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Nocturnal Hypoxia Activation of the Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity.

Publication ,  Journal Article
Sundaram, SS; Swiderska-Syn, M; Sokol, RJ; Halbower, AC; Capocelli, KE; Pan, Z; Robbins, K; Graham, B; Diehl, AM
Published in: Hepatol Commun
July 2019

Chronic intermittent hypoxia and hedgehog (Hh) pathway dysregulation are associated with nonalcoholic fatty liver disease (NAFLD) progression. In this study, we determined the relationship between obstructive sleep apnea (OSA)/nocturnal hypoxia and Hh signaling in pediatric NAFLD. Adolescents with histologic NAFLD (n = 31) underwent polysomnogram testing, laboratory testing, and Sonic Hh (SHh), Indian hedgehog (IHh), glioblastoma-associated oncogene 2 (Gli2), keratin 7 (K7), α-smooth muscle actin (α-SMA), and hypoxia-inducible factor 1α (HIF-1α) immunohistochemistry. Aspartate aminotransferase (AST) correlated with SHh, r = 0.64; Gli2, r = 0.4; α-SMA, r = 0.55; and K7, r = 0.45 (P < 0.01), as did alanine aminotransferase (ALT) (SHh, r = 0.51; Gli2, r = 0.43; α-SMA, r = 0.51; P < 0.02). SHh correlated with NAFLD activity score (r = 0.39), whereas IHh correlated with inflammation (r = -0.478) and histologic grade (r = -0.43); P < 0.03. Subjects with OSA/hypoxia had higher SHh (4.0 ± 2.9 versus 2.0 ± 1.5), Gli2 (74.2 ± 28.0 versus 55.8 ± 11.8), and α-SMA (6.2 ± 3.3 versus 4.3 ± 1.2); compared to those without (P < 0.03). OSA severity correlated with SHh (r = 0.31; P = 0.09) and Gli2 (r = 0.37; P = 0.04) as did hypoxia severity, which was associated with increasing SHh (r = -0.53), Gli2 (r = -0.52), α-SMA (r = -0.61), and K7 (r = -0.42); P < 0.02. Prolonged O2 desaturations <90% also correlated with SHh (r = 0.55) and Gli2 (r = 0.61); P < 0.05. Conclusion: The Hh pathway is activated in pediatric patients with NAFLD with nocturnal hypoxia and relates to disease severity. Tissue hypoxia may allow for functional activation of HIF-1α, with induction of genes important in epithelial-mesenchymal transition, including SHh, and NAFLD progression.

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Published In

Hepatol Commun

DOI

EISSN

2471-254X

Publication Date

July 2019

Volume

3

Issue

7

Start / End Page

883 / 893

Location

United States

Related Subject Headings

  • 3202 Clinical sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Sundaram, S. S., Swiderska-Syn, M., Sokol, R. J., Halbower, A. C., Capocelli, K. E., Pan, Z., … Diehl, A. M. (2019). Nocturnal Hypoxia Activation of the Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity. Hepatol Commun, 3(7), 883–893. https://doi.org/10.1002/hep4.1354
Sundaram, Shikha S., Marzena Swiderska-Syn, Ronald J. Sokol, Ann C. Halbower, Kelley E. Capocelli, Zhaoxing Pan, Kristen Robbins, Brian Graham, and Anna Mae Diehl. “Nocturnal Hypoxia Activation of the Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity.Hepatol Commun 3, no. 7 (July 2019): 883–93. https://doi.org/10.1002/hep4.1354.
Sundaram SS, Swiderska-Syn M, Sokol RJ, Halbower AC, Capocelli KE, Pan Z, et al. Nocturnal Hypoxia Activation of the Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity. Hepatol Commun. 2019 Jul;3(7):883–93.
Sundaram, Shikha S., et al. “Nocturnal Hypoxia Activation of the Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity.Hepatol Commun, vol. 3, no. 7, July 2019, pp. 883–93. Pubmed, doi:10.1002/hep4.1354.
Sundaram SS, Swiderska-Syn M, Sokol RJ, Halbower AC, Capocelli KE, Pan Z, Robbins K, Graham B, Diehl AM. Nocturnal Hypoxia Activation of the Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity. Hepatol Commun. 2019 Jul;3(7):883–893.

Published In

Hepatol Commun

DOI

EISSN

2471-254X

Publication Date

July 2019

Volume

3

Issue

7

Start / End Page

883 / 893

Location

United States

Related Subject Headings

  • 3202 Clinical sciences