Reduced binding and removal of chylomicron remnants by ethionine-induced premalignant liver

The suppression of cholesterol synthesis by dietary cholesterol which occurs in the livers of normal animals is absent in hepatomas. This abnormality has been reported to occur in the livers of animals fed hepatocarcinogens, even before there is any histologic evidence of malignancy (premalignant liver). We have proposed, in an earlier publication, that the deletion of feedback inhibition of cholesterol synthesis in malignancy is due, at least in part, to the loss of receptors which bind chylomicron remnants, the lipoprotein particles that transport dietary cholesterol to the liver. This hypothesis was further tested in the premalignant liver model. Rats were fed a diet containing 0.25% of a known hepatic carcinogen, ethionine. After 3 to 5 weeks on this diet, the liver had no histologic evidence of malignancy; the rate of [14C]acetate incorporation into cholesterol by liver homogenates was elevated as compared to that of controls (5.13 +/- 0.70 vs. 0.65 +/- 0.14 nmoles cholesterol per gm per hr), and in contrast to control animals, this was not reduced by the inclusion of 5% cholesterol in the diet for 48 hr before killing. The serum (44.4 +/- 6.3 vs. 51.4 +/- 3.8 mg per 100 ml) and hepatic (15.8 +/- 0.2 vs. 17.0 +/- 0.4 micrograms per mg protein) cholesterol contents were not substantially different in ethionine-fed as compared to control-fed rats. Hepatic cholesterol content increased when cholesterol was included in the diet (15.8 +/- 0.2 to 25.8 +/- 7.3 micrograms per mg protein and 17.0 +/- 0.4 to 36 +/- 3.7 micrograms per mg protein in ethionine-fed and control-fed animals, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)