The alpha-naphthylisothiocyanate (ANIT)-treated rat was evaluated as a model for lipoprotein metabolism in cholestatic liver disease. Alterations in lipoprotein composition over a period of 120 h after ANIT treatment (100 mg/kg) were studied. Eighteen hours after treatment, plasma bilirubin and bile acid levels began to rise, together with significant increases in free cholesterol. C-18/16, C-18/18, and C-18/20 phospholipid molecular species. By 48 h, plasma lipid levels were maximal, free cholesterol was 935%, cholesteryl ester 294%, phospholipid 611%, and triacylglycerols 176% of controls, and the cholesteryl ester to free cholesterol ratio began to recover with a modest shift from cholesteryl esters containing C-20 fatty acids to those containing C-18 fatty acids. Lecithin: cholesterol acyltransferase activity was near normal, lipoprotein lipase activity was increased, and hepatic triacylglycerol lipase activity was decreased. Density gradient ultracentrifugation of rat plasma demonstrated a marked shift in lipoprotein density towards the low density lipoprotein range, with the increased lipid being associated with apolipoproteins A-I and E. The presence of large 300-400 A particles and the high surface to core lipid ratio in this density range was consistent with the presence of lipoprotein-X-like vesicles. Apolipoprotein B-48 accumulation was observed in the high density fractions (d15 > 1.063 g/ml) suggesting that these rats have impaired lipoprotein remnant removal. All of these increased levels returned to near normal by 120 h. This study demonstrates that ANIT-treatment induces a transient, fully reversible, non-surgical intrahepatic cholestasis that results in many of the plasma lipoprotein abnormalities associated with human hepatic cholestasis and the bile duct-ligated rat.