Low and high density lipoproteins and chylomicrons as regulators of rate of cholesterol synthesis in rat liver in vivo.

The steady-state levels of plasma cholesterol carried in high and low density lipoproteins and in chylomicrons were varied over a wide range by use of a constant-infusion technique. After 40 hr, the rates of hepatic cholesterol synthesis and levels of hepatic cholesterol esters were measured and were related to the plasma level of each of the lipoprotein fractions. From the rates of infusion and the steady-state plasma levels attained, the whole animal clearance rates for cholesterol carried in low density and high density lipoproteins and in chylomicrons were calculated to be 0.53, 0.61, and 42.6 ml/hr, respectively. Hepatic cholesterol ester content increased by 0.8 mug/g for each 1.0 mg/dl increase in the steady-state level of plasma low density lipoprotein cholesterol and by 1.4 mug/g for a similar elevation in plasma high density lipoprotein cholesterol. In contrast, the increase in ester content was 300-fold greater when chylomicrons were infused (330 mug/g). The rate of hepatic cholesterol synthesis was inhibited by a factor of 0.004 and 0.007, respectively, per 1.0 mg/dl increase in the steady-state level of plasma cholesterol carried in either low density or high density lipoprotein but the inhibition was by a factor of 0.255, 50-fold greater, when chylomicrons were infused. Thus, in the steady state, cholesterol carried in either low density or high density lipoproteins is apparently taken up by the liver and regulates the rate of hepatic cholesterol synthesis; however, cholesterol carried in chylomicrons is at least 50-fold more effective in this regard. This marked difference can be attributed to the much higher rates of transport of chylomicron cholesterol into the hepatocyte than of cholesterol carried in either low density or high density plasma lipoproteins.