Fatty acids differentially regulate hepatic cholesteryl ester formation and incorporation into lipoproteins in the liver of the mouse

These experiments tested the hypothesis that fatty acids (FAs) that drive cholesterol esterification also enhance sterol secretion and were undertaken using a mouse model where lipoprotein-cholesterol output by the liver could be assessed in vivo. The turnover of sterol in the animals was kept constant (∼160 mg/d per kg) while the liver was enriched with the single FAs 8:0, 14:0, 18:1, or 18:2. Under these conditions, the steady-state concentration of cholesteryl ester in the liver varied 6-fold, from 1.2 to 7.9 mg/g, and the expansion of this pool was directly related to the specific FA enriching the liver (FA 18:1>18:2>8:0> 14:0). Secretion of lipoprotein-cholesterol varied 5-fold and was a linear function of the concentration of cholesteryl ester in the liver. These studies demonstrate that unsaturated FAs drive the esterification reaction and enhance lipoprotein cholesterol secretion by the liver under conditions where cholesterol balance across this organ is constant. Thus, individual FAs interact with cholesterol to profoundly regulate both the output and uptake of sterol by the liver, and these effects are articulated through the esterification reaction.