LIPOLYSIS-INDUCED PARTITIONING OF FREE FATTY-ACIDS TO LIPOPROTEINS - EFFECT ON THE BIOLOGICAL PROPERTIES OF FREE FATTY-ACIDS

Free fatty acids (FFA) released during the lipolysis of triglyceride ( TG)-rich lipoproteins in vivo are generally believed to be bound to se rum albumin. When hypertriglyceridemic (HTG) sera were lipolyzed in vi tro by purified bovine milk lipoprotein lipase (LpL), there was an 11- to 18-fold increase in serum FFA levels, and a major portion (> 80%) of the FFA in serum was partitioned to lipoprotein fractions. The grea test portion (33%) of FFA in lipolyzed HTG serum was associated with n ewly formed flocculent remnants that banded just below low density lip oproteins (LDL) in the density gradient tube. Very lo iv density lipop rotein (VLDL), LDL, and high density lipoprotein (HDL) fractions in li polyzed HTG serum contained 18- to 29-times more FFA molecules than th ose in prelipolysis serum. Analysis of the fatty acyl chain compositio n of FFA in lipolyzed HTG serum showed that the extent of partitioning of saturated FFA into the lipoprotein fractions relative to that of p olyunsaturated FFA was about 4.5- to 11-times greater than that partit ioned into the free protein fraction; most (84%) of FFA partitioned in to flocculent remnants were saturated fatty acids. In vivo lipolysis o f TG-rich lipoproteins in HTG subjects, induced by heparinization, res ulted in only a small (2.8-fold) increase in serum FFA and little or n o increase in the partitioning of FFA to lipoproteins. However, in vit ro incubation of the postheparin serum at 37 degrees C for 90 min resu lted in a 2.9- to 6.8-fold increase in the serum FFA. level and the pa rtitioning of > 66% of total serum FFA into lipoprotein fractions. Stu dies of the interaction of various plasma fractions from control and i n vitro lipolyzed HTG serum with cultured mouse peritoneal macrophages (MPM) showed that FFA partitioned to lipoprotein fractions were highl y cytotoxic to cultured MPM, whereas FFA partitioned to albumin at a 1 0 x greater concentration were not cytotoxic. The cytotoxic potencies of FFA bound to lipoproteins and albumin were further compared after i n vitro incorporation of FFA (oleic acids) into LDL and to albumin. FF A bound to LDL but not to albumin were cytotoxic to cultured MPM; the cytotoxicity of FFA bound to LDL was more closely related to the FFA t o LDL-cholesterol molar ratio than to the total FFA concentration in t he culture dish. The ability of FFA bound to LDL and albumin to induce foam cell formation was studied in THP-1 monocyte-derived macrophages , which were less susceptible to cytotoxicity produced by FFA bound to LDL than MPM. With a sublethal dose, FFA bound to LDL induced a signi ficantly greater accumulation of cellular TG than did the same amount of FFA bound to albumin. The data from this study suggest that the par titioning of an excess amount of FFA to lipoproteins, which could occu r locally at the site of lipolysis in vivo, may be atherogenic.