Liver function and pathological changes in Niemann-Pick disease type C1 mice

doi:10.16098/j.issn.0529-1356.2018.06.009

Abstract

Abstract:

Objective To explore the function and pathology of liver in late Npc1-/-mice (P60) and provide theoretical basis for the pathological and clinical treatment of Niemann-Pick disease type C1 (NPC1). Methods Weighing the mice, the activity of lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of eye canthus were analyzed to evaluate liver function of Npc1-/- mouse. The liver tissues were treated with paraffin and then frozen sections and stained HE staining and oil red O staining was used to observe the morphological changes and fat storage in liver tissue. The collagen deposition in liver tissue was evaluated by Masson staining. The Real-time PCR and Western blotting were used to detect the expression of proinflammatory factors interleukin（IL）-1β, IL-6 and tumer necrosis factor(TNF)-α in liver tissue. The apoptosis of liver tissue was observed by TUNEL staining. Results Compared with the Npc1+/+ mouse, the body weight and liver coefficient of Npc1-/- mouse were decreased significantly (P<0.001), and the activity of LDH, ALT and AST were increased significantly (P<0.001). HE staining showed that morphological changes of the liver were obvious in Npc1-/- mice, and a large number of foam cells appeared. Oil red O staining showed a significant decrease in the positive rate of liver fat cells in Npc1-/- mice. Real-time PCR showed that the expression of IL-1β, IL-6 and TNF-α in the liver of Npc1-/- mice increased significantly (P<0.01,P<0.05 andP<0.001). Western blotting showed that the expression of pro-inflammatory factors IL-1β, IL-6 and TNF-α protein increased (P<0.05, P<0.05 and P<0.01); Inflammatory reaction in the late liver; Masson staining showed no obvious collagen deposition in the liver of Npc1-/- mice. TUNEL staining showed that the number of apoptosis cells increased in the liver of Npc1-/- mice. Conclusion The mutation of Npc1 gene leads to the morphological changes of the liver and the amounts of macrophage aggregation. These increases in macrophage aggregation may cause severe inflammatory reactions in the liver. However, the occurrence of inflammatory reactions in liver may play a crucial role in promoting liver cell apoptosis and impaired liver function.

Key words: Niemann-Pick disease type C1, Liver, Inflammation, Real-time PCR, Western blotting, Mouse

YANG Ji-chao SONG Ying LIU Da TONG Man ZHANG Yang GUAN Li-hong QIAO Liang LIN Jun-tang . Liver function and pathological changes in Niemann-Pick disease type C1 mice[J]. Acta Anatomica Sinica, 2018, 49(6): 745-751.

References

［1］ Probert F, Ruizrodado Ⅴ, Zhang X, et al. Urinary excretion and metabolism of miglustat and valproate in patients with Niemann-Pick type C1 disease: One-and two-dimensional solution-state (1)HNMR studies［J］. J Pharma Biomed Analy, 2015, 117:276-288.

［2］ Patterson MC, Walkley SU. Niemann-Pick disease, type C and Roscoe Brady［J］. Mol Genet Metab, 2017, 120(1-2):34-37.

［3］ Vanier MT. Niemann-Pick diseases［J］. Handb Clin Neurol, 2013, 113: 1717-1721.

［4］ Lyseng-Williamson KA. Miglustat: a review of its use in Niemann-Pick disease type C［J］. Drugs, 2014, 74 (1): 61-74.

［5］ Ebner L, Gl?ser A, Bruer A, et al. Evaluation of two liver treatment strategies in a mouse model of Niemann-Pick-Disease type C1［J］. Int J Mol Sci, 2018, 19(4):972.

［6］ Ebrahimifakhari D, Wahlster L, Bartz F, et al. Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells［J］. Hum Mol Genet, 2016, 25(16):3588-3599.

［7］ Beltroy EP, Richardson JA, Horton JD, et al. Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease［J］. Hepatology, 2005, 42 (4): 886-893.

［8］ Rimkunas VM, Graham MJ, Crooke RM, et al. In vivo antisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick type C-associated liver disease［J］. Hepatology, 2008, 47 (5): 1504-1512.

［9］ Rimkunas VM, Graham MJ, Crooke RM, et al. TNF-{alpha} plays a role in hepatocyte apoptosis in Niemann-Pick type C liver disease［J］. J Lipid Res, 2009, 50 (2): 327-333.

［10］ Li X, Saha P, Li J, et al. Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2［J］. Proc Natl Acad Sci USA, 2016, 113(36):10079-10084.

［11］ Cologna SM, Cluzeau CVM, Yanjanin NM, et al. Human and mouse neuroinflammation markers in Niemann-Pick disease type C1［J］. J Inherit Metab Dis, 2014, 37(1):83-92.

［12］ Ren LP，Du GJ, Cui XP, et al. Study on protective effect of taraxactherba on alcohol-induced liver injury［J］. Chinese Journal of Experimental Traditional Medical Formulae, 2011, 17(11): 179-181.（in Chinese）

任丽平, 杜钢军, 崔新萍,等. 蒲公英对酒精性肝损伤的影响［J］. 中国实验方剂学杂志, 2011, 17(11): 179-181.

［13］ Sun Y, Meng XW, Chi BR, et al. New improvements in the research of hepatic injury induced by alchilic［J］. Jilin Medical Journal, 2006, 27(3): 230-231.（in Chinese）

孙艳, 孟祥伟, 迟宝荣,等. 酒精性肝病发病机制的研究进展［J］. 吉林医学, 2006, 27(3): 230-231.

［14］ Gong X, Qian H, Zhou X, et al. Structural insights into the Niemann-Pick C1 (NPC1)-mediated cholesterol transfer and ebola infection［J］. Cell, 2016, 165 (6): 1467-1478.

［15］ Castellano BM, Thelen AM, Moldavski O, et al. Lysosomal cholesterol activates mTORC1 via an SLC38A9-NiemannPick C1 signaling complex［J］. Science, 2017, 355 (6331): 1306-1311.

［16］ Mac ías-Vidal J, Guerrero-Hernández M, Estanyol JM, et al. Identification of lysosomal Npc1-binding proteins: Cathepsin D activity is regulated by NPC1［J］. Proteomics, 2016, 16(1):150-158.

［17］ Vanier MT. Complex lipid trafficking in Niemann-Pick disease type C［J］. J Inherit Metab Dis, 2015, 38(1):187-199.

［18］ Baudry M, Yao Y, Simmons D, et al. Postnatal development of inflammation in a murine model of Niemann-Pick type C disease: immunohistochemical observations of microglia and astroglia［J］. Exp Neurol, 2003, 184 (2): 887-903.

［19］ Meyer A, Wree A, Günther R, et al. Increased regenerative capacity of the olfactory epithelium in Niemann-Pick disease type C1［J］. Int J Mol Sci, 2017, 18(4):777.

［20］ Voikar V, Rauvala H, Ikonen E. Cognitive deficit and development of motor impairment in a mouse model of Niemann-Pick type C disease［J］. Behav Brain Res, 2002, 132 (1): 1-10.

［21］ Yan X, Yang F, Lukas J, et al. Hyperactive glial cells contribute to axonal pathologies in the spinal cord of Npc1 mutant mice［J］. Glia, 2014, 62(7):1024-1040.

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