Ability of six different lipoprotein fractions to regulate the rate of hepatic cholesterogenesis in vivo

Two in vivo assay procedures were used to study the inhibitory activity of cholesterol carried in three intestinal lymph and three serum lipoprotein fractions on the rate of cholesterol synthesis in the liver. In the first preparation, different lipoproteins were injected intravenously as a bolus into rats at the mid light phase of the diurnal light cycle, following which they were killed 12 hr later at the mid dark phase of the cycle. Using this assay, three intestinal lymph lipoprotein fractions of varying S(f) values all produced a similar degree of inhibition which averaged approximately 11%/mg of cholesterol injected. The serum lipoprotein fractions caused only about one third this amount of inhibition. Detailed analysis of events occurring within the liver during this 12 hr assay period revealed that there were marked differences in the rate of net cholesterol uptake into the liver and in the rate of net removal of cholesterol esters from the liver following injection of each of these different lipoprotein fractions. The amount of inhibition of sterol synthesis produced by any fraction was proportional to the product of the incremental increase in hepatic cholesterol ester content and the time over which this increase in esters occurred. In the second type of assay, where the lipoprotein fractions were administered to the animals as a continuous intravenous infusion over 24 hr, the largest increase in hepatic cholesterol ester content and the greatest inhibition of cholesterol synthesis was found with intestinal lipoproteins having S(f) values >8000. Intestinal lipoprotein fractions with lower S(f) values and all serum lipoprotein fractions were significantly less effective in bringing about an increase in hepatic cholesterol ester content and in producing inhibition of cholesterol synthesis by the liver. These studies emphasize the primary role of cholesterol carried in lipoproteins of intestinal origin in regulating hepatic sterol synthesis. The inhibitory activity of these fractions appears to correlate with the ability of these lipoproteins to bring about a maximal increase in hepatic cholesterol ester content which, in turn, appears to relate to the capacity of these fractions to transfer cholesterol rapidly into the hepatocyte while, at the same time, slowing the rate of cholesterol mobilization from the liver.