Decreased Erythrocyte Membrane Fluidity and Altered Lipid Composition in Human Liver Disease

Abstract

Incubation of normal plasma low-density lipoprotein (LDL) with erythrocytes results in echinocyte formation; the effect is attributed to stimulation of spectrin dephosphorylation through binding of LDL to the cell surface (Hui & Harmony, 1979, Biochimica et Biophysica Acta, 550, 407). No shape change occurs when erythrocytes are incubated with normal highdensity lipoprotein (HDL) and LDL-induced echinocyte formation is inhibited by HDL. We have established that as a consequence of abnormal apoprotein composition (an increased content of ApoE and threonine-poor apoproteins) the HDL of liver disease competes with LD L for binding by the high-affinity receptor on cultured skin fibroblasts. In the present study we have determined whether the abnormal HDL of liver disease (d = 1·063-1·21) will induce echinocyte formation in normal erythrocytes.HDL from several patients which showed the apoprotein abnormalities were tested; all induced marked echinocyte formation when added to a suspension of normal erythrocytes at 37°C (6 x 10 9 cells/ml and 500 ug ofHDL-protein/ml). Patient HDL was 10-100 times more potent than normal LDL and could transform 100% of the cells. Echinocyte formation was rapid (less than 10 s), occurred to a similar extent at 4°C and was also induced by partially delipidated patient HDL. The erythrocyte binding site differed from that on cultured fibroblasts; echinocyte formation was not inhibited by protamine or heparin and also occurred when apoprotein arginine residues were blocked with cyclohexanedione or when erythrocytes from patients with homozygous familial hypercholesterolaemia were used. The morphological changes were associated with increased osmotic resistance and with decreased membrane fluidity as measured by a hydrophobic, fluorescent probe. Attempts to restore biconcave disc morphology by addition of heparin or normal HDL were only moderately successful.Previous studies have implicated changes in erythrocyte membrane lipid composition as underlying the 'spur-cell anaemia' of liver disease (Cooper, Arner, Wiley & Shattil, 1975, Journal of Clinical Investigation, 55, 115); our results suggest that abnormal HDL apoprotein composition may also play a role. DECREASED ER YTHROCYTE MEMBRANE FLUIDITY AND ALTERED LIPID COMPOSITION IN HUMAN LIVER DISEASEAbnormal plasma lipoproteins in patients with liver disease are associated with characteristic changes in erythrocyte membrane lipid composition. The membranes are enriched in cholesterol and lecithin and both the cholesterol/phospholipid (C/P) and lecithin/sphingomyelin (LlSM) molar ratios are increased. Phospholipid fatty acid composition is also abnormal; the proportion of arachidonic acid is decreased and that of palmitic acid raised. In this study we have examined the effects of these membrane lipid abnormalities on membrane fluidity.Erythrocyte membrane fluidity was assessed in 30 patients with a variety of liver diseases, and in 25 normal subjects by using the hydrophobic, fluorescent probe I,6-diphenyl hex a-1,3,5-triene, and the value...

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