The hypercholesterolaemic effect of caffeine in rats fed on diets with and without supplementary cholesterol.

1. The effect of caffeine (2.5 g/kg diet) on lipid metabolism was examined in rats fed on a stock (low-cholesterol) diet or on a cholesterol plus cholic acid-supplemented (high-cholesterol) semi-synthetic diet. 2. When caffeine was induced in the stock diet fed to rats for 7 d, there was a moderate but significant increase in the concentration of serum cholesterol compared to the levels observed in the control rats. This change can be accounted for by the increase that was observed in the rate of cholesterogenesis in the liver. 3. After 25 d of caffeine in the stock diet, hepatic cholesterogenesis was still increased but the concentration of serum cholesterol was now the same as in the control rats. During the experimental period there was a progressive increase in the faecal excretion of neutral sterols in the rats receiving caffeine. 4. When caffeine was added to a cholesterol plus cholic acid-supplemented diet, there was a marked increase in the concentration of serum cholesterol but hepatic cholesterogenesis was now reduced. 5. Caffeine in the high-cholesterol diet appeared to delay, but probably did not reduce, the absorption of an oral dose of radio-labelled cholesterol. This conclusion was confirmed using rats which had not previously received either caffeine or cholesterol in the diet. 6. When the effect of caffeine in the high-cholesterol diet was investigated during a 24 h period, an exacerbation of the hypercholesterolaemia was seen only at certain times. 7. After a 4-month period of feeding rats on the caffeine-supplemented high-cholesterol diet, histological examination did not detect any damage to the heart and aorta. 8. The metabolic regulations involved in the effects of caffeine in the two diets are discussed and the relevance of the present results to observations made with human subjects is considered.