| Autor: |
van der Lienden MJC; Department Medical Biochemistry, Leiden University, 2333 CC Leiden, The Netherlands., Aten J; Department of Pathology, Amsterdam UMC, University of Amsterdam, 1100 DD Amsterdam, The Netherlands., Marques ARA; Chronic Diseases Research Centre, Universidade NOVA de Lisboa, 1150-082 Lisbon, Portugal., Waas ISE; Department of Pathology, Amsterdam UMC, University of Amsterdam, 1100 DD Amsterdam, The Netherlands., Larsen PWB; Department of Pathology, Amsterdam UMC, University of Amsterdam, 1100 DD Amsterdam, The Netherlands., Claessen N; Department of Pathology, Amsterdam UMC, University of Amsterdam, 1100 DD Amsterdam, The Netherlands., van der Wel NN; Electron Microscopy Center Amsterdam, Department of Medical Biology, Amsterdam UMC, 1100 DD Amsterdam, The Netherlands., Ottenhoff R; Department of Medical Biochemistry, Amsterdam UMC, University of Amsterdam, 1100 DD Amsterdam, The Netherlands., van Eijk M; Department Medical Biochemistry, Leiden University, 2333 CC Leiden, The Netherlands., Aerts JMFG; Department Medical Biochemistry, Leiden University, 2333 CC Leiden, The Netherlands. |
| Abstrakt: |
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 Npc1 -/- mice showed a partially reduced GCase protein and enzymatic activity. In contrast, GBA2 levels tended to be reciprocally increased with the GCase deficiency. In Npc1 -/- 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 Npc1 -/- liver was confirmed. Unexpectedly, immunohistochemistry showed that LIMP2 is particularly overexpressed in the hepatocytes of the Npc1 -/- 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 Npc1 -/- hepatocytes might mediate export of cholesterol into the bile and thus protects the hepatocytes. |
