Alcohol and Molecular Regulation of Protein Glycosylation and Function

• Published in: Alcohol (Fayetteville, N.Y.) Vol. 19; no. 3; pp. 239 - 247
• Main Authors: Lakshman, M.R, Rao, Manjunath N, Marmillot, Philippe
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01-11-1999; Elsevier Science
• Subjects: Alcohol; Alcoholism and acute alcohol poisoning; Animals; apoE protein; Apolipoprotein E; Apolipoproteins E - drug effects; Apolipoproteins E - metabolism; Biological and medical sciences; Central Nervous System Depressants - administration & dosage; Cholesterol, HDL - drug effects; Cholesterol, HDL - metabolism; Cholesterol, VLDL - drug effects; Cholesterol, VLDL - metabolism; Ethanol - administration & dosage; Glycosylation; Glycosylation - drug effects; Liver - cytology; Liver - drug effects; Liver - metabolism; Medical sciences; Rats; Rats, Inbred WF; Reverse cholesterol transport; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Sialyltransferases - drug effects; Sialyltransferases - metabolism; Toxicology; Transferrin; Alcohol; Transferrin; Glycosylation; Apolipoprotein E; Reverse cholesterol transport; Ethanol; Rat; Toxicity; Alcoholism; Liver; Biological transport; Rodentia; Review; Gene expression; Cholesterol; Vertebrata; Mammalia; Gene; Animal; Lipoprotein HDL; Mechanism of action; Carbohydrate deficient transferrine
• ISSN: 0741-8329; 1873-6823
• DOI: 10.1016/S0741-8329(99)00041-5

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.