STUDIES ON THE PATHOGENESIS OF THE ETHANOL-INDUCED FATTY LIVER. II. EFFECT OF ETHANOL ON PALMITATE-1-C-14 METABOLISM BY THE ISOLATED PERFUSED RAT LIVER.

In man and in the experimental animal, a fatty liver can result from acute or chronic ethanol in-gestion. In the rat an increase in liver lipid occurs either after a single intoxicating dose of ethanol or after the chronic administration of this drug (2, 3). The lipid that accumulates in the liver under these conditions is predominantly in the form of triglycerides (4). The production of a fatty liver would appear to involve one or more of five possible mecha-nislms: a) increased mobilization of fatty acids from the peripheral adipose depots to the liver, b) increased de novo synthesis! of fatty acids by the liver, c) decreased hepatic catabolism (e.g., oxidation) of fatty acids, d) increased or preferential esterification of fatty acids to triglycerides, or e) a decreased release of lipid from the liver. In considering these mechanisms, it should be noted that studies by Mallov (5) and by Brodie and Maickel (4) have demonstrated an increased mobilization of plasma free fatty acids after relatively large doses of ethanol; this effect is apparently mediated through hypophyseal-adrenal pathways and the sympathetic nervous system (4). Furthermore, the fatty liver produced by ethanol contains large amounts of linoleic acid that is stored in the adipose tissue but not synthesized by mammalian liver (6). Lieber and Schmid (7) have observed that ethanol stimulates * A preliminary report of these observations has appeared previously (1). t Formerly, trainee in gastroenterology under the auspices of U. S. Public Health Service training grant 2A-5146. the synthesis of fatty acids by the liver, but the quantitative importance of this finding remains to be determined. Under conditions of decreased mobilization of fatty acids (e.g., cordotomy) de novo hepatic fatty acid synthesis is still increased after ethanol administration, but a fatty liver does not develop (8). Decreased oxidation of fatty acids to CO2 results after ethanol administration, but this effect occurs also with agents such as glucose and sorbitol, which do not produce a fatty liver (8). Within the liver the free fatty acids are esteri-fied primarily to triglycerides (9), and these are then returned to the plasma in the form of lipo-proteins (10). Several laboratories have presented , evidence indicating that hepatotoxins such as carbon tetrachloride and ethionine interfere with this triglyceride release (11-14), and it has been suggested that the production of fatty liver by these agents is largely due to a decreased release of triglycerides from the …