Laboratory of Clinical Pharmacy and Adverse Drug Reaction, Chengdu, Sichuan, 610041, China.
Department of Pharmacy, State Key Laboratory of Biotherapy, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.
Wound Repair Regen. 2019 Jul;27(4):366-374. doi: 10.1111/wrr.12703. Epub 2019 Feb 14.
Sirtuin 6 (Sirt6) is an NAD+-dependent deacetylase that regulates central metabolic functions such as glucose homeostasis, fat metabolism, and cell apoptosis. However, the tissue-specific function of Sirt6 in liver regeneration remains unknown. Here, we show that liver-specific Sirt6 knockout (Sirt6LKO) impaired liver reconstitution after 2/3 partial hepatectomy, which was attributed to an alteration of cell cycle progression. Sirt6 LKO delayed hepatocyte transition into S phase during liver regeneration, as shown by the analysis of cell cycle-related proteins and the immuno staining of Ki-67 and 5-bromo-2-deoxyuridine (BrdU). The delayed cell cycle in Sirt6 LKO mice was attributed to the disruption of m-TOR and Akt activity, which is an important pro-proliferation pathway in liver regeneration. Sirt6 LKO also reduced carbon tetrachloride (CCl )-induced liver damage. Our results suggest that Sirt6 LKO impaired liver regeneration via delayed cell cycle and impaired m-TOR and Akt activity.
Sirtuin 6（Sirt6）是一种 NAD+-依赖性去乙酰化酶，可调节葡萄糖稳态、脂肪代谢和细胞凋亡等核心代谢功能。然而，Sirt6 在肝脏再生中的组织特异性功能尚不清楚。在这里，我们发现肝特异性 Sirt6 敲除（Sirt6LKO）会损害 2/3 部分肝切除后的肝脏重建，这归因于细胞周期进程的改变。Sirt6LKO 在肝脏再生过程中延迟了肝细胞进入 S 期，这通过细胞周期相关蛋白的分析以及 Ki-67 和 5-溴-2-脱氧尿苷（BrdU）的免疫染色得到证实。Sirt6LKO 小鼠的细胞周期延迟归因于 m-TOR 和 Akt 活性的破坏，这是肝脏再生中重要的促增殖途径。Sirt6LKO 还减少了四氯化碳（CCl）诱导的肝损伤。我们的结果表明，Sirt6LKO 通过延迟细胞周期和破坏 m-TOR 和 Akt 活性来损害肝脏再生。
