Abstract
The non-recirculating, isolated, perfused rat liver system was used to compare hepatic uptake of cholesterol from very low density (VLDL), low density (LDL) and high density (HDL). {('14)C}Cholesterol-containing lipoproteins were separated by ultracentrifugation from serum of donor rats injected with {('14)C}mevalonolactone. Each lipoprotein family was perfused for 10 min. The perfusate was collected at one minute intervals and assayed for {('14)C}cholesterol. Hepatic uptake was calculated from the difference of {('14)C}cholesterol in perfusate before and after the liver. In some experiments unlabelled lipoproteins were perfused and the change in cholesterol mass before and after the liver was measured by GLC.At equal cholesterol concentrations (2 mg/100 ml perfusate) hepatic uptake of {('14)C}cholesterol from VLDL, LDL and HDL was 2.0, 1.7 and 0.4 (mu)g/g liver/min., respectively. Hepatic uptake of cholesterol mass, at the same cholesterol concentration, from VLDL, LDL and HDL was linear with time, while HDL-cholesterol uptake plateaued after 2 min. Uptake of VLDL and LDL-cholesterol at equal cholesterol concentrations was not statistically different, while uptake of HDL-cholesterol was statistically lower.GLC analysis of hepatic uptake of free and esterified cholesterol showed that both forms of cholesterol from VLDL and HDL were taken up at the same rate, while cholesteryl esters were preferentially removed from LDL.Hepatic uptake of VLDL and LDL-cholesterol increased with increasing cholesterol concentrations. HDL-cholesterol uptake remained at a low level despite increasing cholesterol concentrations. Hepatic uptake of VLDL and LDL-cholesterol was not saturated at physiological cholesterol concentrations (VLDL, 4 mg/100ml; LDL, 6mg/100ml). When cholesterol concentrations were adjusted so that the ratio of VLDL:LDL:HDL (1:1.5:7.5) was similar to the in vivo value, uptake of LDL-cholesterol increased proportionally, but there was no increase in uptake of HDL-cholesterol.VLDL and HDL were enriched with free cholesterol by incubation with crystallin cholesterol. A 4.3-fold increase in VLDL-cholesterol resulted in a 4.4-fold increase in hepatic uptake of VLDL-cholesterol. However, a 2-fold increase in HDL-cholesterol resulted in a 4-fold increase in hepatic uptake.Results from these studies support the hypothesis that HDL is not the primary vehicle for delivery of cholesterol to the liver. Both VLDL and LDL are more efficient in this regard. Since VLDL and LDL accept cholesteryl esters from HDL, it seems likely that they may play an important role in transporting peripheral cholesterol excess. VLDL and HDL may have the capacity to expand their cholesterol content and to deliver that cholesterol to the liver.