The effect of remnant lipoproteins on hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and hepatic very low density lipoprotein (VLDL) secretion was studied in the perfused rat liver and in vivo. As had been observed previously, when the liver was perfused with a lipid-free medium, HMG-CoA reductase activity increased about twofold after 150 min, and this increase could be prevented by the addition of chylomicron remnants to the medium. However, suppression below base line activity did not occur even with increasing amounts of remnant cholesterol. When chylomicron remnants prepared from triglyceride-rich particles were included in the medium, reductase activity was increased even above that in the control perfusions despite the fact that approximately the same amount of cholesterol was removed from these particles as from standard particles. In contrast, particles that were low in triglycerides and rich in cholesterol not only prevented the rise in reductase activity but inhibited it significantly below base line activity. Again, the total amount of cholesterol removed was the same as with the other types of particles. These results suggested that both the triglycerides and cholesterol exerted an effect on HMG-CoA reductase. Consistent with this hypothesis, a significant correlation was found between reductase activity and the ratio of triglycerides to cholesterol removed, but not to either alone. To explore the role of triglycerides further, the effect of these lipoprotein particles on VLDL secretion was determined. VLDL secretion was stimulated by both standard and triglyceride-rich remnants but not by triglyceride-poor remnants. The degree of stimulation with standard chylomicron was comparable to that induced by infusion of a comparable fatty acid load as oleic acid bound to albumin. In vivo a similar effect of these lipoproteins on HMG-CoA reductase activity was observed. Rats were injected with a lipoprotein bolus containing 7 mg of cholesterol, and reductase activity in the liver was measured 2 hr later. Standard chylomicrons and triglyceride-rich chylomicrons stimulated reductase to 157% and 187% of control activity, respectively, whereas cholesterol-rich VLDL suppressed reductase activity to 30% of control activity. These observations support the hypothesis that remnant lipoproteins have a dual effect on hepatic HMG-CoA reductase activity; the cholesterol in these lipoproteins suppresses hepatic reductase activity while the triglycerides concommitantly delivered stimulate reductase activity at least in part because they stimulate hepatic VLDL secretion. Therefore, the net response of hepatic HMG-CoA reductase to a particular dietary lipoprotein will depend upon the balance between the cholesterol and triglycerides carried to the liver.-Van Zuiden, P. E. A., S. K. Erickson, and A. D. Cooper. Effect of removal of lipoproteins of different composition on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and hepatic very low density lipoprotein secretion.