title: Down-regulation of liver Galbeta1, 4GlcNAc alpha2, 6-sialyltransferase gene by ethanol significantly correlates with alcoholic steatosis in humans.
abstract: Hepatic steatosis and steatohepatitis are frequent results of long-term ethanol exposure. We have previously demonstrated that long-term ethanol down-regulates Galbetal, 4GlcNAc alpha2, 6-sialyltransferase (ST6Gal1), leading to defective glycosylation of a number of proteins including apolipoprotein (apo) E and apo J and the appearance of asialoconjugates in the blood of continuously alcohol-fed animals as well as in human alcoholics. In the current study, we have explored the possibility of whether ethanol-induced down-regulation of ST6Gal1 could contribute toward alcoholic steatosis in human alcoholics presumably because of impaired lipid and lipoprotein transport caused by this down-regulation. Real-time quantitative polymerase chain reaction analyses of liver samples from nondrinkers, moderate drinkers, and heavy drinkers as well as from subjects with and without alcoholic liver disease revealed direct evidence that the down-regulation of ST6Gal1 may be due to ethanol per se. The ST6Gal1 messenger RNA level was reduced by as much as 70% in moderate and heavy drinkers as well as in patients with alcoholic liver disease, but was not changed in subjects with liver disease due to causes other than alcohol exposure. Biochemical and histopathologic analysis demonstrated that the liver total cholesterol was increased by more than 30% (P < .05) and 75% (P < .01), respectively, in moderate and heavy drinkers compared with nondrinkers, with even more dramatic changes in triglyceride levels. Significantly, there was a strong inverse correlation between ST6Gal1 messenger RNA level and liver lipid deposit (F = 8.68, P < .001) by statistical analysis. Thus, it is suggested that alcohol-mediated down-regulation of hepatic ST6Gal1 gene leads to defective glycosylation of lipid-carrying apolipoproteins such as apo E and apo J, resulting in defective intracellular lipid and lipoprotein transport, which in turn may contribute to alcoholic steatosis.
authors.affiliation: The Lipid Research Laboratory, Veterans Affairs Medical Center, The George Washington University, Washington, DC 20422, USA.
authors.forename: Maokai
authors.initials: M
authors.lastname: Gong
authors.forename: Leslie
authors.initials: L
authors.lastname: Castillo
authors.forename: Robert S
authors.initials: RS
authors.lastname: Redman
authors.forename: Mamatha
authors.initials: M
authors.lastname: Garige
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hirsch
authors.forename: Magnus
authors.initials: M
authors.lastname: Azuine
authors.forename: Richard L
authors.initials: RL
authors.lastname: Amdur
authors.forename: Devanshi
authors.initials: D
authors.lastname: Seth
authors.forename: Paul S
authors.initials: PS
authors.lastname: Haber
authors.forename: M Raj
authors.initials: MR
authors.lastname: Lakshman
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology; D005235:Fatty Liver, Alcoholic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D008074:Lipoproteins; D012333:RNA, Messenger; D000431:Ethanol; D012799:Sialyltransferases; C088391:galactosyl-1-3-N-acetylgalactosaminyl-specific 2,6-sialyltransferase