GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice
The lysosomal storage disease Niemann–Pick type C (NPC) is caused by impaired cholesterol efflux from lysosomes, which is accompanied by secondary lysosomal accumulation of sphingomyelin and glucosylceramide (GlcCer). Similar to Gaucher disease (GD), patients deficient in glucocerebrosidase (GCase)...
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2021-03-01
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| author | Martijn J. C. van der Lienden Jan Aten André R. A. Marques Ingeborg S. E. Waas Per W. B. Larsen Nike Claessen Nicole N. van der Wel Roelof Ottenhoff Marco van Eijk Johannes M. F. G. Aerts |
| author_facet | Martijn J. C. van der Lienden Jan Aten André R. A. Marques Ingeborg S. E. Waas Per W. B. Larsen Nike Claessen Nicole N. van der Wel Roelof Ottenhoff Marco van Eijk Johannes M. F. G. Aerts |
| author_sort | Martijn J. C. van der Lienden |
| collection | DOAJ |
| description | The lysosomal storage disease Niemann–Pick type C (NPC) is caused by impaired cholesterol efflux from lysosomes, which is accompanied by secondary lysosomal accumulation of sphingomyelin and glucosylceramide (GlcCer). Similar to Gaucher disease (GD), patients deficient in glucocerebrosidase (GCase) degrading GlcCer, NPC patients show an elevated glucosylsphingosine and glucosylated cholesterol. In livers of mice lacking the lysosomal cholesterol efflux transporter NPC1, we investigated the expression of established biomarkers of lipid-laden macrophages of GD patients, their GCase status, and content on the cytosol facing glucosylceramidase GBA2 and lysosomal integral membrane protein type B (LIMP2), a transporter of newly formed GCase to lysosomes. Livers of 80-week-old <i>Npc1</i><sup>−/−</sup> mice showed a partially reduced GCase protein and enzymatic activity. In contrast, GBA2 levels tended to be reciprocally increased with the GCase deficiency. In <i>Npc1</i><sup>−/−</sup> liver, increased expression of lysosomal enzymes (cathepsin D, acid ceramidase) was observed as well as increased markers of lipid-stressed macrophages (GPNMB and galectin-3). Immunohistochemistry showed that the latter markers are expressed by lipid laden Kupffer cells. Earlier reported increase of LIMP2 in <i>Npc1</i><sup>−/−</sup> liver was confirmed. Unexpectedly, immunohistochemistry showed that LIMP2 is particularly overexpressed in the hepatocytes of the <i>Npc1</i><sup>−/−</sup> liver. LIMP2 in these hepatocytes seems not to only localize to (endo)lysosomes. The recent recognition that LIMP2 harbors a cholesterol channel prompts the speculation that LIMP2 in <i>Npc1</i><sup>−/−</sup> hepatocytes might mediate export of cholesterol into the bile and thus protects the hepatocytes. |
| first_indexed | 2024-03-09T05:47:09Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T05:47:09Z |
| publishDate | 2021-03-01 |
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| spelling | doaj.art-70f7f422666d4419839e25546388fa0d2023-12-03T12:20:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01225253210.3390/ijms22052532GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C MiceMartijn J. C. van der Lienden0Jan Aten1André R. A. Marques2Ingeborg S. E. Waas3Per W. B. Larsen4Nike Claessen5Nicole N. van der Wel6Roelof Ottenhoff7Marco van Eijk8Johannes M. F. G. Aerts9Department Medical Biochemistry, Leiden University, 2333 CC Leiden, The NetherlandsDepartment of Pathology, Amsterdam UMC, University of Amsterdam, 1100 DD Amsterdam, The NetherlandsChronic Diseases Research Centre, Universidade NOVA de Lisboa, 1150-082 Lisbon, PortugalDepartment of Pathology, Amsterdam UMC, University of Amsterdam, 1100 DD Amsterdam, The NetherlandsDepartment of Pathology, Amsterdam UMC, University of Amsterdam, 1100 DD Amsterdam, The NetherlandsDepartment of Pathology, Amsterdam UMC, University of Amsterdam, 1100 DD Amsterdam, The NetherlandsElectron Microscopy Center Amsterdam, Department of Medical Biology, Amsterdam UMC, 1100 DD Amsterdam, The NetherlandsDepartment of Medical Biochemistry, Amsterdam UMC, University of Amsterdam, 1100 DD Amsterdam, The NetherlandsDepartment Medical Biochemistry, Leiden University, 2333 CC Leiden, The NetherlandsDepartment Medical Biochemistry, Leiden University, 2333 CC Leiden, The NetherlandsThe lysosomal storage disease Niemann–Pick type C (NPC) is caused by impaired cholesterol efflux from lysosomes, which is accompanied by secondary lysosomal accumulation of sphingomyelin and glucosylceramide (GlcCer). Similar to Gaucher disease (GD), patients deficient in glucocerebrosidase (GCase) degrading GlcCer, NPC patients show an elevated glucosylsphingosine and glucosylated cholesterol. In livers of mice lacking the lysosomal cholesterol efflux transporter NPC1, we investigated the expression of established biomarkers of lipid-laden macrophages of GD patients, their GCase status, and content on the cytosol facing glucosylceramidase GBA2 and lysosomal integral membrane protein type B (LIMP2), a transporter of newly formed GCase to lysosomes. Livers of 80-week-old <i>Npc1</i><sup>−/−</sup> mice showed a partially reduced GCase protein and enzymatic activity. In contrast, GBA2 levels tended to be reciprocally increased with the GCase deficiency. In <i>Npc1</i><sup>−/−</sup> liver, increased expression of lysosomal enzymes (cathepsin D, acid ceramidase) was observed as well as increased markers of lipid-stressed macrophages (GPNMB and galectin-3). Immunohistochemistry showed that the latter markers are expressed by lipid laden Kupffer cells. Earlier reported increase of LIMP2 in <i>Npc1</i><sup>−/−</sup> liver was confirmed. Unexpectedly, immunohistochemistry showed that LIMP2 is particularly overexpressed in the hepatocytes of the <i>Npc1</i><sup>−/−</sup> liver. LIMP2 in these hepatocytes seems not to only localize to (endo)lysosomes. The recent recognition that LIMP2 harbors a cholesterol channel prompts the speculation that LIMP2 in <i>Npc1</i><sup>−/−</sup> hepatocytes might mediate export of cholesterol into the bile and thus protects the hepatocytes.https://www.mdpi.com/1422-0067/22/5/2532lysosomeNPCLIMP2storagemacrophageNPC1 |
| spellingShingle | Martijn J. C. van der Lienden Jan Aten André R. A. Marques Ingeborg S. E. Waas Per W. B. Larsen Nike Claessen Nicole N. van der Wel Roelof Ottenhoff Marco van Eijk Johannes M. F. G. Aerts GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice International Journal of Molecular Sciences lysosome NPC LIMP2 storage macrophage NPC1 |
| title | GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice |
| title_full | GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice |
| title_fullStr | GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice |
| title_full_unstemmed | GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice |
| title_short | GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice |
| title_sort | gcase and limp2 abnormalities in the liver of niemann pick type c mice |
| topic | lysosome NPC LIMP2 storage macrophage NPC1 |
| url | https://www.mdpi.com/1422-0067/22/5/2532 |
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