especially after a hepatectomy, hepatocytes experience significant lipid accumulation. These transiently accumulated lipids are generally believed to provide substrates for energy supply or membrane biomaterials for newly generated hepatocytes. Remarkably, a recent study found that acute lipid accumulation during regeneration can act as a signal for chromatin remodeling to regulate regeneration. Chen, Y.H., et al. identified MIER1 (mesoderm induction early response protein 1) as a crucial inhibitor of liver regeneration through CRISPR screening. MIER1 binds to and restrains cell cycle genes' expression. During liver regeneration, acute lipid accumulation suppresses MIER1 translation via the EIF2S pathway, resulting in transient down-regulation of MIER1 protein, which promotes cell cycle gene expression and liver regeneration. Interestingly, the researchers also found that the dynamic regulation of MIER1 was impaired in fatty and aging livers with chronic steatosis, while of knockout of MIER1 in these animals improved their regenerative capacity. In conclusion, this study provides valuable insights into the complex mechanisms underlying liver regeneration and highlights the potential therapeutic applications of targeting MIER1 for improving liver regeneration in disease states associated with impaired lipid homeostasis.
在肝脏再生过程中，尤其是肝切除术后，肝细胞会出现明显的脂质积累。这些短暂积累的脂质通常被认为可为能量供应提供底物，或为新生成的肝细胞提供膜生物材料。值得注意的是，最近一项研究发现，再生过程中的急性脂质积累可作为染色质重塑的信号来调节再生。陈怡宏等人通过CRISPR筛选确定了中胚层诱导早期反应蛋白1（MIER1）是肝脏再生的关键抑制剂。MIER1与细胞周期基因结合并抑制其表达。在肝脏再生过程中，急性脂质积累通过EIF2S途径抑制MIER1的翻译，导致MIER1蛋白短暂下调，从而促进细胞周期基因表达和肝脏再生。有趣的是，研究人员还发现，在患有慢性脂肪变性的脂肪肝和老龄肝脏中，MIER1的动态调节受损，而在这些动物中敲除MIER1可提高其再生能力。总之，这项研究为肝脏再生的复杂机制提供了有价值的见解，并突出了靶向MIER1在改善脂质稳态受损相关疾病状态下肝脏再生方面的潜在治疗应用。
