The Bcl-2 family protein NOXA is a novel regulator of liver regeneration

Robust liver regeneration alleviates liver injury and averts liver failure. In the present study we investigated the regulatory role of phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, also known as NOXA) in liver generation.

Liver regeneration was modeled in vitro by treating primary hepatocytes with hepatocyte growth factor (HGF) and in vivo by subjecting C57BL/6 mice to partial hepatectomy (PHx).

Re-analysis of published RNA-sequencing data showed that NOXA expression was up-regulated in proliferating hepatocytes compared to quiescent hepatocytes. In contrast, NOXA knockdown by small interfering RNAs down-regulated induction of pro-proliferative genes and blunted proliferation (measured by EdU incorporation) in hepatocytes exposed to HGF treatment. Consistently, NOXA deletion in hepatocytes, mediated by adenovirus-associated virus (AAV) delivery of short hairpin RNA targeting NOXA, dampened liver regeneration in mice following the PHx procedure. RNA-seq revealed that NOXA deficiency primarily influenced expression of genes involved in cell cycling and mitosis. Mechanistically, NOXA likely contributed to liver regeneration by regulating the expression of pro-proliferative transcription factors in hepatocytes.

Our data thus uncover a previously unknown role for NOXA in liver regeneration and suggest that boosting NOXA expression/activity might be considered as an approach for intervention of liver failure.