Unesterified fatty acids inhibit the binding of low density lipoproteins to the human fibroblast low density lipoprotein receptor.
Micromolar concentrations of oleate were found to inhibit reversibly the binding of low density lipoprotein (LDL) to the human fibroblast LDL receptor. The decrease in LDL binding caused a parallel reduction of both 125I-LDL uptake and degradation at 37 degrees C. At 4 degrees C, oleate was also found to displace 125I-LDL already bound to the LDL receptor. The effect of oleate was rapid, reaching 70-80% of maximum displacement with 5-10 min of incubation, and was closely correlated to oleate-albumin molar ratios. Partition analysis of unesterified fatty acids between cells and LDL showed that the inhibitory effect of oleate resulted mainly from an interaction of unesterified fatty acids with the cell surface rather than with the LDL particles. Using different unesterified fatty acids and fatty acid analogs, we found that the inhibitory effect was modulated by both the length and the conformation of the monomeric carbon chain and was directly dependent on the presence of a negative charge on the carboxylic group. At 4 degrees C, the inhibitory effect of oleate never exceeded half of maximum binding capacity. This limitation was associated with the ability of oleate to interact only with part of the population of LDL receptors which spontaneously recycles in the absence of ligand, as demonstrated by the fact that oleate did not induce any reduction of LDL binding after cell treatment with monensin in the absence of LDL. Our results indicate that unesterified fatty acids could participate in the control of LDL catabolism in vivo by direct modulation of the ability of LDL receptor to bind LDL.
Bihain
B E
BE
Department of Pediatrics, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
Deckelbaum
R J
RJ
Yen
F T
FT
Gleeson
A M
AM
Carpentier
Y A
YA
Witte
L D
LD
D002478:Cells, Cultured; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005233:Fatty Alcohols / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008985:Monensin / Q000494:pharmacology; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology; D010168:Palmitates / Q000494:pharmacology; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000494:pharmacology
D005230:Fatty Acids, Nonesterified; D005233:Fatty Alcohols; D008077:Lipoproteins, LDL; D009829:Oleic Acids; D010168:Palmitates; D011973:Receptors, LDL; C010268:oleyl alcohol; D012710:Serum Albumin, Bovine; D019301:Oleic Acid; C005576:methyl oleate; D008985:Monensin; C019012:methyl palmitate