Nocturnal Hypoxia Activation Of The Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity

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), alpha-smooth muscle actin (-SMA), and hypoxia-inducible factor 1 (HIF-1) immunohistochemistry. Aspartate aminotransferase (AST) correlated with SHh, r=0.64; Gli2, r=0.4; alpha-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; alpha-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 alpha-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), -SMA (r=-0.61), and K7 (r=-0.42); P<0.02. Prolonged O-2 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-1, with induction of genes important in epithelial-mesenchymal transition, including SHh, and NAFLD progression.