Loss of hepatocyte cell division leads to liver inflammation and fibrosis

The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inflammation. We find that in P14 Cdk1(Liv-/-) mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1(Liv-/-) mice display classical markers of liver damage two weeks after birth, including elevated ALT, ALP, and bilirubin levels, despite the lack of exogenous liver injury. Inflammation was further studied using cytokine arrays, unveiling elevated levels of CCL2, TIMP1, CXCL10, and IL1-Rn in Cdk1(Liv-/-) liver, which resulted in increased numbers of monocytes. Ablation of CDK2-dependent DNA re-replication and polyploidy in Cdk1(Liv-/-) mice reversed most of these phenotypes. Overall, our data indicate that blocking hepatocyte division induces biological processes driving the onset of the disease phenotype. It suggests that the decrease in hepatocyte division observed in liver disease may not only be a consequence of fibrosis and inflammation, but also a pathological cue. Author summary Pathological polyploidy is a hallmark of liver diseases like NAFLD and NASH. Since loss of Cdk1 induces polyploidy, we used a mouse model with a hepatocyte-specific deletion of Cdk1 or Ccna2 to study the immediate effects on liver physiology. To our surprise, impaired hepatocyte proliferation results in the development of inflammation and fibrosis in young animals despite the lack of any treatment to promote liver damage. Furthermore, we show that this could be caused by polyploidy, as concurrent loss of Cdk2 reverses polyploidy and the inflammatory phenotype. Thus, we provide evidence that the loss of hepatocyte proliferation in liver disease is not only an outcome but could also be an etiology of liver pathology.