Chronic ethanol consumption down-regulates CMP-NeuAc:GM3 alpha 2,8-sialyltransferase (ST8Sia-1) gene in the rat brain.
Alcoholics have an increase in sialic acid-deficient glycoconjugates such as carbohydrate-deficient transferrin, sialic acid-deficient gangliosides and free sialic acids. The elevated presence of these asialoconjugates could be a consequence of alcohol-mediated impaired sialylation rate or due to increased desialylation rate. Chronic ethanol-induced brain abnormalities and behavioral changes could be mediated through these asialogangliosides. We have therefore determined the level of brain CMP-NeuAc:GM(3) alpha2,8-sialyltransferase (ST8Sia-1) and Gal-beta1,3GalNAc alpha2,3-sialyltransferase (ST3Gal-11) messenger RNA (mRNA) and correlated with the activity of these key enzymes in male Wistar rats as a function of increasing dietary concentration of ethanol after 8 weeks of feeding. The relative level of brain synaptosomal ST8Sia-1 and ST3Gal-11 mRNA were determined by real-time quantitative polymerase chain reaction (RT-PCR). We compared the observed ST8Sia-1 gene expression with its enzymatic activity in the synaptosomal membrane fraction isolated from the rat brain in the ethanol and pair-fed control groups. The results showed that the relative level of brain ST8Sia-1 mRNA expression was down-regulated by 13% (p<0.05) in 10.6%, by 40% (p<0.01) in 20.8% and by 57% (p<0.01) in the 36% ethanol-calorie groups, compared to the control (0% ethanol-calorie) group. In addition, ethanol at 36% dietary calories caused a significant 61% (p<0.01) decrease in the brain synaptosomal ST8Sia-1 activity compared to the control group. However, ethanol (10.6, 20.8 or 36% level) did not significantly affect the relative level of brain ST3Gal-11 mRNA as compared to the control (0% ethanol-calorie) group. Thus, our findings imply that chronic ethanol exposure preferentially down-regulates brain ST8Sia-1 mRNA accompanied by a concomitant decrease in its activity in a dose-dependent manner. Therefore, the selective loss of 2,8-sialic acid residues from gangliosides might contribute towards the appearance of asialogangliosides and related brain-abnormalities associated with ethanol abuse.
The Lipid Research Laboratory, 151-T, Veterans Affairs Medical Center, 50 Irving Street NW, Washington, DC 20422, USA.
Mamatha
M
Garige
Magnus A
MA
Azuine
M Raj
MR
Lakshman
D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012799:Sialyltransferases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*
D000431:Ethanol; D012799:Sialyltransferases; C029156:N-acetyllactosaminide alpha-2,3-sialyltransferase; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase