Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
Transplantation. 2021 Nov 1;105(11):e215-e225. doi: 10.1097/TP.0000000000003675.
Hepatic steatosis is now the leading cause of liver discards in deceased donors. Previous studies [Yarmush formula (Y) defatting] have successfully reduced the fat content by treating rat steatotic livers on extracorporeal normothermic machine perfusion (NMP) with a multidrug combination including the GW compounds that were linked to an increased risk of carcinogenesis.
We developed a novel multidrug combination by replacing the GW compounds with 2 polyphenols, epigallocatechin-3-gallate (E) and resveratrol (R). Sixteen rat livers were placed on NMP and assigned to control, Y defatting, Y + E + R defatting, or Y'-GW + E + R defatting groups (Y'-GW = 90% dose-reduced Y defatting, n = 4/group).
All livers in defatting groups had significant decreases in hepatic triglyceride content at the end of the experiment. However, livers treated with our novel Y'-GW + E + R combination had evidence of increased metabolism and less hepatocyte damage and carcinogenic potential. Our Y'-GW + E + R combination had increased phosphorylation of AMP-activated protein kinase (P = 0.019) and acetyl-CoA carboxylase (P = 0.023) compared with control; these were not increased in Y + E + R group and actually decreased in the Y group. Furthermore, the Y'-GW + E + R group had less evidence of carcinogenic potential with no increase in AKT phosphorylation compared with control (P = 0.089); the Y (P = 0.031) and Y + E + R (P = 0.035) groups had striking increases in AKT phosphorylation. Finally, our Y'-GW + E + R showed less evidence of hepatocyte damage with significantly lower perfusate alanine aminotransferase (P = 0.007) and aspartate aminotransferase (P = 0.014) levels.
We have developed a novel multidrug combination demonstrating promising defatting efficacy via activation of the AMP-activated protein kinase pathway with an optimized safety profile and reduced hepatotoxicity during ex vivo NMP.
肝脂肪变性是目前导致已故供体肝脏废弃的主要原因。先前的研究[Yarmush 配方 (Y) 脱脂]通过在体外常温机器灌注 (NMP) 中使用包含 GW 化合物的多药物组合治疗大鼠脂肪变性肝脏，成功降低了脂肪含量，GW 化合物与致癌风险增加有关。
我们通过用 2 种多酚，表没食子儿茶素-3-没食子酸酯 (E) 和白藜芦醇 (R)，替代 GW 化合物，开发了一种新的多药物组合。将 16 个大鼠肝脏置于 NMP 上，并分配到对照组、Y 脱脂组、Y+E+R 脱脂组或 Y'-GW+E+R 脱脂组（Y'-GW=Y 降低 90%剂量的脱脂组，n=4/组）。
所有脱脂组的肝脏在实验结束时肝甘油三酯含量均显著降低。然而，用我们新型的 Y'-GW+E+R 组合处理的肝脏显示出代谢增加，肝细胞损伤和致癌潜力降低。与对照组相比，我们的 Y'-GW+E+R 组合增加了 AMP 激活蛋白激酶 (P=0.019) 和乙酰辅酶 A 羧化酶 (P=0.023) 的磷酸化；Y+E+R 组没有增加，而 Y 组实际上减少了。此外，与对照组相比，Y'-GW+E+R 组的 AKT 磷酸化没有增加，因此致癌潜力较低（P=0.089）；Y（P=0.031）和 Y+E+R（P=0.035）组 AKT 磷酸化显著增加。最后，我们的 Y'-GW+E+R 显示出较低的肝细胞损伤证据，灌流液丙氨酸氨基转移酶（P=0.007）和天冬氨酸氨基转移酶（P=0.014）水平显著降低。
我们开发了一种新型多药物组合，通过激活 AMP 激活蛋白激酶途径，显示出有希望的脱脂效果，同时在离体 NMP 中具有优化的安全性和降低的肝毒性。
