The LDL receptor pathway delivers arachidonic acid for eicosanoid formation in cells stimulated by platelet-derived growth factor.
Animal cells can convert 20-carbon polyunsaturated fatty acids into prostaglandins (PGs) and leukotrienes. These locally produced mediators of inflammatory and immunological reactions act in an autocrine or paracrine fashion. Arachidonic acid (AA), the precursor of most PGs and leukotrienes, is present in the form of lipid esters within plasma lipoproteins and cannot be synthesised de novo by animal cells. Therefore, AA or its plant-derived precursor, linoleic acid, must be provided to cells if PGs or leukotrienes are to be formed. Because several classes of lipoproteins, including low-density lipoproteins (LDL), very-low-density lipoproteins, and chylomicron remnants, are taken up by means of the LDL receptor, and because LDL and very-low-density lipoproteins, but not high-density lipoproteins, stimulate PG synthesis, we have suggested previously that PG formation is directly linked to the LDL pathway. Using fibroblasts with the receptor-negative phenotype of familial hypercholesterolaemia and anti-LDL receptor antibodies, we show here that LDL deliver AA for PG production and that an LDL receptor-dependent feedback mechanism inhibits the activity of PGH synthase, the rate-limiting enzyme of PG synthesis. These results indicate that the LDL pathway has a regulatory role in PG synthesis, in addition to its well-known role in the maintenance of cellular cholesterol homeostasis.
Habenicht
A J
AJ
University of Heidelberg, FRG.
Salbach
P
P
Goerig
M
M
Zeh
W
W
Janssen-Timmen
U
U
Blattner
C
C
King
W C
WC
Glomset
J A
JA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone / Q000096:biosynthesis; D011464:Epoprostenol / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D011973:Receptors, LDL / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D008077:Lipoproteins, LDL; D010982:Platelet-Derived Growth Factor; D011453:Prostaglandins; D011973:Receptors, LDL; D016718:Arachidonic Acid; D002738:Chloroquine; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone