Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease.
Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease.
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刺猬途径激活与人类非酒精性脂肪肝病的损伤和纤维化的组织学严重程度相似。
DOI：
10.1002/hep.25559
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发表时间：
2012-06
期刊：
影响因子：
13.5
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
--
作者：
Guy, Cynthia D.;Suzuki, Ayako;Zdanowicz, Marzena;Abdelmalek, Manal F.;Burchette, James;Unalp, Aynur;Diehl, Anna Mae
Hedgehog(HH)信号通路介导了代谢综合征患者体内几个不受调控的过程(例如，脂肪质量调节、血管/内皮重构、肝脏损伤和修复以及癌变)。非酒精性脂肪性肝病(NAFLD)的严重程度与代谢综合征一般相关。因此，我们假设在NAFLD中，HH通路的激活水平与肝损害的严重程度平行增加。为了评估晚期肝病的已知组织学和临床预测因素与HH途径激活之间的潜在相关性，对非酒精性脂肪性肝炎临床研究网络(NASH CRN)数据库1研究中登记的90名NAFLD患者的肝活检进行了免疫组织化学研究。HH活性的增加(HH配体产生细胞和HH反应靶细胞的积累)与门脉炎症、气球膨胀和纤维化阶段(每个P<；0.0001)密切相关，支持HH途径激活和肝损伤之间的关系。通路的活性也与肝修复的标志显著相关，包括肝祖细胞和肌成纤维细胞的数量(P<；0.03)。此外，与组织学进展的NAFLD相关的各种临床参数，包括患者年龄增加(p<；0.005)、体重指数(p<；0.002)、腰围(p<；0.0007)、胰岛素抵抗的稳态模型评估(p<；IR)(p<；0.0001)和高血压(p<；0.02)与肝脏HH活性相关。结论：在NAFLD患者中，肝脏HH途径活性水平与肝脏损害的严重程度和代谢综合征参数高度相关，这些参数被认为是预测晚期肝病的指标。因此，HH信号网络的失控可能与代谢综合征所致肝损伤的发病机制和后遗症有关。
The Hedgehog (Hh) signaling pathway mediates several processes that are deregulated in patients with the 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 the 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), BMI (p<0.002), waist circumference (p<0.0007), homeostatic model assessment of insulin resistance (HOMA-IR) (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 the metabolic syndrome.
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影响因子：
20.3
作者：
Uhmann, Anja;Dittmann, Kai;Hahn, Heidi
通讯作者：
Hahn, Heidi
DOI：
10.1152/ajpgi.00456.2005
发表时间：
2006-05-01
影响因子：
4.5
作者：
Sicklick, JK;Li, YX;Diehl, AM
通讯作者：
Diehl, AM
影响因子：
4.7
作者：
Sicklick, JK;Li, YX;Diehl, AM
通讯作者：
Diehl, AM
影响因子：
13.5
作者：
Jung, Youngmi;McCall, Shannon J.;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae
影响因子：
15.9
作者：
Omenetti, Alessia;Porrello, Alessandro;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae