title: A Critical Evaluation of Liver Pathology in Humans with Danon Disease and Experimental Correlates in a Rat Model of LAMP-2 Deficiency.
abstract: 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.
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Wang
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Weile
authors.initials: W
authors.lastname: Cai
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Guanya
authors.initials: G
authors.lastname: Guo
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Changcun
authors.initials: C
authors.lastname: Guo
authors.affiliation: Center of Electron Microscope, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Huang
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Zheyi
authors.initials: Z
authors.lastname: Han
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Shuoyi
authors.initials: S
authors.lastname: Ma
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China.
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA. megershwin@ucdavis.edu.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, China. hanying1@fmmu.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
mesh_terms: D000818:Animals; D015415:Biomarkers; D002780:Cholestasis, Intrahepatic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D056426:Genetic Loci; D052120:Glycogen Storage Disease Type IIb / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics*; D008822:Mice, Transgenic; D051381:Rats
chemical_list: D015415:Biomarkers; D052119:Lysosomal-Associated Membrane Protein 2
keywords: Intrahepatic cholestasis; Lysosome-associated membrane protein 2; Multidrug resistance-associated protein 2