Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans.
OBJECTIVE
Improving outcomes in alcoholic liver disease (ALD) necessitates better understanding of how habitual ethanol (EtOH) consumption alters normal regenerative mechanisms within the liver. Hedgehog (Hh) pathway activation promotes expansion of progenitor populations in other tissues. We evaluated the hypothesis that chronic EtOH exposure activates Hh signaling in liver.


METHODS
Hh signaling, liver progenitors, transforming growth factor (TGF)-beta induction, and liver damage were compared in mice fed chow, high-fat diets (HF), or HF + EtOH for 4 weeks. Susceptibility to TGF-beta-mediated apoptosis was compared in Hh-responsive liver cells (eg, immature cholangiocytes and oval cells) and mature hepatocytes (which are unresponsive to Hh). Hepatic accumulation of Hh-responsive cells were compared in controls and ALD patients and correlated with a discriminant function (DF) that predicts subacute mortality.


RESULTS
Hh signaling and numbers of Hh-responsive cells were increased in HF mice and greatest in HF+EtOH mice. In both, progenitor and stromal cell populations harbored Hh-responsive cells. More ductular-type progenitors and fibrosis markers were noted in HF+EtOH mice than in HF mice. The former also expressed more TGF-beta-1. TGF-beta-1 treatment selectively promoted the viability of Hh-responsive immature liver cells and caused mature hepatocytes that survived to produce Hh ligands. Hh-responsive cells were increased in ALD patients. Lobular accumulation of Hh-responsive immature ductular cells was greater in those with a DF >32 than those with a DF <32.


CONCLUSIONS
Hh signaling is increased in ALD and may influence ALD outcomes by promoting hepatic accumulation of immature ductular cells.
Jung
Youngmi
Y
Department of Medicine, Duke University, Durham, North Carolina.
Brown
Kevin D
KD
Witek
Rafal P
RP
Omenetti
Alessia
A
Yang
Liu
L
Vandongen
Margon
M
Milton
Richard J
RJ
Hines
Ian N
IN
Rippe
Richard A
RA
Spahr
Laurent
L
Rubbia-Brandt
Laura
L
Diehl
Anna Mae
AM
D000328:Adult; D000818:Animals; D001706:Biopsy; D002452:Cell Count; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000009:adverse effects / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D000431:Ethanol / Q000009:adverse effects* / Q000633:toxicity; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D012720:Severity of Illness Index; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use
D002492:Central Nervous System Depressants; D053823:Hedgehog Proteins; D008024:Ligands; D053773:Transforming Growth Factor beta1; D000431:Ethanol; D012313:RNA