Hedgehog pathway and pediatric nonalcoholic fatty liver disease.
Hedgehog pathway and pediatric nonalcoholic fatty liver disease.
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DOI：
10.1002/hep.26230
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发表时间：
2013-05
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：
Swiderska-Syn, Marzena;Suzuki, Ayako;Guy, Cynthia D.;Schwimmer, Jeffrey B.;Abdelmalek, Manal F.;Lavine, Joel E.;Diehl, Anna Mae
目前还不清楚为什么儿童和成人非酒精性脂肪肝的组织学有时会有所不同。在成人中，门静脉炎症和纤维化的严重程度与Hedgehog通路活性相关。Hedgehog（Hh）信号调节器官发生，但在成年肝脏中沉默，直到损伤重新诱导Hh配体产生。在青春期，肝脏发育完成，儿童的肝脏通常会失去产生和/或响应Hh配体的细胞。我们假设脂肪肝损伤通过增加Hh配体的产生来干扰这一过程，并推测根据年龄、性别和/或青春期状态，儿童对Hh配体的肝脏反应可能不同。使用56例非酒精性肝病（NAFLD）儿童的未染色肝活检切片，我们进行了免疫组织化学，以评估Hh通路激活，并将结果与活检时获得的临床信息相关联。纤维化阶段通常与Hh途径活性相关，如Hh配体产生细胞（P < 0.0001）和Hh反应（胶质瘤相关癌基因2阳性[Gli 2]）细胞（P = 0.0013）的数量所示。Gli 2（+）细胞数与门静脉炎症分级相关（P = 0.0012）。观察到两种不同的带状Hh-配体产生模式，门脉/门脉周围与小叶。较高的门静脉/门静脉周围Hh-配体的产生与男性相关。男性和青春期前也与导管增生（P<0.05），门静脉Gli 2（+）细胞数量增加（P<0.017）和门静脉纤维化有关。结论：青春期前男性肝脏的门静脉/门静脉周围（祖细胞）室表现出高Hh通路活性。这可能解释了儿科NAFLD的独特组织学特征，因为Hedgehog信号传导促进了纤维小管反应。
It is unclear why the histology of pediatric and adult nonalcoholic fatty liver disease sometimes differs. In adults, severity of portal inflammation and fibrosis correlate with Hedgehog pathway activity. Hedgehog (Hh) signaling regulates organogenesis, but is silent in adult livers until injury re-induces Hh ligand production. During adolescence, liver development is completed and children’s livers normally lose cells that produce and/or respond to Hh ligands. We postulated that fatty liver injury interferes with this process by increasing Hh ligand production, and theorized that hepatic responses to Hh ligands might differ among children according to age, gender, and/or puberty status. Using unstained liver biopsy slides from 56 children with nonalcoholic liver disease (NAFLD), we performed immunohistochemistry to assess Hh pathway activation and correlated results with clinical information obtained at biopsy. Fibrosis stage generally correlated with Hh pathway activity, as demonstrated by numbers of Hh-ligand producing cells (P < 0.0001) and Hh-responsive (glioma-associated oncogene 2-positive [Gli2]) cells (P = 0.0013). Numbers of Gli2 (+) cells also correlated with portal inflammation grade (P = 0.0012). Two distinct zonal patterns of Hh-ligand production, portal/peri-portal vs. lobular, were observed. Higher portal/peri-portal Hh-ligand production was associated with male gender. Male gender and pre-puberty were also associated with ductular proliferation (P<0.05), increased numbers of portal Gli2 (+) cells (P<0.017) and portal fibrosis. Conclusion: The portal/peri-portal (progenitor) compartment of pre-pubescent male livers exhibits high Hh pathway activity. This may explain unique histologic features of pediatric NAFLD because Hedgehog signaling promotes the fibro-ductular response.
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影响因子：
24.5
作者：
Feldstein AE;Charatcharoenwitthaya P;Treeprasertsuk S;Benson JT;Enders FB;Angulo P
通讯作者：
Angulo P
DOI：
10.1016/j.biocel.2010.10.015
发表时间：
2011-02
影响因子：
4
作者：
Choi, Steve S.;Omenetti, Alessia;Syn, Wing-Kin;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae
影响因子：
13.5
作者：
Jung, Youngmi;McCall, Shannon J.;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae
DOI：
10.1073/pnas.1201840109
发表时间：
2012-06-12
影响因子：
11.1
作者：
Kisseleva, Tatiana;Cong, Min;Brenner, David A.
通讯作者：
Brenner, David A.
影响因子：
13.5
作者：
Omenetti, Alessia;Bass, Lee M.;Whitington, Peter F.
通讯作者：
Whitington, Peter F.