* A phase 2/3 study evaluating venglustat, an oral glucosylceramide
synthase (GCS) inhibitor, in patients at risk of rapidly progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD) is in the process of being initiated.
Next, the researchers used mass spectrometry analysis, a method of identifying and quantifying the chemical composition of a mixture, to determine ceramide, glucosylceramide
and lactosylceramide levels in the mice.
Miglustat, a glucosylceramide
synthase inhibitor, is indicated as monotherapy for the treatment of adults with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g., due to allergy, hypersensitivity or poor venous access).
Miglustat (ZavescaW, Actelion Pharmaceuticals Ltd, Switzerland), is a reversible inhibitor of glucosylceramide
synthase, that has been shown to be effective in the treatment of progressive neurological manifestations in particularly among those with Late-infantile or Juvenile-onset disease, and has been used in that indication in Europe since 2010.
There are several ways to generate ceramide in mammalian cells (Figure 1): hydrolysis of sphingomyelin, de novo synthesis from palmitoyl-CoA and serine, catabolism of glucosylceramide
and galactosylceramide, synthesis from sphingosine and fatty acid, and dephosphorylation of ceramide-1-phosphate.
Consistent with these results, oral anti-CD3 plus glucosylceramide
(an NKT cell target antigen) treatment has been shown to induce the production of IL-10 and TGF-[beta], which were associated with improved levels of glucose while fasting, visceral adipose tissue inflammation, liver enzymes, and hepatic steatosis in ob/ob mice .
Deficiency of this enzyme leads to accumulation of glucosylceramide
and other glycolipids in the lysosomes of macrophages of the reticuloendothelial system and other organs.
The main sphingolipids include sphingomyelin (SM), ceramide (Cer), ceramide-1-phosphate (C1P), sphingosine (Sph), sphingosine-1-phosphate (S1P), glucosylceramide
(GluCer), lactosylceramide (LacCer), gangliosides, and galactocerebrosides.
Riebeling et al., "Glucosylceramide
and glucosylsphingosine modulate calcium mobilization from brain microsomes via different mechanisms," Journal of Biological Chemistry, vol.
Cer, ceramide; GlcCer, glucosylceramide
; LacCer, lactosylceramide; Gal, galactose; Glc, glucose; GalNAc, N-acetylgalactosamine; Neu5Ac, N-acetylneuraminic acid; Glc T, glucosyltransferase; Gal T, galactosyltransferase; ST, sialyltransferase; GalNacT, N- acetylgalactosaminyltransferase; CASD 1, Cas 1 domain containing 9(7)-O-acetyl transferase.
Miura et al., "Attenuation of acetic acid-induced gastric ulcer formation in rats by glucosylceramide
synthase inhibitors," Digestive Diseases and Sciences, vol.
Heinz, Recently Discovered Functions of Glucosylceramide
in Plants and Fungi.