| First Author | Fleig SV | Year | 2007 |
| Journal | Lab Invest | Volume | 87 |
| Issue | 12 | Pages | 1227-39 |
| PubMed ID | 17952094 | Mgi Jnum | J:128723 |
| Mgi Id | MGI:3767909 | Doi | 10.1038/labinvest.3700689 |
| Citation | Fleig SV, et al. (2007) Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice. Lab Invest 87(12):1227-39 |
| abstractText | 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. |
