Metabolic controls in precancerous liver—IV. Loss of feedback control of cholesterol synthesis and impaired cholesterol uptake in ethionine-fed rats

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We have examined several aspects of the control of cholesterol synthesis in vivo (measured as plasma levels of 7-dehydrocholesterol following a single dose of AY- 9944, an inhibitor of cholesterogenesis) in livers of rats fed the hepatocarcinogen, ethionine. Within two weeks of beginning ethionine treatment hepatic cholesterol synthesis was increased and feedback control over this synthesis was lost. This confirms our earlier studies with two other carcinogens, N-2-fluorenylacetamide and aflatoxin. The degree of loss of control of cholesterol synthesis did not correlate with the variable toxicity of the ethionine to the test rats. The hepatic uptake of 14 C-cholesterol, particularly as cholesterol ester, following a single, intragastric dose of 4- 14 C-cholesterol was considerably reduced by ethionine feeding. This suggests that the ethionine-treated liver is defective in its mechanism for removing chylomicron-cholesterol from the plasma, an essential requirement for effective feedback control of cholesterol synthesis. Defective uptake of dietary cholesterol has also been observed in fully-developed hepatomas, all of which similarly lack feedback control of cholesterol synthesis.