Alcohol and molecular regulation of protein glycosylation and function.
Chronic alcohol exposure leads to the appearance of carbohydrate-deficient transferrin (CDT), a N-glycosylated protein and sialic acid-deficient apolipoprotein E (apoE), an O-glycosylated protein. We show that chronic ethanol treatment destabilizes sialyltransferase (ST) mRNA resulting in a concomitant decreased steady-state level of ST mRNA. As a result, alcohol markedly decreases the hepatic synthetic rate of ST. This leads to impaired sialylation of transferrin and apoE. Consequently, apoE content in plasma high-density lipoproteins (HDL) is decreased. ApoE plays a significant role in the delivery of HDL cholesterol to the liver via apo B/E receptor, a process called reverse cholesterol transport (RCT). Desialylation of apoE results in its decreased association with HDL. Thus, the dissociation constant of HDL for binding to sialo-apoE is 90 +/- 35 nM, whereas that for desialo-apoE is 1010 +/- 250 nM. More importantly, the uptake of labeled cholesterol by human HepG2 cells is decreased by 30-40% from reconstituted HDL particles (rHDL)-containing desialo-apoE compared to rHDL with sialo-apoE. We conclude that chronic alcohol exposure down-regulates the expression of sialyltransferase genes resulting in impaired sialylation of apoE. This leads to its decreased binding to plasma HDL and thereby, impairs the RCT function of HDL.
Lakshman
M R
MR
Lipid Research Laboratory, DVA Medical Center, and Department of Medicine, The George Washington University, Washington, DC 20422, USA. rlax@erols.com
Rao
M N
MN
Marmillot
P
P
D000818:Animals; D001057:Apolipoproteins E / Q000187:drug effects* / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D008076:Cholesterol, HDL / Q000187:drug effects / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage*; D006031:Glycosylation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011920:Rats, Inbred WF; D012799:Sialyltransferases / Q000187:drug effects* / Q000378:metabolism; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D001057:Apolipoproteins E; D002492:Central Nervous System Depressants; D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; D012333:RNA, Messenger; D000431:Ethanol; D012799:Sialyltransferases; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase