Liver Galbeta1,4GlcNAc alpha2,6-sialyltransferase is down-regulated in human alcoholics: possible cause for the appearance of asialoconjugates.
Galbetal,4GlcNAc alpha2,6-sialyltransferase (ST6GalI) mediates the glycosylation of proteins and lipids to form functionally important glycoproteins and glycolipids in the Golgi compartment. Our previous work demonstrated that long-term ethanol feeding in rats caused a marked 59% decrease in ST6GalI activity as well as ST6GalI messenger RNA (mRNA) level in the liver that was due to decreased stability of the mRNA. Clinical observations show that down-regulation of ST6GalI gene and consequent impaired activity of ST6GalI seems to be the major cause for the appearance of asialoconjugates in the blood of long-term alcoholics. The plasma carbohydrate-deficient transferrin (CDT) and sialic acid index of plasma apolipoprotein J were also altered in the alcoholic group compared with the nondrinkers. We have now investigated how alcohol affects the gene regulation of ST6GalI and the possible mechanism in postmortem human liver specimens taken from nondrinkers, moderate alcohol drinkers, and heavy alcohol drinkers. Real-time polymerase chain reaction analyses of the liver RNA extract showed that ST6GalI mRNA level was progressively decreased by 49% in moderate drinkers (P < .01) and by 69% in heavy drinkers (P < .01) compared with nondrinkers. Western blot analysis showed that liver ST6GalI protein level was negligibly decreased in moderate drinkers but decreased by 30% (P < .05) in heavy drinkers compared with nondrinkers. We further demonstrated a single ST6GalI mRNA-binding protein complex in the normal human liver extract, which progressively decreased in the liver extracts of moderate and heavy alcohol drinkers. Thus, it is concluded that the appearance of asialoconjugates in alcoholics is possibly due to the down-regulation of ST6GalI gene expression.
Gong
Maokai
M
Department of Biochemistry, Molecular Biology and Medicine, George Washington University, Washington, DC 20052, USA.
Garige
Mamatha
M
Hirsch
Kenneth
K
Lakshman
M Raj
MR
D000428:Alcohol Drinking / Q000097:blood / Q000235:genetics; D000437:Alcoholism / Q000235:genetics* / Q000473:pathology; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D051152:Clusterin / Q000097:blood / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D012794:Sialic Acids / Q000097:blood* / Q000737:chemistry; D012799:Sialyltransferases / Q000235:genetics* / Q000378:metabolism; D014168:Transferrin / Q000031:analogs & derivatives / Q000032:analysis; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D015703:Antigens, CD; D051152:Clusterin; D012333:RNA, Messenger; D012794:Sialic Acids; D012799:Sialyltransferases; D014168:Transferrin; C495242:CLU protein, human; C056759:carbohydrate-deficient transferrin; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
Gut. 2000 Mar;46(3):359-66
10673297
J Pharmacol Exp Ther. 2006 Sep;318(3):1076-82
16720754
Biochimie. 2001 Aug;83(8):727-37
11530204
Alcohol. 2001 Nov;25(3):173-9
11839462
Alcohol. 2001 Nov;25(3):195-200
11839466
Exp Cell Res. 2002 May 15;276(1):101-10
11978012
J Biol Chem. 2002 Nov 29;277(48):45719-28
12235148
Eur J Biochem. 2003 Mar;270(5):950-61
12603328
Gynecol Oncol. 2003 Jun;89(3):395-401
12798701
Glycobiology. 2003 Aug;13(8):591-600
12672700
J Biochem. 2003 Aug;134(2):287-96
12966079
J Biol Chem. 2003 Nov 28;278(48):48245-50
14500706
Glycobiology. 2004 Jan;14(1):39-49
14514712
Alcohol Clin Exp Res. 1981 Fall;5(4):545-9
7030111
Nucleic Acids Res. 1987 Nov 11;15(21):8783-98
3684574
Glycobiology. 1993 Jun;3(3):201-18
8358147
Biochem Soc Trans. 1993 Aug;21 ( Pt 3)(3):583-95
8224473
Alcohol Clin Exp Res. 1994 Apr;18(2):392-7
8048744
Metabolism. 1995 Jul;44(7):890-8
7616848
J Biochem. 1996 Jul;120(1):1-13
8864835
Alcohol Clin Exp Res. 1997 Apr;21(2):348-51
9113274
Int Rev Cytol. 1997;175:137-240
9203358
Metabolism. 1999 Jun;48(6):797-803
10381157
Biochim Biophys Acta. 2001 May 31;1536(2-3):148-60
11406350