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Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease.
Gastroenterology. 2009 Oct; 137(4):1478-1488.e8.G

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.

Authors+Show Affiliations

Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19577569

Citation

Syn, Wing-Kin, et al. "Hedgehog-mediated Epithelial-to-mesenchymal Transition and Fibrogenic Repair in Nonalcoholic Fatty Liver Disease." Gastroenterology, vol. 137, no. 4, 2009, pp. 1478-1488.e8.
Syn WK, Jung Y, Omenetti A, et al. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology. 2009;137(4):1478-1488.e8.
Syn, W. K., Jung, Y., Omenetti, A., Abdelmalek, M., Guy, C. D., Yang, L., Wang, J., Witek, R. P., Fearing, C. M., Pereira, T. A., Teaberry, V., Choi, S. S., Conde-Vancells, J., Karaca, G. F., & Diehl, A. M. (2009). Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology, 137(4), 1478-e8. https://doi.org/10.1053/j.gastro.2009.06.051
Syn WK, et al. Hedgehog-mediated Epithelial-to-mesenchymal Transition and Fibrogenic Repair in Nonalcoholic Fatty Liver Disease. Gastroenterology. 2009;137(4):1478-1488.e8. PubMed PMID: 19577569.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. AU - Syn,Wing-Kin, AU - Jung,Youngmi, AU - Omenetti,Alessia, AU - Abdelmalek,Manal, AU - Guy,Cynthia D, AU - Yang,Liu, AU - Wang,Jiangbo, AU - Witek,Rafal P, AU - Fearing,Caitlin M, AU - Pereira,Thiago A, AU - Teaberry,Vanessa, AU - Choi,Steve S, AU - Conde-Vancells,J, AU - Karaca,Gamze F, AU - Diehl,Anna Mae, Y1 - 2009/07/03/ PY - 2009/02/20/received PY - 2009/06/19/revised PY - 2009/06/24/accepted PY - 2009/7/7/entrez PY - 2009/7/7/pubmed PY - 2009/10/16/medline SP - 1478 EP - 1488.e8 JF - Gastroenterology JO - Gastroenterology VL - 137 IS - 4 N2 - 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. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/19577569/Hedgehog_mediated_epithelial_to_mesenchymal_transition_and_fibrogenic_repair_in_nonalcoholic_fatty_liver_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(09)01136-6 DB - PRIME DP - Unbound Medicine ER -