A Critical Evaluation of Liver Pathology in Humans with Danon Disease and Experimental Correlates in a Rat Model of LAMP-2 Deficiency
A Critical Evaluation of Liver Pathology in Humans with Danon Disease and Experimental Correlates in a Rat Model of LAMP-2 Deficiency
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对患有 Danon 病的人类肝脏病理学的严格评估以及 LAMP-2 缺陷大鼠模型中的实验相关性
DOI：
10.1007/s12016-017-8598-3
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发表时间：
2017-01
影响因子：
9.1
通讯作者：
Han Ying
中科院分区：
文献类型：
--
作者：
Wang Lu;Wang Jingbo;Cai Weile;Shi Yongquan;Zhou Xinmin;Guo Guanya;Guo Changcun;Huang Xiaofeng;Han Zheyi;Zhang Shuai;Ma Shuoyi;Zhou Xia;Fan Daiming;Gershwin M. Eric;Han Ying
Danon病是一种溶酶体相关膜蛋白2 （LAMP-2）的遗传缺陷，这是溶酶体膜的一种高度糖基化的成分，以心肌病、骨骼肌病和认知障碍为特征。然而，患者通常表现为肝脏异常，但肝功能尚未得到很好的评估，该综合征相对罕见。因此，我们利用一只缺失了LAMP-2的大鼠来研究LAMP-2对肝功能的相对作用。有趣的是，与野生型幼崽相比，缺乏LAMP-2的大鼠血清碱性磷酸酶（ALP）显著增加，胆汁流量显著减少。重要的是，通过超微结构分析，缺陷大鼠表现为小管扩张，缺乏微绒毛，并有含胆小体的证据。此外，在胆管结扎后，lamp -2缺陷大鼠早在6小时后就出现了迅速而严重的晚期胆汁淤积，血清胆红素升高。在野生型对照大鼠中，多药耐药相关蛋白2 （Mrp2）通常集中在胆管膜，将结合胆红素分泌到胆汁中。然而，在LAMP-2y/−大鼠中，与p -糖蛋白、二肽基肽酶IV （CD26）和氨基肽酶（CD13）等其他管状蛋白相比，Mrp2在肝细胞中被检测到。我们的数据进一步表明，LAMP-2与膜细胞骨架蛋白radixin和F-actin相互作用，决定了整体膜蛋白的定位。
Danon disease is a genetic deficiency in lysosome-associated membrane protein 2 (LAMP-2), a highly glycosylated constituent of the lysosomal membrane and characterized by a cardiomyopathy, skeletal muscle myopathy, and cognitive impairment. Patients, however, often manifest hepatic abnormalities, but liver function has not been well evaluated and the syndrome is relatively uncommon. Hence, we have taken advantage of a rat that has been deleted of LAMP-2 to study the relative role of LAMP-2 on liver function. Interestingly, rats deficient in LAMP-2 develop a striking increase in serum alkaline phosphatase (ALP) and a decrease in bile flow compared with wild-type littermates. Importantly and by ultrastructural analysis, deficient rats manifest dilated canaliculi that lack microvilli with evidence of bile-containing bodies. Moreover, following bile duct ligation, LAMP-2-deficient rats develop rapid and severe evidence of advanced cholestasis, with an increase in serum bilirubin, as early as 6 h later. In wild-type control rats, multidrug resistance-associated protein 2 (Mrp2) normally concentrates at the bile canalicular membranes to secrete conjugated bilirubin into bile. However, in LAMP-2y/−rats, Mrp2 was detected in hepatocytes compared with other canalicular proteins including P-glycoproteins, dipeptidyl peptidase IV (CD26), and aminopeptidase (CD13). Our data further suggest that LAMP-2 interacts with the membrane cytoskeletal proteins radixin and F-actin in determining the localization of integral membrane proteins.
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DOI：
--
发表时间：
2016
期刊：
--
影响因子：
--
作者：
J. Rigalli;V. Perdomo;Nadia Ciriaci;D. Antonio;Francés;M. T. Ronco;A. Bataille;C. Ghanem;María;Laura Ruiz;J. Manautou;V. Catania
通讯作者：
J. Rigalli;V. Perdomo;Nadia Ciriaci;D. Antonio;Francés;M. T. Ronco;A. Bataille;C. Ghanem;María;Laura Ruiz;J. Manautou;V. Catania
影响因子：
5.5
作者：
Suda, Jo;Zhu, Lixin;Karvar, Serhan
通讯作者：
Karvar, Serhan
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
30.5
作者：
Valdor, Rut;Mocholi, Enric;Botbol, Yair;Guerrero-Ros, Ignacio;Chandra, Dinesh;Koga, Hiroshi;Gravekamp, Claudia;Cuervo, Ana Maria;Macian, Fernando
通讯作者：
Macian, Fernando
影响因子：
19
作者：
Kaushik S;Cuervo AM
通讯作者：
Cuervo AM