Long-term ethanol administration alters the degradation of acetaldehyde adducts by liver endothelial cells

Abstract

effects of ethanol on liver endothelial cells (LECs). However, Previous reports have shown that long-term ethanolRees et al. 1 have shown recently that the uptake and degradaadministration alters receptor-mediated endocytosis tion of formaldehyde-modified albumin (f-Alb) by the scaven-(RME) of a variety of macromolecules by liver endotheger receptor on LECs is decreased markedly by long-term lial cells (LEC). Acetaldehyde is the major metabolic ethanol consumption. product of ethanol metabolism and has been shown toResearch for the last several years has shown that LECs bind to proteins to form adducts. In this study, the level play an active role in the reticuloendothelial system of the of protein modification by acetaldehyde necessary for liver. Specifically, LECs are involved in clearance from blood the uptake and degradation of acetaldehyde-modified of a variety of substances, including connective tissue compoproteins by LEC was investigated. Bovine serum albunents and several types of modified proteins. 2 In fact, RME min (BSA) acetaldehyde adducts were prepared by incubation of albumin with acetaldehyde at 100 mmol/L for and degradation by LECs are the major mechanisms for 1 hour at 37ЊC, and 1 mmol/L or 0.2 mmol/L for 5 days clearance of circulating hyaluronic acid, denatured collagens, at 37ЊC. In situ liver perfusion in the presence of these the N-terminal propeptide of type III collagen PIIINP, lamiadducts resulted in the degradation of 107 { 10.02 mg, nin, mannosylated glycoproteins, acetylated low-density lipo-69.82 { 5 mg, and 2.5 { 0.42 mg of acetaldehyde-adducted protein (LDL), and f-Alb. Receptors for chemically modified albumin, respectively, during a 4-hour period. These val-proteins, such as acetylated LDL and f-Alb, have been collecues were decreased by 53%, 67%, and nearly 100%, re-tively referred to as scavenger receptors. There has been spectively, in livers from ethanol-fed rats. Additionally, some debate as to whether there is one receptor for acetylated modification of protein with 1 mmol/L of acetaldehyde LDL and f-Alb or whether there is one receptor for each. for different periods of time and/or pH altered the Although macrophages and LECs can clear f-Alb and aceamount of 14 C-acetaldehyde binding, but no signifi-tylated LDL, they are cleared predominantly from the circucant changes in degradation were observed. Finally, lation by LECs. 3,4 Horiuchi et al. have shown that, although an excess of formaldehyde-modified albumin totally acetylated LDL did inhibit binding of f-Alb to sinusoidal endoinhibited the degradation of acetaldehyde adducts, thelial cells, the converse did not occur. 5 Additionally, an suggesting that they use the same receptor. These antibody specific for the f-Alb receptor did not inhibit endocydata show that acetaldehyde-modified proteins may tosis of acetylated LDL. 6 Some investigators maintain that be taken up and degraded by the scavenger receptor there are different receptors for these modified proteins, 7,8 on LEC. This uptake and degradation are dependent ...

Chronic ethanol consumption impairs receptor-mediated endocytosis of MAA-modified albumin by liver endothelial cells

“…Previous studies by our laboratories have shown that fAlb and AA-Alb are degraded very efficiently by in situ perfused rat livers [5,6,[8][9][10][11][12], and that chronic ethanol consumption impairs this process. Also in these studies, it was possible to show that the removal of KCs by gadolinium chloride did not alter the degradation of f-Alb or AAAlb in situ.…”

“…LECs have been shown to bind and degrade formaldehyde and acetaldehyde-modified proteins [8,9,17], and chronic ethanol consumption has been shown to result 6 cells/mL) were incubated at 378 with 125 I-MAA-Alb (25 mg/mL of protein) for the indicated amount of time, aliquots of the cell suspensions (1 mL) were removed, and acid-soluble radioactivity was determined as described in Section 2. Results are expressed as means AE SD (N ¼ 6 in each group), and values significantly different from controls ( in a significant decrease (50-60%) in the ability of LECs to degrade these ligands.…”

“…The f-Alb ligand has been used extensively to characterize LECs as; it is almost exclusively taken up by only this cell type [3,25,26]. Additionally, the degradation of f-Alb has been shown to be impaired when LECs were isolated from the livers of rats chronically consuming ethanol, suggesting that the removal of this ligand by RME was affected at the postinternalization step in the process [8,9]. However, while formaldehyde-modified proteins are readily degraded by Fig.…”

“…In contrast, acetaldehyde adducts that could form following chronic ethanol consumption are physiologically relevant, but do not result in high levels of degradation (approximately 100 mg or less) depending upon the level of modification [8]. Thus, the significance of impaired RME in LECs has been, to this point, lessened by the lack of a physiological relevant ligand (adduct).…”

“…This includes the impaired degradation of both acetaldehyde-modified proteins (AA-Alb) and f-Alb [8,9]. Tuma et al [5] have shown that MDA and AA bind to proteins to form a hybrid molecule termed the MAA adduct.…”