The LDL receptor pathway delivers arachidonic acid for eicosanoid formation in cells stimulated by platelet-derived growth factor

Abstract

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.

15(S)-Lipoxygenase-1 associates with neutral lipid droplets in macrophage foam cells: evidence of lipid droplet metabolism

“…Interestingly, the amount of 15( S )-HETE in the 15-LO-1 RAW increased with cholesterol loading via acLDL. These data are consistent with that of Habenicht et al ( 26 ) who showed that LDL delivers arachidonic acid for prostaglandin biosynthesis in fi broblasts.…”

Platelet-Activating Factor Acetylhydrolase Activity Indicates Angiographic Coronary Artery Disease Independently of Systemic Inflammation and Other Risk Factors

“…PAF-AH resides on dLDL, 22,29 and LDL particles are an important source for the essential compound arachidonic acid. 31 Therefore, we have suggested that dLDL may contribute to atherogenesis by functioning as a vector that provides both the essential substrate and the crucial enzyme activity necessary for prostaglandin synthesis. 22 This concept would acknowledge PAF-AH as having an active role in atherogenesis rather than being a mere risk marker.…”

True

“…AA is then present in serum either as an albumin-bound acid, or as part of lipids present in lipoproteins. Habenicht et al (1990) have demonstrated that cholesteryl-AA is taken up by the cells via the LDL receptor pathway. Serum albumin-bound AA enters the cells by endocytosis (Geuskens et al, 1994;Iturralde et al, 1991;Uriel et al, 1994).…”