Sundaram Shikha S, Swiderska-Syn Marzena, Sokol Ronald J, Halbower Ann C, Capocelli Kelley E, Pan Zhaoxing, Robbins Kristen, Graham Brian, Diehl Anna Mae
Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute Children's Hospital Colorado and University of Colorado School of Medicine, Anschutz Medical Campus Aurora CO.
Duke University Durham NC.
Hepatol Commun. 2019 Apr 17;3(7):883-893. doi: 10.1002/hep4.1354. eCollection 2019 Jul.
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, = 0.64; Gli2, = 0.4; α-SMA, = 0.55; and K7, = 0.45 ( < 0.01), as did alanine aminotransferase (ALT) (SHh, = 0.51; Gli2, = 0.43; α-SMA, = 0.51; < 0.02). SHh correlated with NAFLD activity score ( = 0.39), whereas IHh correlated with inflammation ( = -0.478) and histologic grade ( = -0.43); < 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 ( < 0.03). OSA severity correlated with SHh ( = 0.31; = 0.09) and Gli2 ( = 0.37; = 0.04) as did hypoxia severity, which was associated with increasing SHh ( = -0.53), Gli2 ( = -0.52), α-SMA ( = -0.61), and K7 ( = -0.42); < 0.02. Prolonged O desaturations <90% also correlated with SHh ( = 0.55) and Gli2 ( = 0.61); < 0.05. : 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.
慢性间歇性缺氧和刺猬（Hh）信号通路失调与非酒精性脂肪性肝病（NAFLD）的进展相关。在本研究中，我们确定了小儿NAFLD中阻塞性睡眠呼吸暂停（OSA）/夜间缺氧与Hh信号之间的关系。组织学确诊为NAFLD的青少年（n = 31）接受了多导睡眠图测试、实验室检测以及音猬因子（SHh）、印度刺猬因子（IHh）、胶质母细胞瘤相关癌基因2（Gli2）、细胞角蛋白7（K7）、α平滑肌肌动蛋白（α-SMA）和缺氧诱导因子1α（HIF-1α）免疫组化检测。天冬氨酸转氨酶（AST）与SHh（r = 0.64）、Gli2（r = 0.4）、α-SMA（r = 0.55）和K7（r = 0.45）相关（P < 0.01），丙氨酸转氨酶（ALT）也是如此（SHh，r = 0.51；Gli2，r = 0.43；α-SMA，r = 0.51；P < 0.02）。SHh与NAFLD活动评分相关（r = 0.39），而IHh与炎症（r = -0.478）和组织学分级（r = -0.43）相关；P < 0.03。患有OSA/缺氧的受试者SHh（4.0±2.9对2.0±1.5）、Gli2（74.2±28.0对55.8±11.8）和α-SMA（6.2±3.3对4.3±1.2）更高；与未患OSA/缺氧的受试者相比（P < 0.03）。OSA严重程度与SHh（r = 0.3 ; P = 0.09）和Gli2（r = 0.37 ; P = 0.04）相关，缺氧严重程度也是如此，其与SHh（r = -0.53）、Gli2（r = -0.52）、α-SMA（r = -0.61）和K7（r = -0.42）升高相关；P < 0.02。持续氧饱和度<90%也与SHh（r = 0.55）和Gli2（r = 0.61）相关；P < 0.05。结论：在患有夜间缺氧小儿NAFLD患者中Hh信号通路被激活，且与疾病严重程度相关。组织缺氧可能使HIF-1α功能激活，诱导在上皮-间质转化中重要的基因，包括SHh，从而促进NAFLD进展。
