Cholesterol exchange and synthesis in the live rat.

Abstract

The turnover of plasma cholesterol and de novo cholesterol synthesis were measured simultaneously in the live rat, immediately after administration of [3H]water together with a large volume exchange transfusion of whole blood prelabeled with [14C]cholesterol. It was possible to separate the exchange of unesterified cholesterol from the uptake and secretion of lipoprotein cholesteryl ester, and also to assess the impact of plasma cholesterol exchange on the measurement of in vivo rates of cholesterolgenesis by individual tissues. Cholesterol was measured by an HPLC procedure that effectively separated cholesterol from other structurally similar sterols, and synthesis was determined by the incorporation of [3H]water into cholesterol. Plasma unesterified cholesterol turnover was multiphasic and exceedingly rapid (initial T1/2, 4.1 min) in contrast to the near linear and much slower turnover of plasma cholesteryl ester (initial T1/2, 59.4 min). Plasma unesterified cholesterol equilibrated with different tissues at different rates, with the liver and adrenal equilibrating most rapidly. Full equilibration of plasma unesterified cholesterol was not achieved with any tissue during the course of this study. For rapidly exchanging tissues like the liver, which was responsible for about 60% of plasma unesterified cholesterol exchange, unesterified cholesterol appeared to be kinetically compartmentalized into rapidly, and much less rapidly, exchangeable pools. After [3H]water administration, the content of newly synthesized cholesterol was greatest in the liver, adrenal, and intestine, and appreciably lower in all other tissues studied. Hepatectomy and intestinal resection resulted in a profound reduction of newly synthesized cholesterol in the plasma and adrenal, but no certain change in the already low amounts at other sites. Thus, while it is clear that appreciable amounts of newly synthesized cholesterol in the adrenal were derived from the plasma by exchange, it was not possible to make this assessment for other selected individual tissues. When, however, newly synthesized cholesterol was determined in the total mass of all extrahepatic and extraintestinal tissues together, exchange could be calculated to account for close to 50% of the new cholesterol recovered in the carcass (in studies of 60 min duration). After correcting for exchange, the liver accounted for 82% of all newly synthesized cholesterol, the intestine for about 10%, and the remaining tissues of the body for just 9%. These results are in marked contrast to recent findings of others and demonstrate that in the live rat cholesterol synthesis is principally confined to the liver.