ABILITY OF S-ADENOSYL-L-METHIONINE TO AMELIORATE LIPOPROTEIN-INDUCED MEMBRANE LIPID ABNORMALITIES AND CELLULAR DYSFUNCTIONS IN HUMAN LIVER-DISEASE

Liver disease is associated with characteristic changes in the surface coat of circulating lipoprotein particles. Cholesterol and lecithin molecules accumulate as hepatic secretion of lecithin-cholesterol acyltransferase diminishes, phospholipid fatty acyl chains are deficient in arachidonate, the precursor of eicosanoid production, and the apolipoprotein composition, particularly of high density lipoproteins (HDLs), is abnormal. Increasing evidence suggests that such aberrant circulating lipoproteins are not simply an epiphenomenon: they have pathophysiological consequences through 2 independent mechanisms. Firstly, while it is well documented that abnormal plasma lipoproteins change the membrane lipid composition in the erythrocytes of jaundiced patients by an exchange-equilibration mechanism, it is now clear from studies in both human and experimental liver disease that other cell types are similarly affected, suggesting a widespread occurrence. Because the correct functioning of membrane proteins, which serve as receptors or are responsible for transport and enzymatic processes, is dependent on the fluidity and/or the composition of their lipid bilayer matrix, it follows as a corollary that lipoprotein-induced extrahepatic membrane dysfunction should be a general feature of severe liver disease; experimental evidence is accumulating to support this concept. Secondly, the abnormal HDL particles from cirrhotic patients are reported to have direct, adverse effects on a variety of cells. The cellular functions disturbed are diverse, but the mechanism appears common inasmuch as they are mediated by apolipoprotein interaction with the cell surface without either lipid transfer or uptake of the intact HDL particle. It seems reasonable to propose, therefore, that several of the metabolic abnormalities accompanying hepatic disease result from, or are exacerbated by, lipoproteins interfering with normal cellular metabolism, either by direct action or indirectly by inducing changes in membrane lipid composition and fluidity. Importantly, this scenario also suggests that drugs or agents that can improve the lipoprotein milieu of cell membranes or normalise membrane fluidity might be of therapeutic benefit. Preliminary results have demonstrated that treatment of cirrhotic patients with S-adenosyl-L-methionine helps to reverse the accumulation of cholesterol in lipoprotein surfaces and to correct HDL apolipoprotein composition. These changes were accompanied by a reduction in erythrocyte cholesterol content and by an improvement in the fluidity and functioning of erythrocyte membranes.