Acetyl coenzyme A acetyltransferase 2 is a novel regulator of liver regeneration in mice.

AIMS: Resumption of proliferation by quiescent hepatocytes in response to liver injury is a hallmark event in live regeneration. We have previously reported that the zinc finger transcription factor GATA4 contributes to liver regeneration by promoting hepatocyte proliferation. In the present study we investigated the underlying mechanism.

METHODS AND MATERIALS: Cellular transcriptome was evaluated by RNA-seq and ChIP-seq. Liver regeneration was evaluated in a murine model of partial hepatectomy.

KEY FINDINGS: Integrated transcriptomic analysis uncovered acetyl coenzyme A acetyltransferase 2 (Acat2) as one of the potential GATA4 targets in hepatocytes. Quantitative PCR and Western blotting confirmed that GATA4 knockdown down-regulated Acat2 expression whereas ChIP assay detected direct binding of GATA4 to the Acat2 promoter. Supplementation with a wild type, but not a catalytically inactive, Acat2 rescued the deficiency of proliferation in hepatocytes depleted of GATA4. Consistently, liver specific Acat2 knockdown dampened liver regeneration and exacerbated liver injury in mice. Importantly, a correlation between ACAT2 expression, hepatocyte proliferation, and liver injury was observed in patients with liver failure.

SIGNIFICANCE: Our data suggest that Acat2, as a novel target for GATA4, may play a key role in liver regeneration.