OLEATE AND OTHER LONG-CHAIN FATTY-ACIDS STIMULATE LOW-DENSITY-LIPOPROTEIN RECEPTOR ACTIVITY BY ENHANCING ACYL-COENZYME A-CHOLESTEROL ACYLTRANSFERASE ACTIVITY AND ALTERING INTRACELLULAR REGULATORY CHOLESTEROL POOLS IN CULTURED-CELLS

Modification of dietary fatty acid composition results in changes in p lasma cholesterol levels in man. We examined the effect of in vitro fa tty acid supplementation on low density lipoprotein (LDL) receptor act ivity in cultured cells and questioned whether changes were related to fatty acid-induced alterations in acyl-CoA: cholesterol acyltransfera se (ACAT) activity, Preincubation of cultured cells (i.e, human skin f ibroblasts, J774 macrophages, and HepG2 cells) with oleic acid (oleic acid:bovine serum albumin molar ratio 2:1) at 37 degrees C for longer than 2 h resulted in a 1.2- to 1.5-fold increase in LDL cell binding a t 4 degrees C and LDL cell degradation at 37 degrees C, Scatchard anal ysis showed that oleic acid increased LDL receptor number but not LDL affinity (K-d). Fatty acid supplementation of J774 macrophages increas ed both LDL receptor activity and cholesteryl ester accumulation, The ACAT inhibitor, 58-035, eliminated both effects, and increased ACAT ac tivity preceded stimulation of LDL receptor activity by 1-2 h, Supplem entation of macrophages with triolein emulsion particles also increase d LDL cell binding and degradation, and addition of cholesterol to the emulsions abolished this effect. Among fatty acids tested, oleate (18 :1), arachidonate (20:4), and eicosapentanoate (20:5) demonstrated the greatest effects, We hypothesize that certain fatty acids delivered t o cells either in free form, or as triglyceride, first increase cellul ar ACAT activity, which then causes a decrease in an intracellular fre e cholesterol pool, signaling a need for increased LDL receptor activi ty. This mechanism may play a role in the effect of certain dietary fa tty acids on LDL metabolism in vivo.