Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Fleig, SV; Choi, SS; Yang, L; Jung, Y; Omenetti, A; VanDongen, HM; Huang, J; Sicklick, JK; Diehl, AM

Published Date

  • December 2007

Published In

Volume / Issue

  • 87 / 12

Start / End Page

  • 1227 - 1239

PubMed ID

  • 17952094

Electronic International Standard Serial Number (EISSN)

  • 1530-0307

Digital Object Identifier (DOI)

  • 10.1038/labinvest.3700689


  • eng

Conference Location

  • United States