EVIDENCE FOR THE OPERATION OF THE EXTRA-HEPATIC LIPOPROTEIN RECEPTOR SYSTEM INVIVO IN RATS - EFFECT OF DIETARY-CHOLESTEROL AND OROTIC-ACID, ALONE OR IN COMBINATION, ON THE RATE OF SYNTHESIS OF CHOLESTEROL AND FATTY-ACID IN VARIOUS TISSUES, MEASURED BY USING (H2O)-H-3

The biosynthesis of cholesterol in vivo was studied at a number of tissue sites in rats by using 3H2O as precursor. Overall, the mass of cholesterol synthesized was in good agreement with the rate of cholesterogenesis, as determined by kinetic analysis of cholesterol specific-radioactivity-time curves after administration of radiolabelled cholesterol. Dietary cholesterol increased the circulating concentration of cholesterol and inhibited endogenous cholesterogenesis, with concomitant increases in the concentration of esterified cholesterol, in all tissues studied. Addition of orotic acid to the cholesterol-supplemented diet tended to reverse each of these changes in extrahepatic tissues. The co-ordinated change in cholesterol biosynthesis and esterification, with no change in total cholesterol content, in extrahepatic tissues, is attributed to control by receptor-mediated lipoprotein uptake. Further reduction of the concentration of the apoprotein B-containing lipoproteins by addition of orotic acid to a diet without supplementary cholesterol did not further enhance cholesterogenesis. We consider that the relatively high rates of extrahepatic cholesterogenesis in normolipidaemic rats are attributable to the low concentration of low-density lipoprotein.