A Critical Evaluation of Liver Pathology in Humans with Danon Disease and Experimental Correlates in a Rat Model of LAMP-2 Deficiency

Lu Wang, Jingbo Wang, Weile Cai, Yongquan Shi, Xinmin Zhou, Guanya Guo, Changcun Guo, Xiaofeng Huang, Zheyi Han, Shuai Zhang, Shuoyi Ma, Xia Zhou, Daiming Fan, M. Eric Gershwin, Ying Han

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalClinical Reviews in Allergy and Immunology
DOIs
StateAccepted/In press - Jan 26 2017

Fingerprint

Glycogen Storage Disease Type IIb
Lysosome-Associated Membrane Glycoproteins
Protein Deficiency
Pathology
Bile
Liver
Bilirubin
Membrane Proteins
P-Glycoproteins
Dipeptidyl Peptidase 4
Aminopeptidases
Cytoskeletal Proteins
Membranes
Cholestasis
Muscular Diseases
Microvilli
Bile Ducts
Serum
Cardiomyopathies
Ligation

Keywords

  • Intrahepatic cholestasis
  • Lysosome-associated membrane protein 2
  • Multidrug resistance-associated protein 2

ASJC Scopus subject areas

  • Immunology and Allergy

Cite this

A Critical Evaluation of Liver Pathology in Humans with Danon Disease and Experimental Correlates in a Rat Model of LAMP-2 Deficiency. / 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.

In: Clinical Reviews in Allergy and Immunology, 26.01.2017, p. 1-12.

Research output: Contribution to journalArticle

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. / A Critical Evaluation of Liver Pathology in Humans with Danon Disease and Experimental Correlates in a Rat Model of LAMP-2 Deficiency. In: Clinical Reviews in Allergy and Immunology. 2017 ; pp. 1-12.
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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.",
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AU - Wang, Lu

AU - Wang, Jingbo

AU - Cai, Weile

AU - Shi, Yongquan

AU - Zhou, Xinmin

AU - Guo, Guanya

AU - Guo, Changcun

AU - Huang, Xiaofeng

AU - Han, Zheyi

AU - Zhang, Shuai

AU - Ma, Shuoyi

AU - Zhou, Xia

AU - Fan, Daiming

AU - Gershwin, M. Eric

AU - Han, Ying

PY - 2017/1/26

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N2 - 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.

AB - 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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