Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

Abstract

Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase, leading to the accumulation of glucocerebroside (GC). The relatively high prevalence of this disease within an ethnic group is believed to reflect a selective advantage. Treatment with enzyme replacement therapy (ERT) is safe and effective in ameliorating the primary symptoms of the disease, yet there have been reports that some patients on ERT have developed type 2 diabetes or metabolic syndrome, malignancies and central nervous system disorders. A series of animal studies suggest that these complications may be related to the reduction of GC levels by the enzyme administered. GC has been shown to have an immunomodulatory effect through the promotion of dendritic cells, natural killer T cells, and regulatory T cells. The break down of GC to ceramide can underline part of these findings. Clinical trials suggested a beneficial effect of GC in type 2 diabetes or nonalcoholic steatohepatitis. This review of the data from animal models and humans proposes that the increased level of GC may provide an evolutionary advantage for patients with GD. Indirectly, these data support treating symptomatic patients with mild/moderate GD with lowdose ERT and re-evaluating the use of ERT in asymptomatic patients.

How I treat Gaucher disease

“…Although we also noticed the increased incidence of monoclonal gammopathies and multiple myeloma in GD, 20,21 we have not seen an increased incidence of other malignancies; indeed, we query the low incidence of breast, ovarian, and prostate cancers relative to the general Ashkenazi Israeli population. 20,98,102 Similarly, although not formally studied, we have not seen any unusual trends for increased vascular events or for decreased life expectancy among our patients.…”

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…All of these underscore that ineffective T cell control exposes GD patients to inflammatory reactions, poor immune responses against infectious agents, and impaired immune surveillance associated with an increased risk of neoplasm (93,95,118,122,161,165). A contrasting point of view suggests that GC accumulation may result to several evolutionary advantages (79,88,83), as secondary biochemical pathways upstream and downstream of GC that regulate phospholipid metabolism are affected in GD. Carriers of GD might not have an increased risk in other diseases (100,136,140).…”

“…The insulin receptor is localized at the cell surface in a GSL-containing lipid microdomain (32,93,97). Cer, GC, ganglioside GM3, and other SLs are related to insulin resistance, pancreatic ␤-cell failure, and vascular dysfunction (33,75,79). Both Cer and GC are minor components of the lipid milieu in most tissues and they are potential pathogenic lipids in several conditions, including states of excess adiposity (24,25,33,34,75,79).…”

“…Cer, GC, ganglioside GM3, and other SLs are related to insulin resistance, pancreatic ␤-cell failure, and vascular dysfunction (33,75,79). Both Cer and GC are minor components of the lipid milieu in most tissues and they are potential pathogenic lipids in several conditions, including states of excess adiposity (24,25,33,34,75,79). GSLs are structural membrane components located mainly in the plasma membrane, with their sugar moieties exposed at the cell surface (4,5,31).…”

“…Much has been learned about the role of GSLs in the immune system from patients with GD (79,83,88). These patients have altered humoral and cellular immune profiles, including altered NKT cell numbers and function.…”