effects of ethanol on liver endothelial cells (LECs). However, Previous reports have shown that long-term ethanol Rees 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 to
Research 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 valproteins, such as acetylated LDL and f-Alb, have been collecues were decreased by 53%, 67%, and nearly 100%, retively 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 signifitylated 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 whereas other investigators believe that the evidence supon the extent modification of the protein by acetaldeports the existence of a single receptor with different affinihyde, and long-term ethanol consumption decreases ties for these various ligands. 9 the degradation of acetaldehyde-protein adducts.
In vivo, f-Alb seems to be taken up almost exclusively by (HEPATOLOGY 1996; 24:643-648.)
LECs. 2,10,11 Although extrahepatic macrophages also express the receptor, 12 Kupffer cells have been shown not to endocytose this ligand in vivo to a significant degree. In 1984, Blom-Long-term ethanol abuse is a major cause of liver disease. hoff et al. 11 showed that 125 I-f-Alb injected in vivo was taken Although there is evidence that the products of ethanol meup mainly by endothelial cells with only negligible amounts tabolism are hepatotoxic, the mechanisms by which liver (õ5%) being recovered in Kupffer cells prepared by centrifuinjury develops remain to be defined. Long-term ethanol ingal elutriation of nonparenchymal cells. Again in 1989, gestion is known to have a deleterious effect on protein-traf-Eskild et al. 10 showed that only about 5% of an intravenously ficking pathways, including receptor-mediated endocytosis injected dose of 125 I-f-Alb is recovered with the Kupffer cell (RME) in hepatocytes. Little is currently known about the fraction when the animal is killed 1 hour after injection and the cell fractions are separated by centrifugal elutriation. Recently, Jansen et al. 13 have shown that Kupffer cells can be involved in the endocytosis of f-Alb but only when the Abbreviations: RME, receptor-mediated endocytosis; LEC, liver endothelial cell; f-Alb, product has polymerized. Finally, the f-Alb receptor also recformaldehyde-modified albumin; LDL, low-density lipoprotein; BSA, bovine serum albumin; AA-Alb, acetaldehyde-modified albumin; GdCl3, gadolinium chloride.