Signals from dying hepatocytes trigger growth of liver progenitors.
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-kappaB (NF-kappaB) 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. Ikkbeta 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-kappaB 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.


CONCLUSIONS
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.
Jung
Youngmi
Y
Division of Gastroenterology, Duke University, Snyderman Building (GSRB-1), 595 LaSalle Street, Durham, NC 27710, USA.
Witek
Rafal P
RP
Syn
Wing-Kin
WK
Choi
Steve S
SS
Omenetti
Alessia
A
Premont
Richard
R
Guy
Cynthia D
CD
Diehl
Anna Mae
AM
D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D019394:Ki-67 Antigen / Q000378:metabolism; D008024:Ligands; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D051996:Transcription Factor RelA / Q000378:metabolism
D053823:Hedgehog Proteins; D019394:Ki-67 Antigen; D008024:Ligands; C498355:Mki67 protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse