Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice.
Progenitors regenerate fatty livers but the mechanisms involved are uncertain. The Hedgehog pathway regulates mesendodermal progenitors and modulates mesenchymal-epithelial interactions during tissue remodeling. To determine if Hedgehog signaling increases in liver progenitors during fatty liver injury, we compared expression of Hedgehog ligands and target genes across a spectrum of injury. Leptin-deficient ob/ob mice with fatty livers and their healthy lean littermates were studied before and after exposure to the hepatotoxin, ethionine. At baseline, ob/ob mice had greater liver damage than controls. Ethionine induced liver injury in both ob/ob and lean mice, with greater injury occurring in ob/ob mice. After ethionine, the ob/ob mice developed liver atrophy and fibrosis. Liver injury increased hepatic accumulation of progenitors, including ductular cells that produced and responded to Hedgehog ligands. A dose-response relationship was demonstrated between liver injury and expansion of Hedgehog-responsive progenitors. In severely damaged, atrophic livers, nuclei in mature-appearing hepatocytes accumulated the Hedgehog-regulated mesenchymal transcription factor, Gli2 and lost expression of the liver epithelial transcription factor, hepatocyte nuclear factor 6 (HNF-6). Hepatic levels of collagen mRNA and pericellular collagen fibrils increased concomitantly. Hence, fatty liver injury increases Hedgehog activity in liver progenitors, and this might promote epithelial-mesenchymal transitions that result in liver fibrosis.
Fleig
Susanne V
SV
Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA.
Choi
Steve S
SS
Yang
Liu
L
Jung
Youngmi
Y
Omenetti
Alessia
A
VanDongen
Hendrika M
HM
Huang
Jiawen
J
Sicklick
Jason K
JK
Diehl
Anna Mae
AM
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005001:Ethionine; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism*; D051559:Hepatocyte Nuclear Factor 6 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015398:Signal Transduction; D000074290:Zinc Finger Protein Gli3
C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051559:Hepatocyte Nuclear Factor 6; D051741:Kruppel-Like Transcription Factors; D020738:Leptin; D008024:Ligands; D009419:Nerve Tissue Proteins; C496606:Onecut1 protein, mouse; D000074290:Zinc Finger Protein Gli3; D005001:Ethionine