Abstract
BackgroundGaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure.ResultsTo elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct Gba1 point-mutated mice (V394L/V394L and D409 V/null). About 0.9 to 3% of genes had altered expression patterns (≥ ± 1.8 fold change), representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk) of INFγ-regulated pro-inflammatory (13) and IL-4-regulated anti-inflammatory (11) cytokine/mediator networks showed tissue differential profiles in the lung and liver of the Gba1 mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the Gba1 mutation.ConclusionsBiochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology.
Highlights
Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide
The pathologic hallmark of Gaucher disease is the presence of lipid laden macrophages, a.k.a., Gaucher cells, in visceral organs [1]
By LC-MS/MS analyses, accumulations of glucosylceramide were detected in 9 V/null lung and liver as early as at 4 wk (2- to 6-fold over the WT controls), and progressed up to 33-fold during 12 to 28 wk and >40-fold at 52 wk (Figure 1)
Summary
Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure. C.3.2.1.45) in all cells leads to the substrate accumulation including glucosylceramide and glucosylsphingosine, and the various clinical phenotypes. The pathologic hallmark of Gaucher disease is the presence of lipid laden macrophages, a.k.a., Gaucher cells, in visceral organs [1]. The macrophages are thought to be the primary visceral cells involved in all variants, and these cells become progressively numerous and engorged with glucosylceramide by phagocytic processes. This process leads to tissue dysfunction that can result in fibrosis and scarring during the later stages of the disease
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