Hedgehog-mediated Epithelial-to-mesenchymal Transition and Fibrogenic Repair in Nonalcoholic Fatty Liver Disease

Overview

Journal Gastroenterology

Specialty Gastroenterology

Date 2009 Jul 7

PMID 19577569

Citations 129

Authors

Wing-Kin Syn

Youngmi Jung

Alessia Omenetti

Manal Abdelmalek

Cynthia D Guy

Liu Yang

Jiangbo Wang

Rafal P Witek

Caitlin M Fearing

Thiago A Pereira

Vanessa Teaberry

Steve S Choi

J Conde-Vancells

Gamze F Karaca

Anna Mae Diehl

Affiliations

Soon will be listed here.

Abstract

Background & Aims: Repair responses define the ultimate outcomes of liver disease. This study evaluated the hypothesis that fibrogenic repair in nonalcoholic fatty liver disease (NAFLD) is mediated by Hedgehog (Hh) pathway activation and consequent induction of epithelial-to-mesenchymal transitions (EMT) in ductular-type progenitors.

Methods: Immature ductular cells were exposed to Sonic hedgehog (Shh) in the presence or absence of the Hh inhibitor cyclopamine to determine whether Hh-pathway activation directly modulates EMT in liver progenitors. Potential biologic correlates of progenitor cell EMT were assessed using mice fed methionine-choline-deficient + ethionine (MCDE) diets with or without cyclopamine. The effects of increased Hh signaling on EMT and fibrogenic repair during diet-induced NAFLD were also compared in wild-type (WT) and Patched haplo-insufficient (Ptc(+/-)) mice. Finally, evidence of Hh-pathway activation and EMT was examined in liver sections from patients with NAFLD.

Results: In cultured progenitors, Shh repressed expression of epithelial genes and EMT inhibitors but induced genes that are expressed by myofibroblasts. Cyclopamine reversed these effects. In mouse NAFLD models, Hh-pathway activation, EMT, expansion of myofibroblastic populations, and liver fibrosis occurred. Cyclopamine inhibited Hh-pathway activation and induction of EMT. Ptc(+/-) mice, which have an overactive Hh pathway, exhibited sustained overinduction of Hh target genes and more EMT, myofibroblast accumulation, and fibrosis than WT mice. Numbers of Shh-producing cells and Hh-responsive ductular cells that expressed EMT markers increased in parallel with liver fibrosis in patients with NAFLD.

Conclusions: Hh-mediated EMT in ductular cells contributes to the pathogenesis of cirrhosis in NAFLD.

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