Article Text
Abstract
Objective The death rate of mature hepatocytes is chronically increased in various liver diseases, triggering responses that prevent liver atrophy, but often cause fibrosis. Mice with targeted disruption of inhibitor kappa B kinase (Ikk) in hepatocytes (∆HEP mice) provide a model to investigate this process because inhibiting Ikk–nuclear factor-κB (NF-κB) signalling in hepatocytes increases their apoptosis.
Methods Cell proliferation, apoptosis, progenitors, fibrosis and production of Hedgehog (Hh) ligands (progenitor and myofibroblast growth factors) were compared in ∆HEP and control mice before and after feeding methionine choline-deficient ethionine-supplemented (MCDE) diets. Ikkβ was deleted from primary hepatocytes to determine the effects on Hh ligand production; Hh signalling was inhibited directly in progenitors to determine the effects on viability. Liver sections from patients were examined to assess relationships between hepatocyte production of Hh ligands, accumulation of myofibroblastic cells and liver fibrosis.
Results Disrupting the Ikk–NF-κB pathway in hepatocytes inhibited their proliferation but induced their production of Hh ligands. The latter provided viability signals for progenitors and myofibroblasts, enhancing accumulation of these cell types and causing fibrogenesis. Findings in the mouse models were recapitulated in diseased human livers.
Conclusion Dying mature hepatocytes produce Hh ligands which promote the compensatory outgrowth of progenitors and myofibroblasts. These results help to explain why diseases that chronically increase hepatocyte death promote cirrhosis.
- Hedgehog
- Ikkβ
- liver regeneration
- non-alcoholic steatohepatitis (NASH)
- progenitors
- stem cells
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Funding This work was supported by NIH grant 5R01-DK077794 to AMD.
Competing interests None.
Ethics approval This study was conducted with the approval of the Duke University, Division of Gastroenterology and Department of Pathology, Duke University School of Medicine Tissue Bank Shared Resource.
Provenance and peer review Not commissioned; externally peer reviewed.
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