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Hedgehog pathway and pediatric nonalcoholic fatty liver disease.

Publication ,  Journal Article
Swiderska-Syn, M; Suzuki, A; Guy, CD; Schwimmer, JB; Abdelmalek, MF; Lavine, JE; Diehl, AM
Published in: Hepatology
May 2013

UNLABELLED: It is unclear why the histology of pediatric and adult nonalcoholic fatty liver disease (NAFLD) sometimes differs. In adults, severity of portal inflammation and fibrosis correlate with Hedgehog pathway activity. Hedgehog (Hh) signaling regulates organogenesis, but is silent in adult livers until injury reinduces Hh ligand production. During adolescence, liver development is completed and children's livers normally lose cells that produce and/or respond to Hh ligands. We postulated that fatty liver injury interferes with this process by increasing Hh ligand production, and theorized that hepatic responses to Hh ligands might differ among children according to age, gender, and/or puberty status. Using unstained liver biopsy slides from 56 children with NAFLD, we performed immunohistochemistry to assess Hh pathway activation and correlated the results with clinical information obtained at biopsy. Fibrosis stage generally correlated with Hh pathway activity, as demonstrated by the numbers of Hh-ligand-producing cells (P < 0.0001) and Hh-responsive (glioma-associated oncogene 2-positive [Gli2]) cells (P = 0.0013). The numbers of Gli2(+) cells also correlated with portal inflammation grade (P = 0.0012). Two distinct zonal patterns of Hh-ligand production, portal/periportal versus lobular, were observed. Higher portal/periportal Hh-ligand production was associated with male gender. Male gender and prepuberty were also associated with ductular proliferation (P < 0.05), increased numbers of portal Gli2(+) cells (P < 0.017) and portal fibrosis. CONCLUSION: The portal/periportal (progenitor) compartment of prepubescent male livers exhibits high Hh pathway activity. This may explain the unique histologic features of pediatric NAFLD because Hh signaling promotes the fibroductular response.

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Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

May 2013

Volume

57

Issue

5

Start / End Page

1814 / 1825

Location

United States

Related Subject Headings

  • Zinc Finger Protein Gli2
  • Vimentin
  • Signal Transduction
  • Sex Factors
  • Portal System
  • Nuclear Proteins
  • Non-alcoholic Fatty Liver Disease
  • Male
  • Liver
  • Kruppel-Like Transcription Factors
 

Citation

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Swiderska-Syn, M., Suzuki, A., Guy, C. D., Schwimmer, J. B., Abdelmalek, M. F., Lavine, J. E., & Diehl, A. M. (2013). Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology, 57(5), 1814–1825. https://doi.org/10.1002/hep.26230
Swiderska-Syn, Marzena, Ayako Suzuki, Cynthia D. Guy, Jeffrey B. Schwimmer, Manal F. Abdelmalek, Joel E. Lavine, and Anna Mae Diehl. “Hedgehog pathway and pediatric nonalcoholic fatty liver disease.Hepatology 57, no. 5 (May 2013): 1814–25. https://doi.org/10.1002/hep.26230.
Swiderska-Syn M, Suzuki A, Guy CD, Schwimmer JB, Abdelmalek MF, Lavine JE, et al. Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology. 2013 May;57(5):1814–25.
Swiderska-Syn, Marzena, et al. “Hedgehog pathway and pediatric nonalcoholic fatty liver disease.Hepatology, vol. 57, no. 5, May 2013, pp. 1814–25. Pubmed, doi:10.1002/hep.26230.
Swiderska-Syn M, Suzuki A, Guy CD, Schwimmer JB, Abdelmalek MF, Lavine JE, Diehl AM. Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology. 2013 May;57(5):1814–1825.
Journal cover image

Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

May 2013

Volume

57

Issue

5

Start / End Page

1814 / 1825

Location

United States

Related Subject Headings

  • Zinc Finger Protein Gli2
  • Vimentin
  • Signal Transduction
  • Sex Factors
  • Portal System
  • Nuclear Proteins
  • Non-alcoholic Fatty Liver Disease
  • Male
  • Liver
  • Kruppel-Like Transcription Factors