Cell Death and Disease (Nov 2022)

Manipulating PP2Acα-ASK-JNK signaling to favor apoptotic over necroptotic hepatocyte fate reduces the extent of necrosis and fibrosis upon acute liver injury

  • Ke Lu,
  • Si-Yu Shen,
  • Ou-Yang Luo,
  • Yue Lu,
  • Tian-Shu Shi,
  • Jing Wu,
  • Qi Cheng,
  • Hua-Jian Teng,
  • Di Chen,
  • Xiang Lu,
  • Chao-Jun Li,
  • Qing Jiang,
  • Lei Fang,
  • Bin Xue

DOI
https://doi.org/10.1038/s41419-022-05353-z
Journal volume & issue
Vol. 13, no. 11
pp. 1 – 13

Abstract

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Abstract In the widely used Carbon tetrachloride (CCl4)-induced acute liver injury (ALI) mouse model, hepatocytes are known to die from programmed cell death (PCD) processes including apoptosis and necroptosis. Both in vivo and in vitro experiments showed that CCl4 treatment could induce both apoptosis and necroptosis. Treatment of mice with the apoptosis inducer SMAC mimetic reduced necroptosis, led to less pronounced liver damage, and improved overall liver function. By LC-MS/MS, we found that PP2Acα expression was increased in ALI mice liver, and we confirmed its high expression in subacute hepatitis patients. We observed that ALI severity (including aggravated fibrogenesis) was significantly alleviated in hepatocyte-specific PP2Acα conditional knockout (PP2Acα cKO) mice. Furthermore, the relative extent of apoptosis over necroptosis was increased in the PP2Acα cKO ALI mice. Pursuing the idea that biasing the type of PCD towards apoptosis may reduce liver damage, we found that treatment of PP2Acα cKO ALI mice with the apoptosis inhibitor z-Vad-fmk increased the extent of necroptosis and caused severer damage. Mechanistically, disruption of PP2Acα prevents the dephosphorylation of pASK1(Ser967), thereby preventing the sustained activation of JNK. Inhibition of PP2Acα prevents CCl4-induced liver injury and fibrogenesis by disrupting ASK/JNK pathway mediated PCD signaling, ultimately improving liver function by biasing hepatocytes towards an apoptotic rather than necroptotic cell fate. Thus, targeting PP2A and/or ASK1 to favor apoptotic over necroptotic hepatocyte fate may represent an attractive therapeutic strategy for treating ALI.