Lack of β‐catenin in Hepatocytes Impairs Proliferation and Leads to Increased Morbidity in Response to a Choline‐Deficient Ethionine‐Supplemented Diet

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Despite the liver's capacity for regeneration, liver disease is the 12th leading cause of death in the United States. Treatments for chronic liver disease are limited due to incomplete understanding of liver regeneration mechanisms. Although activation of liver stem cells (LSCs) is thought to contribute to liver regeneration when hepatocyte proliferation is impaired, the role and origin of these cells is still controversial. The choline‐deficient ethionine‐supplemented (CDE) diet model of liver injury is known to induce proliferation of LSCs. However, recent evidence has supported repair primarily driven by hepatocyte self‐duplication in the CDE diet model. As a member of the WNT signaling pathway, β‐catenin plays an important role in liver regeneration by promoting hepatocyte proliferation. However, the role of β‐catenin in liver regeneration after injury from the CDE diet has not been previously characterized. We show that lack of β‐catenin‐driven WNT signaling in mouse livers leads to a defect in hepatocyte proliferation and increased morbidity in response to the CDE diet. Mice with liver‐specific deletion of β‐catenin (β‐catenin KO) and control wild‐type littermates (WT) on the CDE diet showed comparable initial levels of liver injury and inflammation. After 14 days on the CDE diet, WT mice demonstrated significant hepatocyte proliferation and reduced liver injury markers. In contrast, β‐catenin KO mice displayed a lack of hepatocyte proliferation, sustained liver injury, and increased fibrosis. Mice lacking WNT signaling via liver‐specific deletion of co‐receptors LRP5 and LRP6 (LRP5‐6 DKO) also displayed sustained liver injury after 14 days on the CDE diet. Interestingly, we observed proliferation of LSCs in WT, β‐catenin KO, and LRP5‐6 DKO mice, suggesting liver regeneration occurs independently from LSC activation. Therefore our results indicate a role of β‐catenin in liver regeneration through hepatocyte proliferation and provide additional evidence to support a model of regeneration driven by hepatocyte self‐duplication rather than LSC amplification.Support or Funding InformationThis research was funded by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under award number T32EB0010216. Support was provided by the Cellular and Molecular Pathology Graduate Training Program of the University of Pittsburgh.