| First Author | Lu K | Year | 2022 |
| Journal | Cell Death Dis | Volume | 13 |
| Issue | 11 | Pages | 985 |
| PubMed ID | 36418313 | Mgi Jnum | J:331900 |
| Mgi Id | MGI:7387289 | Doi | 10.1038/s41419-022-05353-z |
| Citation | Lu K, et al. (2022) Manipulating PP2Acalpha-ASK-JNK signaling to favor apoptotic over necroptotic hepatocyte fate reduces the extent of necrosis and fibrosis upon acute liver injury. Cell Death Dis 13(11):985 |
| abstractText | In the widely used Carbon tetrachloride (CCl(4))-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 CCl(4) 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 PP2Acalpha 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 PP2Acalpha conditional knockout (PP2Acalpha cKO) mice. Furthermore, the relative extent of apoptosis over necroptosis was increased in the PP2Acalpha cKO ALI mice. Pursuing the idea that biasing the type of PCD towards apoptosis may reduce liver damage, we found that treatment of PP2Acalpha cKO ALI mice with the apoptosis inhibitor z-Vad-fmk increased the extent of necroptosis and caused severer damage. Mechanistically, disruption of PP2Acalpha prevents the dephosphorylation of pASK1(Ser967), thereby preventing the sustained activation of JNK. Inhibition of PP2Acalpha prevents CCl(4)-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. |
