Hepatic Snai1 and Snai2 promote liver regeneration and suppress liver fibrosis in mice

Liver injury stimulates hepatocyte replication and hepatic stellate cell (HSC) activation, thereby driving liver regeneration. Aberrant HSC activation induces liver fibrosis. However, mechanisms underlying liver regeneration and fibrosis remain poorly understood. Here, we identify hepatic Snai1 and Snai2 as important transcriptional regulators for liver regeneration and fibrosis. Partial hepatectomy or CCl4 treatment increases occupancies of Snai1 and Snai2 on cyclin A2 and D1 promoters in the liver. Snai1 and Snai2 in turn increase promoter H3K27 acetylation and cyclin A2/D1 expressions. Hepatocyte-specific deletion of both Snai1 and Snai2, but not one alone, suppresses liver cyclin A2/D1 expression and regenerative hepatocyte proliferation after hepatectomy or CCl4 treatments but augments CCl4-stimulated HSC activation and liver fibrosis. Conversely, Snai2 overexpression in the liver enhances hepatocyte replication and suppresses liver fibrosis after CCl4 treatment. These results suggest that hepatic Snai1 and Snai2 directly promote, via histone modifications, reparative hepatocyte replication and indirectly inhibit liver fibrosis. [Display omitted] •Snai1 and Snai2 activate cyclin A2 and D1 genes via histone modifications•Deletion of both hepatic Snai1 and Snai2, but not one alone, impairs liver regeneration•Deletion of both hepatic Snai1 and Snai2, but not one alone, augments liver fibrosis•Snai2 overexpression accelerates liver regeneration and suppresses liver fibrosis Wang et al. show that hepatic Snai1 and Snai2 proteins support liver regeneration and defend against liver fibrosis. Snai1 and Snai2 stimulate regenerative hepatocyte replication by regulating transcriptions of cell-cycle genes. The Snai1/Snai2 pathway provides a genomic paradigm for studying liver injury, regeneration, and fibrosis.