LKB1 as a Gatekeeper of Hepatocyte Proliferation and Genomic Integrity during Liver Regeneration

Liver kinase B1 (LKB1) is involved in several biological processes and is a key regulator of hepatic metabolism and polarity. Here, we demonstrate that the master kinase LKB1 plays a dual role in liver regeneration, independently of its major target, AMP-activated protein kinase (AMPK). We found that the loss of hepatic Lkb1 expression promoted hepatocyte proliferation acceleration independently of metabolic/energetic balance. LKB1 regulates G0/G1 progression, specifically by controlling epidermal growth factor receptor (EGFR) signaling. Furthermore, later in regeneration, LKB1 controls mitotic fidelity. The deletion of Lkb1 results in major alterations to mitotic spindle formation along the polarity axis. Thus, LKB1 deficiency alters ploidy profile at late stages of regeneration. Our findings highlight the dual role of LKB1 in liver regeneration, as a guardian of hepatocyte proliferation and genomic integrity. [Display omitted] •LKB1 inactivation promotes mass recovery during liver regeneration•LKB1 regulates hepatocyte proliferation via EGFR signaling•LKB1 regulates metaphase spindle orientation and organization•LKB1 controls the genomic integrity of hepatocytes during liver regeneration Maillet et al. demonstrate that the master kinase LKB1 plays a dual role in liver regeneration, independently of its major target, AMPK. LKB1 acts as a guardian of hepatocyte proliferation by controlling G0/G1 transition through EGFR activation. These findings also show that LKB1 is a gatekeeper of mitotic fidelity and hepatocyte ploidy integrity.