Heme oxygenase 1 (Hmox1), a ubiquitous enzyme degrading heme to carbon monoxide, iron, and biliverdin, is one of the\ncytoprotective enzymes induced in response to a variety of stimuli, including cellular oxidative stress. Gangliosides, sialic acidcontaining\nglycosphingolipids expressed in all cells, are involved in cell recognition, signalling, and membrane stabilization.\nTheir expression is often altered under many pathological and physiological conditions including cell death, proliferation, and\ndifferentiation. The aim of this study was to assess the possible role of Hmox1 in ganglioside metabolism in relation to oxidative\nstress. The content of liver and brain gangliosides, their cellular distribution, and mRNA as well as protein expression of key\nglycosyltransferases were determined in Hmox1 knockout mice as well as their wild-type littermates. To elucidate the possible\nunderlying mechanisms between Hmox1 and ganglioside metabolism, hepatoblastoma HepG2 and neuroblastoma SH-SY5Y cell\nlines were used for in vitro experiments. Mice lacking Hmox1 exhibited a significant increase in concentrations of liver and\nbrain gangliosides and in mRNA expression of the key enzymes of ganglioside metabolism. A marked shift of GM1 ganglioside\nfrom the subsinusoidal part of the intracellular compartment into sinusoidal membranes of hepatocytes was shown in Hmox1\nknockout mice. Induction of oxidative stress by chenodeoxycholic acid in vitro resulted in a significant increase in GM3, GM2,\nand GD1a gangliosides in SH-SY5Y cells and GM3 and GM2 in the HepG2 cell line. These changes were abolished with\nadministration of bilirubin, a potent antioxidant agent. These observations were closely related to oxidative stress-mediated\nchanges in sialyltransferase expression regulated at least partially through the protein kinase C pathway. We conclude that\noxidative stress is an important factor modulating synthesis and distribution of gangliosides in vivo and in vitro which might\naffect ganglioside signalling in higher organisms.
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