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Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease.

Publication ,  Journal Article
Guy, CD; Suzuki, A; Zdanowicz, M; Abdelmalek, MF; Burchette, J; Unalp, A; Diehl, AM; NASH CRN
Published in: Hepatology
June 2012

UNLABELLED: The Hedgehog (HH)-signaling pathway mediates several processes that are deregulated in patients with metabolic syndrome (e.g., fat mass regulation, vascular/endothelial remodeling, liver injury and repair, and carcinogenesis). The severity of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome generally correlate. Therefore, we hypothesized that the level of HH-pathway activation would increase in parallel with the severity of liver damage in NAFLD. To assess potential correlations between known histologic and clinical predictors of advanced liver disease and HH-pathway activation, immunohistochemistry was performed on liver biopsies from a large, well-characterized cohort of NAFLD patients (n = 90) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Database 1 study. Increased HH activity (evidenced by accumulation of HH-ligand-producing cells and HH-responsive target cells) strongly correlated with portal inflammation, ballooning, and fibrosis stage (each P < 0.0001), supporting a relationship between HH-pathway activation and liver damage. Pathway activity also correlated significantly with markers of liver repair, including numbers of hepatic progenitors and myofibroblastic cells (both P < 0.03). In addition, various clinical parameters that have been linked to histologically advanced NAFLD, including increased patient age (P < 0.005), body mass index (P < 0.002), waist circumference (P < 0.0007), homeostatic model assessment of insulin resistance (P < 0.0001), and hypertension (P < 0.02), correlated with hepatic HH activity. CONCLUSION: In NAFLD patients, the level of hepatic HH-pathway activity is highly correlated with the severity of liver damage and with metabolic syndrome parameters that are known to be predictive of advanced liver disease. Hence, deregulation of the HH-signaling network may contribute to the pathogenesis and sequelae of liver damage that develops with metabolic syndrome.

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Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

June 2012

Volume

55

Issue

6

Start / End Page

1711 / 1721

Location

United States

Related Subject Headings

  • Zinc Finger Protein Gli2
  • Stem Cells
  • Signal Transduction
  • Severity of Illness Index
  • Nuclear Proteins
  • Non-alcoholic Fatty Liver Disease
  • Myofibroblasts
  • Middle Aged
  • Male
  • Liver Cirrhosis
 

Citation

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ICMJE
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Guy, C. D., Suzuki, A., Zdanowicz, M., Abdelmalek, M. F., Burchette, J., Unalp, A., … NASH CRN. (2012). Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology, 55(6), 1711–1721. https://doi.org/10.1002/hep.25559
Guy, Cynthia D., Ayako Suzuki, Marzena Zdanowicz, Manal F. Abdelmalek, James Burchette, Aynur Unalp, Anna Mae Diehl, and NASH CRN. “Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease.Hepatology 55, no. 6 (June 2012): 1711–21. https://doi.org/10.1002/hep.25559.
Guy CD, Suzuki A, Zdanowicz M, Abdelmalek MF, Burchette J, Unalp A, et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 2012 Jun;55(6):1711–21.
Guy, Cynthia D., et al. “Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease.Hepatology, vol. 55, no. 6, June 2012, pp. 1711–21. Pubmed, doi:10.1002/hep.25559.
Guy CD, Suzuki A, Zdanowicz M, Abdelmalek MF, Burchette J, Unalp A, Diehl AM, NASH CRN. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 2012 Jun;55(6):1711–1721.
Journal cover image

Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

June 2012

Volume

55

Issue

6

Start / End Page

1711 / 1721

Location

United States

Related Subject Headings

  • Zinc Finger Protein Gli2
  • Stem Cells
  • Signal Transduction
  • Severity of Illness Index
  • Nuclear Proteins
  • Non-alcoholic Fatty Liver Disease
  • Myofibroblasts
  • Middle Aged
  • Male
  • Liver Cirrhosis