Glucosylsphingosine Causes Hematological and Visceral Changes in Mice—Evidence for a Pathophysiological Role in Gaucher Disease

Abstract

Glucosylceramide and glucosylsphingosine are the two major storage products in Gaucher disease (GD), an inherited metabolic disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The build-up of glucosylceramide in the endoplasmic reticulum and prominent accumulation in cell lysosomes of tissue macrophages results in decreased blood cell and platelet counts, and skeletal abnormalities. The pathological role of the deacylated form of glucosylceramide, glucosylsphingosine (lyso-Gb1), a recently identified sensitive and specific biomarker for GD, is not well investigated. We established a long-term infusion model in C57BL/6JRj mice to examine the effect of lyso-Gb1 on representative hallmark parameters of GD. Mice received lyso-Gb1 at a dosage of 10 mg·kg−1 per day as a continuous subcutaneous administration, and were routinely checked for blood lyso-Gb1 levels using liquid chromatography-multiple reaction monitoring mass spectrometry (LC/MRM-MS) measurements at four-weekly intervals throughout treatment. The C57BL/6JRj mice showed a stable increase of lyso-Gb1 up to->500-fold greater than the normal reflecting concentrations seen in moderately to severely affected patients. Furthermore, lyso-Gb1 accumulated in peripheral tissues. The mice developed hematological symptoms such as reduced hemoglobin and hematocrit, increased spleen weights and a slight inflammatory tissue response after eight weeks of treatment. The above findings indicate a measurable visceral and hematological response in treated mice that suggests a role for lyso-Gb1 in the development of peripheral signs of GD.

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

“…Thirty non-randomized clinical trials and observational studies with full-study reporting were assessed using the Newcastle–Ottawa scoring tool [ 3 , 26 , 33 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ], of which 19 were deemed to have a high risk of bias (score 0–3; Table S2 ). Thirty-two animal studies were assessed using the SYRCLE risk of bias tool [ 45 , 53 , 58 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ,…”

“…Of the 74 articles included, 56 articles pertained to lyso-Gb1 and GD pathology. They encompassed (in a non-mutually exclusive manner) ten clinical (autopsy) studies [ 54 , 55 , 56 , 57 , 58 , 59 , 61 , 62 , 63 , 93 ] and 48 studies reporting preclinical data (19 studies reporting in vitro data and 32 studies reporting in vivo data) [ 26 , 45 , 53 , 58 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ,…”

“…Results from 14 of 17 experimental animal models of GD have shown that lyso-Gb1 is associated with: pro-inflammatory effects [ 75 ]; hepatosplenomegaly [ 67 , 74 , 75 , 77 ]; poor hematologic [ 75 , 77 ], skeletal [ 77 ], and neurologic outcomes [ 68 , 76 , 82 , 83 ]; B-cell malignancy [ 79 ]; death [ 89 , 90 ] ( Table 3 ). Two in vivo studies did not evaluate the effect of lyso-Gb1 in specific aspects of GD pathology [ 45 , 78 ].…”

Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

“…Gaucher cells would also produce chemokines leading to an immune cell infiltration (with macrophages, dendritic cells, neutrophils and lymphocytes) in organs, as observed in GD mouse models [56][57][58]. In addition, subcutaneous administration of GlcSph in C57BL/6JRj mice resulted in a splenomegaly characterized by an infiltration of M2 macrophages and a slight elevation in circulating TNFα and IL-1β [59]. Of note, GlcCer has been reported as a specific ligand for macrophage-inducible C-type lectin (Mincle) of antigen-presenting cells, leading to the production of TNFα and MIP-2, as well as the up-regulation of costimulatory molecules presentation [60].…”

Biomarker combination is necessary for the assessment of Gaucher disease?

“…Lyso-Gb1 appears to induce tissue inflammation in mice (19) but it is still unknown if it is tissue specific and the modifications in inflammatory response that occurs after treatment. Despite all this, Lyso-Gb1 promises to be useful biomarker in patients without ChT activity.…”